Good morning, and welcome to Revolution Medicines' Conference Call. At this time, all participants are in a listen-only mode. After the speaker's presentation, there will be a question-and-answer session. To ask a question during the session, you will need to press star one one on your telephone. You will then hear an automated message advising your hand is raised. To withdraw your question, please press star one one again. Please be advised that today's conference is being recorded. I'd now like to hand the conference over to your first speaker, to Erin Graves, Senior Director of Corporate Communications and Investor Relations. Please go ahead.
Thank you, and welcome everyone to today's investor webcast. Joining me on today's call are Dr. Mark Goldsmith, Revolution Medicines Chairman and Chief Executive Officer, Dr. Steve Kelsey, our President of R&D, and Dr. Wei Lin, our Chief Medical Officer. Peg Horn, our Chief Operating Officer, and Jack Anders, our Chief Financial Officer, will join us for the Q&A portion of today's call. As we begin, I would like to note that our presentation will include statements regarding the current beliefs of Revolution Medicines with respect to our business and the proposed acquisition of EQRx, including statements regarding our development plans and timelines for our portfolio and pipeline, and the expected timing and benefits of the proposed acquisition, all of which are intended to be covered by the safe harbor provisions of the Private Securities Litigation Reform Act of 1995, the forward-looking statement.
These statements are subject to a number of assumptions, risks, and uncertainties. Actual results may differ materially from these statements, and except as required by law, the company undertakes no obligation to revise or update any forward-looking statements. I encourage you to review the legal disclaimer slide of our corporate presentation and all our filings with the SEC concerning these and other matters. During this call, we will be referring to slides from our corporate presentation, which was posted to our website prior to this call. With that, I will turn the call over to Dr. Mark Goldsmith, Revolution Medicines' Chairman and Chief Executive Officer. Mark?
On behalf of the employees of Revolution Medicines and our many collaborators and partners, it's my pleasure to welcome you to this R&D review following multiple exciting scientific presentations by our collaborating investigators at the Triple and ESMO meetings. Our company's mission is to revolutionize treatment for patients with RAS-addicted cancers through the discovery, development, and delivery of innovative targeted medicines. Today, I'll begin by briefly reviewing our pioneering class of drug candidates that target the oncogenic RAS(ON) drivers of common life-threatening cancers. Next, Dr. Steve Kelsey, our President of R&D, will recap the recent presentations on our unprecedented RAS multi inhibitor, RMC-6236, and RAS G12C selective inhibitor, RMC-6291, our first two RAS(ON) inhibitors that have shown differentiated and promising initial clinical profiles. And then Dr.
Wei Lin, our Chief Medical Officer, will summarize our initial single agent and combination development strategies, aiming to deliver durable clinical benefit broadly to patients with RAS-addicted cancers. The fundamental biologic principle behind our work is that excessive RAS(ON) signaling, caused by tumor RAS mutations, drives malignant growth in many human cancers. These oncogenic mutations can occur in any of the natural isoforms of RAS, KRAS, NRAS, or HRAS, and most frequently occur at mutational hotspots at amino acids G12, G13, or Q61. Such mutations are responsible for over 200,000 new cancer diagnoses in the U.S. alone each year, and in particular, are frequent causes of lung, pancreatic, and colorectal cancer.
Innovative work by Kevan Shokat and John Ostrem paves the way for first-generation inhibitors that bind to the KRAS G12C mutant in the inactive or off form and prevent conversion into the active or on form. We have taken a very different approach, developing oral compounds that bind to and inhibit the active or on form of RAS. We built an industrial-strength product engine, incorporating a vision and early work by Greg Verdine and colleagues at Warp Drive Bio, a company we acquired five years ago. We call our compounds tri-complex inhibitors, since they are designed to bind selectively and with high affinity to a relatively flat surface on the disease target by forming tri-complex structures that contain the disease target, a highly abundant cellular chaperone protein, such as cyclophilin A, and the tri-complex inhibitor bound in a pocket between them.
Drug candidates in our collection of more than 20,000 design-based RAS inhibitors directly and rapidly inhibit the intended oncogenic RAS(ON) cancer drivers and tumor cells, and induce deep and durable suppression of RAS cancer signaling by a mechanism of action that defies common ways that tumors can resist RAS(OFF) inhibitors. The studies we will review today have provided compelling clinical validation of the first two RAS(ON) inhibitors as single agents, and we believe for this new class of inhibitors broadly. Today, we will touch on several of our six named development-stage RAS(ON) inhibitors that, as a group, were designed to treat nearly all patients with RAS cancers.
The first of these investigational drugs, RMC-6236, is clearly unique in that it potently binds to and inhibits every form of K, N, or HRAS we've ever tested, including nearly all known oncogenic variants, as well as the wild type of normal RAS proteins. We call this bold compound a RAS(ON) multi inhibitor. The other RAS(ON) inhibitors in our pipeline are designed as mutant-selective compounds targeting individual oncogenic RAS variants. These two distinct and complementary approaches, an inhibitor of the RAS family of proteins and specific inhibitors of individual RAS mutants, are intended to enable multiple monotherapy and combination strategies against RAS-addicted cancers. You will hear more about how we plan to implement these strategies later in this presentation.
I'll take a moment now to introduce the remarkable drug candidate, RMC-6236, that is summarized here, and then Steve will take it from there into the clinical data. As shown in this example of a preclinical RAS-dependent non-small cell lung cancer model, the oral potent tri-complex RAS family inhibitor, RMC-6236, induces dose-dependent regressions in RAS-addicted cancers, even at low doses. Regressions representing partial or complete responses have been observed most frequently in the dose range of 10-25 mg/kg. Preclinically, RMC-6236 is well tolerated in this active range, and as you'll see, plasma exposures in humans corresponding to this preclinical dose range are achieved at doses of 80-120 mg/day, with objective tumor responses.
As recapitulated here, we've shown examples of compelling response rates to RMC-6236 in xenograft tumor models carrying five different KRAS G12 mutations and representing the three major epithelial RAS-addicted human cancers. Such responses to RMC-6236 were also characterized by impressive durability in most models, as indicated. Earlier this year, we disclosed a small preliminary set of encouraging clinical findings from the RMC-6236-001 single-agent dose escalation study that in many ways appeared to mirror the preclinical profile. I'm pleased to invite Dr. Steve Kelsey to review our significantly larger preliminary clinical data set that is consistent with, and substantially extends, the encouraging trends seen in those initial findings. Steve?
Thanks, Mark. I'm going to summarize the key data from the three presentations on RMC-6236 and RMC-6291 that were recently given at the Molecular Targets and Cancer Therapeutics, or Triple meeting, and earlier today at the ESMO meeting. Slide 11 is to remind you of the study design for the RMC-6236 phase I dose escalation study, which currently focuses on patients with advanced solid cancers that harbor KRAS mutations at positions G12, currently excluding G12C mutations. We have escalated the dose of RMC-6236 up to 400 mg daily. The color coding of the boxes is synchronized with the data slides that we will show shortly. Dose optimization is still ongoing, particularly for patients with non-small cell lung cancer and pancreatic ductal adenocarcinoma.
We have not yet decided whether to test the 500-milligram dose level, as we are still evaluating 400 milligrams daily. Recall that doses below 80 milligrams daily were not expected to be associated with tumor regressions in patients based on preclinical exposures and human PK modeling, which turned out to be reasonably concordant with clinical reality. As of the eleventh of September, 131 patients had been treated with RMC-6236, the majority with either pancreatic ductal adenocarcinoma or non-small cell lung cancer. The spectrum and frequency of the G12 mutations in the study were consistent with the epidemiologic distribution. Patients have received a median of two prior regimens for their RAS mutant cancer.
The pharmacokinetics of RMC-6236 as a single agent showed good oral bioavailability, kinetics consistent with once daily dosing, and dose-dependent increase in exposure. Beginning at 160 mg daily, and more consistently at 200 mg daily or above, steady-state exposures were within the range of those observed in mice at 25 mg/kg daily. A dose that you've just heard delivered significant and broad activity in the tumor xenograft study shown on slide 10. I'd also like to note that dosing at 80 mg in patients provided exposures below, but approaching that of the 10 mg/kg mice exposure, at which tumor regressions were observed in sensitive preclinical models. Dosing at 120 mg or above in patients achieved exposures more consistent with, and frequently exceeding, that of 10 mg/kg daily in mice.
As we have previously reported, RMC-6236, despite its ability to potently inhibit both mutant and wild-type RAS, was well tolerated across dose levels and with drug exposures that were well within the range required for potent inhibition of mutant and wild-type RAS. We have seen few Grade 3 or greater adverse events overall and have not yet defined a maximum tolerated dose. Skin rash remains the most frequent treatment-related adverse event and the most common dose-limiting toxicity as defined by the protocol. At higher dose levels, some gastrointestinal toxicity has been observed, although grade 3 events were likewise uncommon. Only one treatment-related grade 4 event has been observed, a gastrointestinal perforation at 80 milligrams daily that has been previously described in some detail and is believed to be due to shrinkage of the full thickness bowel tumor.
The safety and tolerability profile of RMC-6236 compares favorably with that of previously reported for some KRAS G12C (OFF) inhibitors and with historical profiles for standard of care cytotoxic chemotherapy. The overall toxicity profile, including only infrequent and relatively modest increases in transaminases, increases our confidence that RMC-6236 will be tolerated in combination with standard of care treatments. Potential drug combinations include immune checkpoint inhibitors, such as pembrolizumab, and our own in-portfolio mutant-selective RAS(ON) inhibitors, such as RMC-6291 and RMC-9805. Recall that the RMC-6236-001 study is a first-in-human phase one dose escalation study. Necessarily, the first cohorts of patients were treated at doses below those that were expected to result in significant antitumor activity. In fact, as discussed on slide 13, exposures in patients reached those at which tumor regressions could be anticipated at around 80-120 milligrams daily and above.
This prediction was elegantly supported and exemplified by Dr. Spira in his recent presentation and poster on RMC-6236 at the Triple Meeting on the 13th of October. The case history of a patient with ovarian cancer was reported. This patient, who had progressed on prior therapies, had stable disease when started on RMC-6236 at 20 milligrams daily. But on escalation to 80 milligrams daily, the tumor reduced in size, and the patient achieved a partial and sustained response. Therefore, we have reported antitumor activity for efficacy evaluable patients with non-small cell lung cancer and pancreatic cancer, who started treatment with RMC-6236 at a dose of 80 milligrams daily or greater, at least 8 weeks prior to the data cutoff for ESMO, which was October 12.
The timing of this analysis ensures that all reported patients had received at least one follow-up CT scan reported to us at the time of the analysis. You can see from the waterfall plot of 40 evaluable patients with KRAS G12 mutant non-small cell lung cancer, the overall response rate, including unconfirmed partial responses, was 38%. There was one confirmed complete response. The overall response rate observed so far compares favorably with inhibitors of KRAS G12C that have been tested in KRAS G12C mutant non-small cell lung cancer, and is above historical response rates to standard of care chemotherapy, exemplified by docetaxel. The majority of unconfirmed partial responses in our non-small cell lung cancer cohort have been subsequently confirmed, and some RECIST responses were observed for the first time after the initial six-week scan.
Due to the relatively short follow-up for patients enrolled at the higher dose levels in this study, it is possible that the observed overall response rate for RMC-6236 in lung cancer is an underestimate of the eventual outcome, and we will continue to assess this. As predicted by the preclinical work, multiple tumors with either KRAS G12D or KRAS G12V mutations were responsive to RMC-6236. To our knowledge, RMC-6236 is the first RAS inhibitor described with clinical activity against lung cancer, with either of the two most common RAS mutations in human cancer. Furthermore, in lung cancer, the G12D and G12V genotypes together are about as common as the G12C genotype, or roughly 12.5%.
Although we haven't tested RMC-6236 in patients with a G12C mutation yet, preclinical data shows that RMC-6236 is highly active in tumors harboring the KRAS G12C mutation, and we'd expect it to be so in patients. We also expect tumors harboring other mutations to be sensitive as well, but none have been represented sufficiently in the lung cancer patient cohort so far to be able to assess this. Furthermore, while the data set is too small and early to determine whether any differences exist in outcomes across the different G12 genotypes, overall, RMC-6236 could well prove to be applicable in 25 to 30% of human non-small cell lung cancer patients. Slide 16 shows more temporal information on each patient with non-small cell lung cancer.
The median follow-up is relatively short at 3.1 months, and the majority of patients remain on study therapy. To reinforce the anti-tumor activity of RMC-6236 in KRAS mutant lung cancer, I would like to highlight this case presented by Dr. Arbour at ESMO earlier today, of an 83-year-old female with a heavy smoking history, who was diagnosed with KRAS G12V mutant non-small cell lung cancer. Her prior treatment for non-small cell lung cancer included a checkpoint inhibitor doublet and subsequently, chemotherapy, but she progressed and presented with dyspnea at rest and cough before starting RMC-6236 at 300 milligrams daily. Within one week, she noticed a marked decrease in both symptoms, and she started playing golf again. Her first CT scan showed a complete response, which was confirmed on her next scan, and she currently continues on treatment.
Slide 18 shows the waterfall plot of 46 patients with KRAS G12 mutant pancreatic cancer. Again, only including patients at doses above 80 milligrams daily, and who started treatment with RMC-6236 at least 8 weeks prior to the data cutoff on October 12, so as to ensure that information from at least one follow-up CT scan was captured on each patient. The overall response rate, including unconfirmed partial responses, was 20%, although one of these patients did discontinue RMC-6236 prior to response confirmation. This overall response rate compares favorably with historical data for salvage chemotherapy in pancreatic cancer, where response rates are typically around 10%. The disease control rate was 87%, meaning that only 13% of pancreatic cancer patients treated with RMC-6236 had progressed at their first response evaluation.
Typically, around 30 to 40% of patients with advanced pancreatic cancer will have been found to have progressed at their first response assessment when receiving salvage chemotherapy, after their initial chemotherapy has failed. As with non-small cell lung cancer, pancreatic adenocarcinoma tumors with KRAS G12D and G12E mutations were responsive to RMC-6236. In addition, two patients with pancreatic tumors harboring KRAS G12R mutations, a mutation almost exclusive to pancreatic cancer, and the third most common RAS mutation in pancreatic cancer, also responded. With the three RAS mutations that are most commonly found in this tumor type showing sensitivity, we believe the breadth of activity is consistent with the preclinical experience and highly encouraging for our efforts to help patients. The swimmer plot on slide 19 confirms the short follow-up for patients in this study.
As with the lung cancer cohort, it is too early to calculate a median progression-free survival, but it is encouraging that only two patients with pancreatic cancer who had an initial response have progressed after 18 and 25 weeks on treatment, respectively. Median progression-free survival for patients treated with chemotherapy has been reported to be in the range of 12-14 weeks. Durability of anti-tumor effect, irrespective of RECIST response, will be an important factor in determining the clinical impact of RMC-6236. To confirm the anti-tumor activity of RMC-6236, we evaluated mutant KRAS allelic burden in circulating tumor DNA before and on treatment. Slide 20 shows that treatment with RMC-6236 was associated with a significant reduction in circulating mutant KRAS DNA. Consistent with previous reports, reduction in ctDNA tracked with clinical response by RECIST.
So to date, and while dose optimization is still ongoing, RMC-6236 is well-tolerated at active dose levels with significant anti-tumor activity in both non-small cell lung cancer and pancreatic cancer, and against at least three common RAS genotypes. The early overall response rate in both lung cancer and pancreatic cancer compares favorably with current standard of care for patients with advanced tumors who have failed prior systemic therapy. Now, let's turn to RMC-6291, our mutant-selective KRAS G12C inhibitor that binds covalently to the ON state of KRAS G12C and rapidly and irreversibly inhibits it. This compound is highly potent, inducing tumor stasis in preclinical models at 3 milligrams per kilogram daily, and regressions, including frequent complete responses at 10 milligrams per kilogram daily or higher. RMC-6291 has a number of distinguishing properties from the RAS(ON) inhibitors based on its unique binding and mechanism of action.
For example, it is highly active in some preclinical tumor models that are resistant to first-generation RAS(OFF) inhibitors. Shown here are two examples of significant anti-tumor activity by RMC-6291 in tumors that are resistant to sotorasib on the left or adagrasib on the right, carrying associated resistant mechanisms that are believed to be clinically relevant. Further, in some preclinical models in which RMC-6236 or RMC-6291 as single agents were only partially active-... The combination of these two compounds delivers significant and highly sustained antitumor benefit. This observation supports an important part of our overall strategy for the RAS on inhibitors that will be discussed later. Slide 25 shows the study design for the RMC-6291 single-agent phase 1 dose escalation study. As a reminder, the study focuses on patients with advanced solid cancers that harbor KRAS G12C mutations, the majority of which have either non-small cell lung cancer or colorectal cancer.
To date, we have escalated the dose of RMC-6291 up to 400 milligrams twice daily. All of the doses tested were predicted to have some degree of antitumor activity based on preclinical modeling. As with the RMC-6236 results shown earlier, the color coding of the boxes is synchronized with the dose levels on the data slides that we will show shortly. Dose optimization for RMC-6291 is still ongoing and the data are preliminary, but we believe provide a meaningful early snapshot of the potential of our first mutant-selective tri-complex RAS(ON) inhibitor. To date, 63 patients have been treated with RMC-6291, of which 23 have non-small cell lung cancer and 33 have colorectal cancer. The remaining 7 have various tumor types, including cholangiocarcinoma and gynecologic cancers. 25 or 40% of these patients had previously received a KRAS G12C OFF inhibitor.
Most of these patients received their KRAS G12C OFF inhibitor as their most recent prior therapy before being treated with RMC-6291. All of the patients previously treated with a KRAS G12C OFF inhibitor had progressed on their prior KRAS OFF inhibitor, and the gap in the time between discontinuing RAS(OFF) inhibitor and starting RMC-6291 was a median of 9 weeks, although with a wide range of 2 weeks to around 2 years. As with many phase 1 dose escalation studies in this space, patients have received a median of three prior therapies for their cancer. With particular relevance to interpreting the safety and tolerability of RMC-6291 in the non-small cell lung cancer population, please note that one-third of the lung cancer patients treated with RMC-6291 had received an immune checkpoint inhibitor within 12 weeks of starting RMC-6291.
Prior immune checkpoint inhibitor therapy within the previous 12 weeks was reported by investigators at Memorial Sloan Kettering Cancer Center as a predictor of significant toxicity with KRAS G12C OFF inhibitor therapy, particularly hepatotoxicity associated with Sotorasib. The pharmacokinetic profile of RMC-6291 shows that it is already bioavailable and exposures increase in a dose-dependent manner. The clearance of RMC-6291 from plasma is consistent with the twice-daily dosing regimen, which was initiated at the 200 milligram dose level. The exposure to target engagement relationship in preclinical studies predicts greater than 90% average cross-linking of total KRAS G12C in human subjects receiving 100 milligrams twice daily or higher. Please note that distinct from KRAS G12C OFF inhibitors, most or all of cross-linked intratumoral G12C should represent direct inhibition of the active or ON state of mutant KRAS G12C.
RMC-6291 was generally well tolerated up to 400 milligrams twice daily. Grade 1 or Grade 2 gastrointestinal toxicities, predominantly nausea and/or diarrhea, were the most frequent treatment-related adverse events. QTc prolongation has been observed, although only one case, representing 2% of patients overall, showed an increase in QTc to greater than 500 milliseconds, and there have been no cardiac toxicities associated with this electrocardiographic abnormality. Only one treatment-related AE, a Grade 3 QTc prolongation in a patient who was tolerating RMC-6291 well otherwise, required discontinuation of RMC-6291 per protocol. Increases in liver enzymes were of low grade and low frequency, supporting the potential for combination with immune checkpoint inhibitors. Slide 29 shows the clinical activity of RMC-6291 in all patients with non-small cell lung cancer. 3 out of 7, or 43%, of lung cancer patients who had not previously received a KRAS G12C OFF inhibitor responded.
5 out of 10, or 50%, of the lung cancer patients who had previously received a KRAS G12C OFF inhibitor responded. The disease control rate for both sets of patients was 100%, with no early progression. Efficacy is also shown for the 20 patients with colorectal cancer who had not previously received a KRAS G12C OFF inhibitor. 8 patients, or 40%, had a partial response, and the disease control rate was 80%. We have not reported on the clinical activity of the 8 patients with colorectal cancer who had previously received KRAS G12C OFF inhibition. The potential clinical activity of RMC-6291 was compromised by the detection of multiple additional pathogenic mutations in the circulating tumor DNA of these patients prior to starting RMC-6291, and it is likely that different approaches will be required for these tumors.
The swimmer plots on slide 31 provide additional temporal information about the patient populations that appear on the waterfall plots. Follow-up for most patients is short. Although it is too early to calculate a median progression-free survival, no patient with an initial unconfirmed objective response and a follow-up scan has subsequently failed to confirm, and no patient who has responded by RECIST has yet progressed or discontinued treatment. To confirm the antitumor activity of RMC-6291, we're also showing the reduction in circulating KRAS G12C mutant allelic frequency by dose and by response. With the caveat of small numbers and considerable heterogeneity, molecular responses are, as expected, associated with tumor shrinkage. Molecular responses do not seem to increase in depth with dose, dose levels greater than 200 milligrams twice daily.
Overall, the initial data show encouraging clinical activity for RMC-6291 in patients with KRAS G12C mutant non-small cell lung cancer and colorectal cancer. In particular, the response rates in patients with non-small cell lung cancer that previously received a KRAS G12C off inhibitor compare very favorably with recently reported data on the experience with other KRAS G12C inhibitors. The overall response rate for single-agent RMC-6291 in colorectal cancer is similar to that reported for other KRAS inhibitors in combination with anti-EGFR antibodies. While preliminary, these data are consistent with the differentiated mechanism of action for RMC-6291 that has previously been presented and support the potential of RMC-6291 for further development. I will now turn back to Mark.
Thank you, Steve, for that clear review of important data from the first two RAS(ON) inhibitor investigational drugs in our pipeline, with encouraging clinical activity across multiple common KRAS G12 tumor genotypes and tumor types, data that we believe provide clinical validation of this exciting and highly differentiated class of drug candidates. I'd also like to remind everyone that a third investigational drug from this class is also undergoing initial clinical evaluation, although we don't have sufficient experience to report on it today. This compound, RMC-9805, is an unprecedented oral inhibitor that selectively and covalently engages KRAS G12D, the most common mutated driver of RAS-addicted cancers. It is highly active preclinically, and we look forward to reporting on its clinical profile at the appropriate time.
I'm also pleased to introduce formally RMC-5127, the newest exciting mutant-selective compound from the RAS(ON) inhibitor class to enter development at RevMed. This oral inhibitor is highly selective and potent against the second most common driver of RAS-addicted cancers, KRAS G12V. This compound is in IND-enabling development, and we look forward to bringing it into the clinic. A reminder that previously we've described two other mutant-selective RAS(ON) inhibitors in development, RMC-0708, targeting the KRAS Q61H variant, and RMC-8839, targeting the KRAS G13C variant. We are proud of our extensive portfolio of R&D assets focused on RAS-addicted cancers, now dominated by this deep collection of RAS(ON) inhibitors.
We've reviewed the current status of our three clinical stage compounds, including the first two for which we have initial safety, tolerability, and clinical activity data, as well as three additional development candidates and a further pipeline of preclinical and discovery assets. In a moment, we'll bring on Dr. Wei Lin to give us a preview of what's next for the exciting compound, RMC-6236. Let me comment here that we also believe RMC-6291 is quite promising, and we await additional monotherapy data to help guide prioritization of the multiple potential paths by which we can drive clinical impact and ultimately pursue commercial value from this compound. In the meantime, you'll see that we are already moving forward with the study of the combination of RMC-6291 and RMC-6236.
Let me now update you on two RAS companion inhibitors we have in clinical development. First, RMC-4630 is a selective inhibitor of the RAS regulator SHP2 that we envisioned as a potential combination drug with RAS inhibitors. Despite encouraging early data from the CodeBreaK 101 study, in the global phase 2 RMC-4630-03 study, the combination of RMC-4630, dosed at 200 mg day one, day two, with sotorasib dosed at 960 mg QD, showed additive side effects compared to either agent alone. A clinical benefit in response rate or durability was not observed, likely limited by dose interruptions and discontinuations due to intolerability.
Given the exciting clinical profile of RMC-6236, we have given this compound priority over RMC-4630 for evaluation in combination with our mutant-selective RAS(ON) inhibitors, but RMC-4630 continues as an option for possible evaluation in other combinations in the future. Second, RMC-5552, a first-in-class bi-steric selective mTORC1 inhibitor, was designed to treat cancer patients with RAS mutant tumors bearing co-mutations that upregulate mTORC1 signaling. The ongoing RMC-5552-01 study has provided objective evidence of single-agent clinical activity in patients at tolerated doses, as recently updated at the Triple Meeting, including partial responses. Consistent with our initial vision for this compound, future development will focus on combination treatment with RAS(ON) inhibitors, particularly for patients with tumors carrying both a RAS mutation and markers of mTORC1 hyperactivation.
Let's now return to our headline asset, RMC-6236. As Steve showed, this inhibitor has proven to be broadly active in patients with multiple common tumor types and driven by multiple common RAS genotypes. We plan to execute further development of RMC-6236, with both speed and breadth, by making parallel investments in both late-stage monotherapy trials and clinical studies of combination approaches. As you'll see, we are committed to expanding the scope of development for RMC-6236, by evaluating the broadest possible range of RAS genotypes, of lines of treatment, and of tumor types. Dr. Lin will provide this overview of our current thinking, which of course, remains subject to data-driven decisions and consultation with investigators and regulatory authorities. Wei?
Thank you, Mark. Our vision for the development of RMC-6236 is to bring the benefit of direct RAS(ON) inhibition, the greatest number of patients with RAS-addicted cancers. To achieve this vision, we will pursue in parallel the initial registration of RMC-6236 as monotherapy in multiple later line indications with high unmet need, while exploring combinations that may significantly improve the standard of care in the first line and adjuvant settings. To broaden the impact of RMC-6236 on the lives of patients with RAS-addicted cancers, we aim to build on the proof of concept emerging from our first-in-human study and expand the development of RMC-6236 in multiple dimensions. These plans include going beyond KRAS G12 mutations, going to earlier lines of therapy, and going into all solid tumor types. Let me describe in more detail these three dimensions.
First, RAS mutations. In our first-in-human trial, the preliminary safety and antitumor activity of RMC-6236 have been established in patients with lung and pancreatic cancers, specifically harboring KRAS G12 mutations. However, preclinical data indicate that RMC-6236 is broadly active across all three canonical RAS isoforms, KRAS, NRAS, and HRAS, as well as against all three common mutation hotspots, G12, G13, and Q61. Therefore, in our potential future registration trials, we aim to broaden the biomarker selection to include all three RAS isoforms and all three mutation hotspots. As we expand from populations where we have established clinical proof of concept to populations where we are relying on preclinical proof of concept, we use nested designs and hierarchical testing to mitigate potential risks from including expanded populations. I'll illustrate this approach in our proposed monotherapy randomized trial designs later in the presentation.
Second, lines of therapy. While the highest unmet needs are in previously treated patients, the untreated first-line and adjuvant patients represent the largest number, over 200,000 patients with RAS-mutated cancers newly diagnosed in the United States each year. Furthermore, adjuvant therapy presents the only setting where we may be able to offer cancer patients the potential for a cure. Our strategy in expanding into early lines of therapy involves a multi-pronged approach that includes development of our RAS(ON) inhibitor doublets, as well as combinations of a RAS(ON) inhibitor with standard care and other anticancer therapies. Third, tumor types. While lung, pancreatic, and colorectal cancers are the most common RAS-addicted cancers, many other solid tumors, such as melanoma, ovarian, endometrial, and cholangiocarcinoma, contain RAS mutations at a high frequency....
The most significant approach, efficient approach to expand the evaluation of RAS(ON) inhibition to these patients is a tissue-agnostic registration strategy via a potential single-arm phase 2 trial, and our current strategy is to explore initiating this type of trial. Now, I want to delve more deeply into our monotherapy development plan in non-small cell lung cancer. Each year, approximately 200,000 people in the United States and 2,000,000 people worldwide are diagnosed with non-small cell lung cancer. The majority will die from their disease at some point, making it the most lethal of all cancers. RAS signaling plays a role in the majority of non-small cell lung cancer, and RAS is the most common oncogenic driver in non-small cell lung cancer, with approximately 30% of newly diagnosed non-small cell lung cancer patients having tumors that harbor a RAS mutation.
The current global standard care for second-line patients who are being treated with immunotherapy and platinum-based chemotherapy is docetaxel. Docetaxel plus ramucirumab, while approved, is not widely used. Sotorasib and adagrasib are indicated for use only in patients with KRAS G12C mutated non-small cell lung cancer. Because they have not gained full approval, they're not formally considered standard care by major health authorities. As the table on the right illustrates, while sotorasib has shown a higher response rate, improvement in median progression-free survival is only 1.1 months, from 4.5 to 5.6 months, and there was no overall survival benefit. Therefore, the entire population of patients with RAS mutated non-small cell lung cancer share a common global standard of care in docetaxel, and expect median survival of less than one year represents a major unmet need.
To address this high unmet need, we're planning a global randomized Phase 3 trial comparing RMC-6236 against docetaxel in patients with RAS mutated non-small cell lung cancer who have been treated with immunotherapy and platinum-containing chemotherapy. The biomarker selection will include KRAS, NRAS, and HRAS. We include G12C and non-G12C mutations, and we'll include G13 and Q61 mutations. The study endpoints are progression-free survival, overall survival, and patient-reported outcomes. In our currently contemplated trial design, we've taken into account the potential complexity associated with including patients with RAS mutations spanning positions G12, G13, and Q61. We expect that a package to support a broad approval will need to include sufficient data to demonstrate efficacy in each mutation subgroup.
We have a number of approaches to serve this goal, including a nested design with hierarchical statistical testing that begins with a focus on the patient group with the highest probability of success and sequentially expands into additional groups. We will be discussing our proposed analysis plan with the FDA before finalizing our phase 3 design. The design presented here is preliminary and has not been reviewed by health authorities, so the final design may change. What will not change are our belief that a high unmet need exists, and our commitment to evaluate RMC-6236 broadly in patients with RAS mutated non-small cell lung cancer, as we try to improve the standard of care for these patients. Next, let's review a potential monotherapy development plan for RMC-6236 in pancreatic cancer.
This disease is notorious for having the worst prognosis among all major cancers. Most of the approximately 50,000 patients in the United States and 500,000 patients worldwide, who are newly diagnosed with pancreatic cancer each year, will die from the disease. More than 90% of pancreatic cancer harbors a RAS mutation, making it the dominant oncogenic driver in this disease. Among the chemotherapy regimens commonly used in the second-line setting, the median progression-free survival is between 3 and 3.5 months, and median overall survival is between 6 and 7 months, making this indication one of the highest unmet need in oncology. While the first generation KRAS G12C off inhibitors have shown antitumor activity, KRAS G12C mutation occurs in only 1% of pancreatic cancer, so these inhibitors are not relevant for most pancreatic cancer patients.
However, their initial evidence of efficacy provides the first proof of concept that human pancreatic cancer is a RAS-addicted cancer, and together with the clinical data we presented at ESMO and the Triple Meeting, strongly supports the continued evaluation of RMC-6236 in the broader population of RAS-mutated pancreatic cancer. To address this high unmet need-... We're considering a potential global randomized phase 3 trial, comparing RMC-6236 against a physician's choice of chemotherapy regimens in patients with RAS mutated pancreatic cancer. These are second-line patients whose tumors harbor a RAS mutation. The broad biomarker selection will include all RAS isoforms and G12, G13, and Q61 mutations. The study endpoints would include progression-free survival, overall survival, and patient-reported outcomes. Similar to our non-small cell lung cancer phase 3 trial, this trial design has to account for the complexity associated with including multiple mutations.
At appropriate time, we'll be discussing our proposed analysis plan, including a potential nested approach with the FDA, before finalizing our phase 3 design. Therefore, the final design may change based on regulatory feedback. Our goal is to provide a robust data set to support a broad approval in RAS-mutated pancreatic cancer. The high prevalence of RAS mutations in pancreatic cancer is a strong indicator that this is a RAS-addicted cancer. Therefore, we are committed to evaluating the potential of RMC-6236 to improve the standard of care for these patients broadly. So far, you've heard how we're thinking about the development of RMC-6236 as a monotherapy, using non-small cell lung cancer and pancreatic ductal adenocarcinoma as priority examples. Of course, we believe that the potential clinical utility of RMC-6236 and our entire RAS inhibitor pipeline is much broader.
Now, I want to share four strategies expanding RMC-6236 development from monotherapy to combinations. Combinations underlie our plan in the first-line setting, where effective treatment options may exist, and we'll consider combinations with standard care as a development option. Combinations also underlie our plan in the adjuvant setting, where we may have the opportunity to evaluate a potential cure for patients. And combinations underlie our plan to expand into multiple tumor types. Our first strategy is RAS(ON) inhibitor doublets. We hypothesize that in RAS-addicted tumors, total inhibition of RAS signaling drives efficacy, and the main resistance mechanism is the recovery of RAS signaling in tumor cells. This hypothesis is supported by data on resistance to the first-generation KRAS inhibitors.
Therefore, our first combination strategy is to develop RAS inhibitor doublets, which, based on pre-clinical results we presented, may prevent or delay the emergence of resistance and may translate into longer durability of treatment benefit and longer survival for patients. Given our differentiated mechanism of action based on tri-complex inhibitor technology and our deep pipeline of RAS(ON) inhibitors, Revolution Medicines is uniquely positioned to execute on this strategy. In the RAS G12C space, we have already initiated the development of RMC-6236 plus RMC-6291 in a phase 1 trial and are actively recruiting patients. Our second strategy is to replace chemotherapy with RAS(ON) inhibitors. First-line non-small cell lung cancer, where the standard care is chemo plus immunotherapy, is an ideal indication to explore this strategy.
RAS(ON) inhibitors or RAS(ON) inhibitor doublets aim to deliver better outcomes for patients by targeting the oncogenic addiction with greater efficacy, while improving on the safety profile of chemotherapy. The combination development of RMC-6236 plus anti-PD-1 and RMC-6291 plus anti-PD-1 is currently in advanced planning stage. Our third strategy is to combine with other targeted therapies. In colorectal cancer, receptor tyrosine kinase reactivation, especially EGFR, is a primary mechanism that appears to limit the efficacy of the first-generation KRAS G12C RAS(OFF) inhibitors. Combination with anti-EGFR therapy has shown benefit in addressing this limitation. While KRAS G12C mutation represents only approximately 3 to 4% of colorectal cancer, RAS mutations overall occur in approximately 50% of colorectal cancer. We therefore expect to evaluate the combination of RMC-6236 plus anti-EGFR antibody in this large patient population.
Our fourth strategy is to combine RMC-6236 plus standard care. Pancreatic cancer is a good example for this strategy. For patients with RAS-mutated pancreatic cancer, neither immunotherapy nor targeted therapy is approved, and the standard care remains chemotherapy for both first line and the adjuvant settings. Combination with chemotherapy offers RMC-6236 an alternative development path, especially for patients with tumors harboring an additional mutation not addressed by RAS inhibitor doublets. The combinations of RMC-6236 plus chemotherapy are currently in advanced planning stage. Of course, these four strategies may evolve as we learn more about each of our RAS(ON) inhibitors, their combinability, their efficacy in different tumor types, and lines of therapy. We believe that this multi-prong approach will improve our chance to change the standard of care in RAS-addicted cancers. Back to you, Mark.
Thank you, Wei. As you can see, we've made a great deal of progress with our rich portfolio of RAS(ON) inhibitors, and we have exciting ongoing activities and development plans. To put the clinical findings to date in perspective, together, the first two of our investigational drugs from this class have already shown significant antitumor activity in patients against the four most common oncogenic RAS G12X mutations, which we believe validates our ability to target the large RAS G12X subset. Together, these compounds have also shown significant activity across the three major types of RAS-addicted epithelial cancers. Projecting the validated RAS G12X subset onto the epidemiology of these common solid tumors, it can be inferred that these first two compounds, in aggregate, credibly may be able to serve a remarkable three-fourths of the RAS mutated forms of these three major cancers.
This compelling scope of opportunity may become even more inclusive as we expand clinical evaluation of RMC-6236 to the G13 and Q61 mutated RAS genotypes and to other tumor types, and continue advancing other assets in our pipeline. We are most grateful to the patients and their families who have participated in our trial so far or plan to, to our investigators and collaborators, to our employees, partners, and advisors, and to our investors for helping us sustain our ambitious program in order to outsmart cancer.
Thank you. As a reminder, to ask a question, you will need to press star one one on your telephone. To withdraw your question, please press star one one again. Please stand by while we compile the Q&A roster. And I show our first question comes from the line of Marc Frahm from TD Cowen. Please go ahead.
Hi, thanks for taking my question, and congrats on the data over the past week. Maybe to start off with, well, with the data today, it does look like there's maybe a bit more delayed responses sometimes in pancreatic cancer than maybe what you're seeing in lung cancer. Is there biological rationale that, you know, based on your preclinical data, you're seeing that might explain that?
Thanks, Marc, for your question. Really appreciate it. I'm going to ask Steve Kelsey first to comment on that, and we'll see where we go from there.
It's not at all clear that the data to support the delayed response in pancreatic cancer comes from preclinical models necessarily. I think it comes from a wealth of clinical experience with pancreatic cancer generally, that it is a very different disease from non-small cell lung cancer, both in terms of the way it's constituted, with a lot of the bulk of the tumor often being not actually tumor tissue. So that's the first thing. So even if you eradicate all the tumor, you may still end up with a significant lump on a CT scan, which takes a while to remodel because it's mainly fibrous tissue. The second obvious difference between pancreatic cancer and non-small cell lung cancer is the involvement of the immune system.
That, you know, a lot, a lot of non-small cell lung cancers have a lot of immune effector cells in there, and those can significantly debulk the tumor, whereas pancreatic cancer is notoriously difficult for the immune effector cells to access, and so it may just take a lot longer. And I think that's what we're seeing. I think that's what we're seeing, Mark, with the difference between how long it takes for a patient to achieve a partial response to 6236 in the pancreatic cancer versus the lung cancer patients.
Great. Thanks. That's really helpful. And then maybe just on the idea of expanding out beyond G12X, when can you run this preclinically, if you see any meaningful differences in the level of activity against some of these other hotspots, but then also, while you're kind of finalizing these designs with regulators, are there any plans to start enrolling some of those patients on a single-arm basis just to kind of reconfirm clinical activity?
Why don't I comment on the first question, and then Steve can hit on the second one? The first question, differences between G12 mutants and G13/Q61. In the preclinical work, you may recall, we studied a very large panel of cell lines, which is sort of the best way we have to get at this. And across many different genotypes and many different tumor types, really the only difference we could see in terms of response rates was between the G12 mutants and all the other mutants. They were all sensitive. As we've mentioned, we've not really found a mutant, oncogenic mutant or variant of RAS that isn't as sensitive to some degree to RMC-6236. But there was a quantitative difference between the G12s and all the others, and that's why we prioritized G12, you know, in this study.
Of course, as I mentioned, we're probably covering three quarters or more of all RAS cancers, even just with the G12 mutations. But there just seems to be some difference in sensitivity. And I think Wei's comment about the nested design with hierarchical testing, statistical testing, is a really convenient and practical way for us to both focus on the highest probability subgroup, representing three quarters of cancers, and then also testing the others without taking a penalty for including them in the trial. With regard to your second question, could you repeat the second part of the question?
It was just if there was gonna be any plan to, at least in the interim, while you're finalizing that design, enroll some of these patients with G13 or Q61 mutations?
Oh, sure. Sure. Maybe, Steve, do you want to comment on that?
Yes, is, is the answer. We, we have been focused very much on pancreatic, colorectal, and personal and non-small cell lung cancer up to now. I think as we are moving... Well, firstly, we're more confident we have an active drug, and secondly, moving closer to, dose optimization. We are planning to do a number of things, and, and Wei described some of those, you know, particularly the combinations that will allow us to move into earlier lines of therapy. Also, it's high priority for us to get some data in the other mutations beyond the G12 mutations, and also in some of the other tumor types that have the G12 mutations as well, particularly colorectal cancer and some of the gynecologic malignancies. That's very much, part of our plan for the next sort of 6 to 12 months.
If I could add to that, you know, investigator and patient demand for RMC-6236 remains very high, as we've talked about before, and that continues to be the case based on feedback, as recently as today from ESMO. Investigators are very interested, they have many ideas for other patients, and the needs are quite deep. And so we will certainly be making the compound available in a variety of contexts, expansion contexts, both to serve patients while we're still evaluating things, but also to collect the kinds of data you're talking about. So, I think we're about to hit sort of more of an inflection point in opening things up to a broader group of patients.
Wei, maybe he could comment also, though, on the tumor agnostic trial concept, which he talked about briefly, but is an important expansion tool and something to move on, you know, relatively quickly, although you'd like to do that at, you know, at a recommended phase two dose. But to move relatively quickly on and to run in parallel with the more dedicated, randomized phase three trials. Wei, do you want to comment a little bit further on how that works and what the value of it is?
Sure. Happy to, Mark. Yeah, as Mark mentioned, and Joe, and Steve as well, that we are going to be enrolling in the expansion cohort of our first-in-human study, additional solid tumors that cover other histologies, and other mutations to really expand on the preclinical observation that RMC-6236 is active, much more broadly than in the patient population. We've shown data so far for so far. I think, if the data continue to support that, that's, that would lead, that could potentially lead to a discussion with health authorities for a potential tissue-agnostic registration in all solid tumors. Thanks.
Thank you. Once again.
Thanks, Mark.
Thank you. Our next question comes from the line of Jonathan Chang from Leerink Partners.
Hi, guys. Thanks for taking my questions. First question: Given the early stage, still early stage nature of the 6236 efficacy data, can you talk about whether you think the data could improve from here, whether it's a function of higher dose levels, longer follow-up, or otherwise? And then second question: If the data evolve over time in a way that's largely consistent with the data presented today, can you talk about your thoughts on whether the data are sufficiently compelling versus standard of care benchmarks? Thank you.
Sure. Thanks. Maybe, maybe Steve can comment on both of those questions.
Yeah. So the first question about what do we expect to happen to the data over time, I think our expectation is that the data will at least stay as is, if not improve, and there are a number of reasons for that. The first is that we've shown you data for all patients treated at 80 milligrams daily and above. And there's a big difference between 80 milligrams daily and 400 milligrams daily. So the overall response rates right now, don't forget, are driven in large part by the patients that are enrolled at the lower dose levels, and not so much by the patients who enroll at the higher dose levels, for whom we have less data.
The second reason is, you know, as you can see from those waterfall plots, there is a tendency for patients for their disease to continue to shrink, and for some patients who have not achieved the criteria for partial response to move into the criteria for partial response. And actually, when we have done the analysis, when we've actually looked at the response rates for patients that have been followed for longer than those that were included in this ESMO analysis, the response rates are actually higher than the response rates that were reported at ESMO. So it is quite possible that the response rates will improve. Now, the thing that will really be telling, I think, and we'll have to wait some more months for the data, is the durability.
Not just the durability of responses, but the durability of freedom from progression for patients who have had some degree of tumor shrinkage, and have not progressed. And I think that will be probably more important and will be a bigger driver of the long-term impact of RMC-6236, than whether or not the response rate goes up or down by a few percentage points.
Yeah, maybe I can add to that. I think a couple of things that tend to get lost in that particular topic. One, is the tolerability and safety profile is viewed by investigators and patients as very strong, and that has real impact on so many things going forward. And so from a, "Do we need to improve in that regard?" I don't think we need to improve in that regard. Secondly, the breadth of genotype activity is unprecedented, and I don't think we need to improve in that regard. And third, so far, the durability that we've measured is very strong.
We just don't have enough observation period, so as Steve said, "Well, we'll just need to see," and we'll watch it, but there's really no indication today that we have anything but a compound that will provide durability. And ultimately, that is really going to drive most of the approvals that we spoke about earlier. The only one I think in which the response rate matters is in that tumor agnostic study, where that'll be an important endpoint. So, we're pretty pleased with where we are today, and with the collection of data and patient outcomes so far. We can't predict the future, but we're quite encouraged by it. And I'd also add that as I mentioned earlier, investigators are very excited about this.
They're clamoring to be part of the studies of 6236, and they want to put their patients on the compound. So I don't think that there is much for us to be concerned about from the point of view of the caregivers who are responsible for these patients, recognize the deep unmet needs, and frankly, the very strong and highly differentiated outcomes that we've described today, for which there simply is no other comparator.
Yeah. So, you also asked specifically about benchmark comparisons. I think the easier one here is non-small cell lung cancer. I mean, the comparator is docetaxel. The overall response rate in lung cancer is more tightly linked to the temporal endpoints of progression-free survival, and possibly even overall survival. And so, you know, I think we have a fairly compelling case there, and that's why we're intending to move forward. The difficulty with pancreatic cancer, I mean, look, firstly, the response rate is double anything that's ever been seen in G12X mutant pancreatic cancer, right? I mean, there have been reports of G12C specific inhibitors being used in G12C mutant pancreatic cancer, which is an extremely small patient population.
The outcomes are similar to what we've been, what we've shown for RMC-6236, and our investigator base, as Mark said, is really excited about this. The challenge there is not so much whether the overall response rate is better than standard of care. It clearly is. The challenge is whether or not the durability... Because overall response rate is not so tightly linked to progression-free survival, we have to wait until we're confident that the progression-free survival is of a nature that is gonna be, you know, significantly impact patients by being significantly better than standard of care.
And so we're confident at the moment with the preliminary data that we have, that the trajectory is in the right direction, but we just don't have enough information right now, and particularly not at the, what will ultimately be the recommended phase 2 dose to be able to report out what we are likely to have.
Understood. Thank you.
Thank you. I show our next question comes from the line of Eric Joseph from J.P. Morgan. Please go ahead.
... Mr. Joseph, please go ahead with your questions.
Oh, great. Thanks for taking the questions, and let me add my congrats on these data. I guess with dose selection in the planned phase 3 still pending, I'd be curious to know sort of what additional follow-up you're seeking to arrive at dose selection, and sort of perhaps if there's a timeframe that you might attach to that? And, Mark, you've previously talked about the possibility of advancing tumor-specific dose regimens, you know, one dose taken into lung cancer, another for pancreatic. I guess, any additional thoughts on that potential strategy in light of the data that you're presenting here today? Thank you.
Great. Thanks very much, Eric. Let me preface the first part of the answer to your first question. Let me provide a first part of the answer on with regard to timeline, which is that, we have indicated, and I think continue to believe, that, we have a very good shot at starting a first randomized phase 3 global trial in at least one indication in 2024. We can't be more specific than that for the reasons that are kind of embedded in your question, but, we're well on our way towards designing such a trial, and of course, we need a little bit more information.
Maybe Wei can then fill in a little bit, not so much in terms of time, but just what are we doing to get to that dose selection, for lung cancer and, and for pancreatic cancer, as well, which by the way, could end up being the same dose. I think I've earlier just said, it is always possible that one would end up, proceeding with a dose that's working very well on lung cancer, while you're still evaluating, higher doses in pancreatic cancer. And that's sort of a TBD right now. We're just being transparent about it. But maybe Wei can comment on that further, and then we'll come back to the second part of your question.
Sure. Happy to, Mark. Yeah. As you know, FDA has published guidance called Project Optimus on how to optimize dose, and we're following that guidance very closely in expanding on patients who have non-small cell lung cancer and pancreatic cancer at more than 1 dose level to really optimize and identify the optimal dose to move forward, and to discuss with FDA as the recommended phase 2 dose. And I think, like Mark mentioned, it's possible that these 2 tumor histologies will arrive at the same dose or different. I think we'll be very data driven in that regard.
So that would be one of the key gatings identified RP2D for opening up our first and hopefully many registration trials in the coming year.
And then your second question, really, I guess I've already commented on, and Wei did as well, which is, do we end up with different doses? You know, and I think that was sort of embedded a little bit in Jonathan's question about response rates, and I think Steve gave you our very clear view that we're in a strong place today with the response rates, but it's also not the main thing that we're looking for, which is something I've talked about for the last number of months, as you know. The disease control rate is very high for both lung and pancreatic cancer, even at the doses that we've tested.
And those, we believe, are more likely to be a predictor of durability, which is going to be the key to approvals, rather than response rate per se. And I think Steve also mentioned the response rates. You know, they're calculated at a moment in time. They're calculated to include patients who've had only one scan and haven't even had the opportunity to convert, and we've seen very high rates of conversion. So I don't think we're too focused on those those specific numbers. But there is a difference in the unmet needs between lung and pancreatic cancer, and patients and their caregivers may be willing to take their time and tolerate higher doses. So there may, there may actually be a justification for pushing dose sort of more aggressively in one population versus another.
Again, I'm not advising that that's what we will do, but that's a subject of ongoing discussion, and we haven't reached an MTD yet in either population, so there certainly is room to go. And in general, with RAS inhibitors, one's observed that more is better, a phrase I've used many times in the past, and so that's something for us to keep on the table, and we'll see whether things converge or diverge.
Yeah. Thanks. That's helpful. And maybe just a quick follow-up, if I could. I guess, is there anything in this, this, 6236 data set that speaks to the potentiality for mutant KRAS heterogeneity or, you know, a mix of KRAS mutations within a given patient's tumor? Were there any cases in this, in this, data set so far? And can -- if so, could you speak to the activity of 6236 in that type of setting?
I don't think we have, you know, since for RMC-6236, there are no patients in the study who have previously received a RAS inhibitor, so there hasn't been any real selection pressure for the emergence of those rarer second mutations that tend to become enriched over time in patients who've had a RAS(ON) inhibitor. But we haven't evaluated any patients like that simply because the protocol design. So I don't think, to my knowledge, I don't think we've seen any second RAS mutations within the data set. Steve or Wei, if they wanna elaborate... add to that. I think we just don't know.
Not in the 6236 dataset, no. The 6291 dataset, we've seen a number of patients with colorectal cancer who progressed on a KRAS G12C inhibitor, that have had multiple additional mutations and amplifications, and that's, I think, one of the, you know, I know we're talking about 6236, but we did mention that, you know, we hadn't reported outcomes for patients with colorectal cancer who were treated with 6291, who had been previously treated with another G12C inhibitor, and that's because the, the G12C inhibition with the G12C off inhibitors frequently induces, other mutations in colorectal cancer.
But in the 6236 dataset, we have not seen that, and I think that's for the reasons that Art mentioned, is that because there are currently no other RAS inhibitors being used in these patients, the selection pressure is very different, that these patients are undergoing selection pressure with cytotoxic chemotherapy. And so the primary driver RAS mutation tends to still be the predominant driver in these, in these patients.
Which I think does set up, just to sort of close out that point, it does set up the concept here that RMC-6236, which we continue to believe is going to be active against many different mutant forms, and the preclinical evidence strongly supports that, that it may in fact provide a much more robust and durable suppression of the RAS pathway, because those clones that might be lurking as ultra-rare, you know, clones and heterogeneity in the background, simply don't have the opportunity to emerge. And, we'll take every benefit that might be able to provide. I think that could really serve patients. But that's a concept today based on the preclinical data. Of course, we just don't have any clinical data yet to validate it.
Okay. Okay, great. Well, congrats again, and, and thanks for taking the questions.
Thank you.
Thank you. And I show our next question comes from the line of Chris Shibutani from Goldman Sachs. Your line is open.
Hi, everyone. This is Charlie on for Chris. Thanks so much for taking our questions, and I'll add my congratulations as well, really exciting. So first, we were wondering, just in terms of the ongoing work to pursue, lung and registrational studies, whether you are considering the inclusion of active brain metastases, considering the preclinical evidence for activity within the CNS? And then, as a follow-up, I was just wondering, with the lung complete responder, can you provide some clarity on when that patient had dosed down to 200 mg? Thanks so much.
Sure. Active brain mets. Wei, you want to comment on what we're contemplating with regard to active brain mets in a registration study?
Yeah, sure. Happy to do. So the current plan is to actually follow a very data-driven approach. And so the current phase 1 study has not included patients with active brain mets. They all have included patients with treated brain mets. And so since that's the dataset that's been generated, and we'll follow that, so the patient population plan for the phase 3 would also include only patients with treated brain mets, and not active brain mets. However, in the future, we do at the right moment plan to really possibly explore patients with active brain mets, and then evaluate the activity of 6236, as well as 6291 in those populations.
Yeah, and just to build on Wei's comments, and as you sort of built into your question, we have shown preclinical data for all three of our clinical stage RAS(ON) inhibitors that showed activity in a model of brain metastases. RMC-6236 showed activity in an identical model to that used with adagrasib and KRAS G12C tumors, and 6236 was as good or superior to that. So I think it is active. On the other hand, the two mutant selective inhibitors showed even greater activity in the preclinical model. We don't know exactly how well either of those predicts clinical behavior, but we're encouraged by them. And as Wei said, we will in parallel...
I think a key point to all of this is that we're gonna study all of these different questions in parallel, while we're also driving towards the earliest possible and strongest possible approval. So more to come, but I think parallel, parallel, parallel should be the theme of the day. Your second question had to do with the patient who had a complete response, a pretty amazing response. Probably had a response faster than we measured it, simply because based on her clinical behavior, but I think the scan, the first scan was done for protocol at six weeks. Wei, do you know, I think the question being asked here was whether-
When did they dose?
Yeah, when did they dose reduce? And specifically, I infer from that, that you're trying to relate that to the antitumor activity at 200 versus 300, but maybe Wei can clarify that.
Yeah. So the patient who experienced a complete response was dose reduced in the middle of cycle three.
So that would have been between the first CT scan and the confirmation?
That's right. Correct. Yeah. So yeah, the first dose, and then so which means that the confirmation was achieved at the lower dose.
Great, that's so helpful. Thank you so much, and congrats again.
Thank you.
Thank you. I show our next question comes from the line of Amy Fadia from Needham. Please go ahead.
... Hi, good afternoon. I'll add my congratulations on, on the data that's been presented over the last several days. My first question is just, how do we think about, where the response rates may be landing for lung and PDAC? And, you know, if you look at the responses by dose, you know, your overall response rate across doses was about 38%, but if you look at the 160 mg dose in lung, that's, you know, at 56%, and perhaps the higher doses don't have enough follow-up yet. So, and then, you know, for PDAC, I'm sort of seeing about 20 to 25% for the 160 and 200 mg dose.
So my first question is, you know, would you expect that as data matures and as you dose up, response rates in lung could trend more towards that, you know, mid-50s range? And is, you know, for PDAC, do you think that 20 to 25% is kind of where we will see the data as it matures? And then I have one other question.
Thanks, Amy. Appreciate the questions. I think I probably could just comment on this and then Steve or Wei, if they wanna add to it. You know, we can't predict the future. So, I think we're always very cautious about sort of guiding you to what we might see at some point when we have a different data set than we have today. But there's no question that in the course of this study, we have had data cutoffs that have shown significantly different response rates than those that you're seeing here. You know, it's a moving target when you're dose-escalating, and I think that was embedded in your preface, which is that we tried to get as late a data cut as we could practically provide for investigators and investors.
The consequence of that is that it's loaded up with patients on higher doses, but who have had very, very little follow-up, and that's just the reality of the calendar, and it doesn't really have any particular significance. So while I don't think we wanna stick a number out there that is simply a speculation, I think Steve said it well, that we expect at least to preserve the rates that we've seen, and we may well see increased rates over time, and I don't know about any particular number. I think the second point about PDAC, I would just reiterate a really important underlying piece of science here, which is, it's been known for decades that pancreatic cancers are predominantly non-tumor cells that drive the bulk of the tumor.
Remember, a CT scan really doesn't differentiate between tumor and non-tumor. The non-tumor, Steve mentioned very briefly, is fibrosis. It's desmoplasia, is the term, and it's a well-known and specific characteristic of pancreatic cancer. So when you're trying to shrink a tumor for a CT scanner, you just get, you get what you get, and it doesn't really tell you anything about what's going on in the tumor itself. It just tells you what the bulk, you know, white shadow is on the scan and the linear dimensions. So we don't know. There's never been a compound of this type to evaluate, so we have nothing to compare it to.
The hypothesis that's been in the literature for a long time, focused on tumor versus stroma or fibrosis, is now being tested with RMC-6236 for the first time in history. So we'll find out what it shows in the future, but we're not particularly anxious about it. I understand some other people might be particularly anxious about it, but not our investigators, and not our patients, and not us. It's just a fact of the complexity of these tumors. So where we'll exactly land, I don't know. As Steve mentioned, we have seen evidence, in fact, even one of the earlier questions was predicated on the idea that the time to response is longer in PDAC versus non-small cell lung cancer, and that has some implications for sort of accumulating the evidence.
So we'll land where we land. And I'll stick by Steve's comment, should be at least as good as where we are right now, if not better. And in the end, this will all be driven by durability response and not by whether we're at 21% or 26%. It makes zero difference to the regulatory authorities, or to caregivers or to patients.
That's, those are very helpful comments. I just have one other quick question. Can you comment on kind of where you're thinking as and is that currently with regards to the possibility of an accelerated approval pathway, with the trial design you've discussed? You know, sounds like, you know, you didn't highlight response rate as a key endpoint in those trials. Would you say that approval would be based on a PFS endpoint?
Well, full approvals for both PDAC and lung for sure, are gonna be based on PFS and trends in overall survival, no question about that. But, we know there's a lot of interest, particularly in the investor community, for what sort of so-called accelerated options we might have. And I think there are several that are already built into the trial design that might not have been called out explicitly, but Wei could comment on that. We've obviously had many internal discussions of it, and maybe he can sort of draw out for you what are the ways in which accelerated approvals could be obtained.
Yeah, happy to do that, Mark. Yeah. I think, also recently, FDA has published guidance about their new perspective on accelerated approval. And I think, you know, historically, accelerated approval has been, largely based on single-arm studies and response rate with durability of response. I think, for, for some indications, that still makes a lot of sense. I think for other indications, it actually, you could run a randomized trial, and have interim readout based on OR or PFS to enable accelerated approval, and then ultimately have a, final readout based on, overall survival or PFS, depends on which indication, to enable full approval, all within the same randomized trial.
And there are certain advantages to that, because that ensures the timely approval, and then it just enables a single trial rather than a single-arm for accelerated approval and a separate phase 3 randomized trial for confirmation. So we're gonna consider all these options, and as we discuss with regulators on what's the fastest way to bring this medicine to patients. After exploring those options, we'll take the ones that actually would really be able to enable us to really benefit patients the most.
If I could just build on that a little bit. I think it's been made abundantly clear by the FDA that for accelerated approval, they are going to require that you have enrolled your full approval trial anyway. And so it's not at all clear that it's faster to run something separate, as well. And, you know, I think the term accelerated is an unfortunate term. We think of it as an interim approval, and I think the evidence of the last month has demonstrated that that's the better way to think about it, rather than as an accelerated approval. Acceleration, accelerated approval and speedy approval are not nearly the same thing.
But nonetheless, I think given the structure of these the requirements for enrollment, again, we've said this for many, you know, for, for many, many months, and I think you everybody can see why, that designing the trials principally around the full approval, but then having opportunities for potential interim looks if the FDA is interested in that, then of course we will do so and make sure that the power, you know, enables the statistical, the structure and the power enables us to do that. And then the second point, Wei, do you just want to comment about the tumor-agnostic trial? Because I think, again, that went by a little bit quickly earlier.
Sure.
Just how we think about it as, in some ways comparable to, but even much more potentially powerful and broader than, than a dedicated, accelerated single arm trial.
Yeah. No, absolutely. So, to expand on what's been discussed earlier, the tissue-agnostic, because RMC-6236 is expected to be broadly active across histologies and across genotypes of RAS mutations has been demonstrated by our preclinical data. I think we believe that accelerated approval based on a tissue-agnostic approach could be a viable approach if there's alignment with the regulators. And then in there, we can enable a single-arm study, because across multiple histologies, there will be no common standard care to really compare against, and these will be patients who have really been treated with previously standard care therapies, and then hence offer them a treatment option that otherwise they would not have.
That would allow us to really broadly really enable this medicine for many patients whose natural prevalence may be fairly low in terms of patient number. So instead of being able to support a randomized phase 3 trial in each individual tumor type, then we can potentially gain approval across multiple tumor types for all solid tumors potentially with this strategy.
Yeah. Thanks, Wei. And so I would just reiterate, obviously, we need feedback from the FDA, who will react to the data. We think, we're excited to be able to have the chance to talk with them at the right time. But, you know, this compound is truly unprecedented, so there just simply aren't examples one can look toward to see the kinds of breadth of opportunities that we uniquely have because of its profile. And you'll see, you can tell we're very committed to maximizing both the speed and breadth and quality of those approvals.
Thank you.
Thank you. I show our next question comes from the line of Alec Stranahan from Bank of America. Please go ahead.
Hey, guys. Congrats on the data, both at ESMO and the Triple Meeting. And thanks for taking our questions. One question I had, and this has sort of been touched on partially in different responses, but maybe not directly. But any color you can provide on why G12C-experienced patients were excluded from the 6236 study, particularly in light of the responses seen with 6291 in these patients. Do you think we could actually see activity for 6236 in this patient population as well? And I imagine this probably feeds back into the commentary from Wei on the rationale for the doublet combo approach as well.
... Oh, sure. Well, I'll take the first one, the easy one, which is, you know, preclinically, 6236 is an extremely active inhibitor of RAS G12C tumor models, and so we fully expect it to be highly active. I think it was excluded simply for practical reasons, which is largely because getting those patients naive and not having previously seen a G12C OFF inhibitor is, you know, requires an extra effort, and it is a potentially a distraction from getting to the breadth. We've showed activity just in the data sets that you've now seen across four different RAS genotypes, with objective responses in three of those genotypes already, D, V, and R.
I think there's very little doubt that this compound is quite active in G12C, and we will evaluate that more explicitly, informally, coming up not too long from now. The second question, I think, was 6291 plus 6236, and maybe Wei, if he wants to add anything to what I just said about G12C, please do, and also then maybe you could address the combination.
Sure. Happy to do that. Yeah. I'm just adding to Mark's comment. I think, you know, the, because, 6291 was developed contemporaneously with, 6236, and I think there's a... I think we believe that we can demonstrate the proof of concept, of activity of 6236 in G12 mutated RAS tumors, just by, looking at, non-G12C, and then leaving the patient potentially, available for 6291's development, which now we're able to show you the data for in non-small cell lung cancer and other tumor types. So, so that's one of the things.
Now we are certainly very enthused about the 6236, plus 6291, and I think, Clayton Gustafson, at the Triple Meeting, had presented some preclinical data, and our research group has also done it, previously as well. So that combination is extremely active. And so we're really enthused about that dual inhibition of the, of the target.
And I think, given just, the data that's emerged from the resistance mechanism for the first generation G12C OFF inhibitors, both sotorasib and adagrasib, I think one of the themes that really emerged is, just by, ctDNA analysis of patients who progress on either sotorasib or adagrasib, more than 80% of patients retain their G12C mutation, and many of the patients have secondary mutations, on RAS, as a, mechanism resistance, to these G12C inhibitors.
It just highlights for many of these patients the tumor is really heavily addicted to RAS, and in spite of exposure to a G12C inhibitor, they continue to be addicted to RAS and try to overcome with a mechanism that we call RAS rescue or rescuing the signaling in the RAS- MAP kinase pathway, either directly with a second mutation at RAS, or even some of them have activation at the RTK upstream and continue to feed signal into RAS and also downstream as well. So that's why we believe that combination could be potentially highly active, even more so than either agent alone. And through that combination, we'd be able to address probably many of the potential mutations that can emerge with either single agent or with G12C off inhibitors.
So, that trial, as I mentioned before, has really opened, and we're actively recruiting patients, and then, when the data is available, we're looking forward to sharing that.
Okay. Got it. Thanks. That's very clear. One more question, if I may. I imagine we're getting toward the end of the Q&A, and I haven't heard this asked yet, but any updates you can provide on the EQRx transaction? What are the next milestones we should be looking for over the next month or so, and how should we be thinking about the recent data updates as it relates to deal pricing and closing?
Thanks for that question. This is Peg, Chief Operating Officer. So this data disclosures over the last couple of days and weeks was a critical element of the EQRx transaction design, as you know, and so I'd say the next critical question is, or next landmark is when we will be having the shareholder meetings, which are scheduled November eighth. Short of that, I think, you know, there's no immediate steps other than continuing to see-
Vote early, vote often.
How our stock goes and how the vote comes in.
Yeah, I'd like to just build on that a little bit. You know, it's pretty clear that this compound, RMC-6236, has extraordinary breadth of activity. It's the first-ever compound of its type, a targeted therapy against all forms of RAS. It deserves a lot of attention, and it will get a lot of attention. The tolerability and safety profile breaks the dogma that had been out there very clearly. The initial durability are encouraging. There's strong investigator and patient interest, so much so that we have wait lists at every one of our clinical sites, which also squeezed out any potential for G12C earlier, but we need to broaden now. And then we have, and will gain additional financial strength that gives us from this EQRx transaction, that gives us the-...
capacity to pursue the breadth of studies and further development and hopefully registration approaches that this compound deserves and that patients deserve with it. So it's a very important transaction for us. We think it's a unique way to strengthen our balance sheet. We appreciate the support of the EQRx team and their shareholders, and we look forward to closing this out shortly.
Great, and, thanks again.
Thank you. Our next question comes from the line of Jay Olson from Oppenheimer. Please go ahead.
Oh, hey, congrats on these results, and thank you for the comprehensive update. For the circulating tumor DNA analysis, it seems like most patients achieved impressive levels of reduction. Can you talk about how this finding may be implemented in future clinical studies and/or in clinical practice? I had a follow-up, if I could.
Yeah, I was just actually looking at that earlier, earlier this morning. I mean, it is, it is quite supportive of the antitumor activity we've seen, and if we're reducing circulating tumor DNA, we're clearly doing something to these tumors that's important. So it's supportive information in the clinical trial context. Wei, do you wanna comment about implications for either future trials or for clinical practice?
Yeah, absolutely. Yeah, it's a great question. I think, the implication may be different for clinical trial conduct and clinical practice, and it may be different for different tumor types and histologies. So, if you look at the 3 major tumor types that we have data for, which include lung cancer, colorectal cancer, and pancreatic cancer, the presence of ctDNA at baseline, it actually varies quite a bit, probably in order of colon being the highest, lung second, and pancreatic probably third. So majority, if not all, colorectal cancer patients at baseline have detectable ctDNA. Lung, probably somewhere between 50 to 100%, so maybe in the 70% range or so, and pancreatic cancer is a bit less than that. That's just based on historical numbers.
That means those numbers may evolve as technology advances, and sensitivity of assays may actually change as well for detecting ctDNA. Having said that, as you can see, you know, if you look at what ended up happening in our trial for 6236, because in higher doses, predominantly enrolled lung and pancreatic cancer patients and non-colorectal, only a portion of the patients that we evaluate ctDNA for have ctDNA at baseline. The ctDNA data you're seeing that we presented is actually for a subset of patients who have ctDNA at baseline. So that implication for conducting trial is, I think it's useful for really supportive data to correlate with tumor response, which we have for every single patient.
I think that provides a really biological support and allows us to maybe establish our proof of concept more confidently and with smaller data sets than otherwise without the ctDNA and if we were just based entirely on radiographic data. Now, in colorectal cancer, because we expect much more higher prevalence of ctDNA, that utility is probably a lot more powerful. And even in a clinical trial design, I think currently, for instance, in the adjuvant setting, patient who have had surgical resection of their primary colorectal cancer, who have earlier stage colorectal cancer, if they have microscopic disease, there's a high likelihood they would have ctDNA. And if that ctDNA, the risk of recurrence is extremely high.
So, in trial design, you can actually use this as way to select patients to randomize into a trial. So you can imagine conducting an adjuvant study in colorectal cancer, enrolling only patients who have had surgery and still have presence of DNA in their blood, highlighting these are the patients who are most likely to recur because they have presence of microscopic metastasis, not visible on CT scan. And so if you enroll those patients, given their high risk of recurrence, they demonstrate ability to demonstrate benefit for patients is actually higher than if you enroll an all-comer population mixed in with patients who would never recur because their disease, they're actually basically disease-free.
So colorectal cancer, I think, you can probably use that both in clinical trial design as well as eventually in clinical practice, because that would translate to then, if the drug were approved, you would pick out those patients to receive the drug in clinical practice based on the present ctDNA after surgery. I think, in other tumor types where the abundance of ctDNA at baseline is lower, it'll probably more remains in use, more supportively, in the design of clinical trials, especially in standard concept. And since not everyone has ctDNA, it's harder to use that in clinical practice. I hope that helps.
Super helpful. Thank you for the detailed explanation. Separately, can you talk about any initial clues of resistance mechanisms you've seen with RMC-6236?
No, we can't. We just don't have much information on that at this point. It's too early, and we just don't, we just don't have any data to speak from.
Okay, fair enough. Thanks for taking the questions.
... Thank you.
Thank you. As a reminder, to ask a question, you will need to press star one one on your telephone. I show our next question comes from the line of Ben Burnett from Stifel. Please go ahead.
Hey, thank you very much, and congrats on the updates. I just want to ask a clarification question on the ORR data. And I can really appreciate that there are a lot of eyes on how the PFS signal unfolds, but just want to make sure that we understand the ORR signals. I think there are three unconfirmed responses that are no longer ongoing. Is that right? And what are the reasons for those patients not continuing therapy?
Steve, do you want to comment on those?
Yeah. Ben, you're correct. We have a total of three patients that had an initial RECIST response and have discontinued treatment, one with pancreatic cancer and two with non-small cell lung cancer. My understanding is that two of those patients had a progression between the first scan and the follow-up scan, and one more patient, I think, withdrew from the study for reasons that were not fully explained to us, but were not related to a drug-related adverse event or an obvious and measurable clinical progression.
Okay, that's very helpful. And if I could just also ask another question just around the strategy of pursuing a tumor agnostic study, which I think is really interesting. But it looks like that this tumor agnostic study would include some of the tumor types that you're also pursuing, I guess, more directly and separately.
Right.
So could you just talk about how do you prosecute all of these in, you know, a capital efficient manner? And I guess, what I'm asking is, are there any go, no-go decisions that would refine your strategy that we should be looking out for?
Yeah, well, one of the reasons to include the tumor types for which there are dedicated studies is that you really have to anchor the tumor agnostic study across one or more tumor types because and then you end up collecting more data from those simply because they tend to be well represented. They're the more common tumor types. So that just has to do with the sort of typical design of those. There's very high demand for RMC-6236. So there's really not gonna be any issue of sort of competition or difficulty finding patients.
You know, sadly, and I think this is just the reality of all of these, clinical indications, that the needs are very deep, and we have not been able to serve everybody, during the conduct of the trial so far because of the sort of regimented way that we have to dose, escalate, and do expansions and so on. So there's lots of opportunity to do these studies. I think from a capital efficiency point of view, I think let's differentiate between spending less money and being capital efficient, which is also includes maximizing value creation. And, given that there are tumor types that simply won't be represented in, the core, phase 3 trials, which necessarily are dedicated to specific indications, the opportunity to try to capture those in other ways, which creates clinical...
potential clinical benefit and opportunity, but also commercial implications associated with that is there. And the, you know, that sort of tumor agnostic trial is not a gigantic study, anyway. So we get to serve more patients at the same time that we're collecting more data, at the same time that we're generating more potentially registrational data across the tumor types, lines of therapy, genotypes, et cetera. So we think that the point now is to maximize value creation, and we will, that is our strategy, will be an aggressive strategy to do so, especially in a competitive environment. And was there a second part to that question?
That was basically it. If there's maybe a go, no-go decision between these-
Oh, yeah. Well, of course, there are. Sure, sure. I'm not gonna lie to you. You asked me the follow-up question of what those are. Those are internal, but obviously, and I think we said it many times here, and, you know, we're very transparent about this, we'll continue to be driven by the data and make data, data-driven decisions. But we're giving you our best projections, you know, genuine data-driven projections for where things are going to go, and also reflects the activities that we're currently doing to support those projected plans. These are not theoretical. This is very high quality, important hard work being done by our development organization to prepare for everything we've mentioned here, there is in some stage of significant planning to do.
Of course, the data will ultimately drive each of these decisions, and, I don't see how we could do it otherwise.
Okay. That's great. I appreciate it, and congrats again.
Thank you.
Thank you. I'm showing no further questions in the queue. At this time, I'd like to turn the call back to Dr. Mark Goldsmith for closing remarks.
Thank you, operator. Thank you to everyone for participating and actively querying us about this large, complex and very exciting program. We very much appreciate your continued support of Revolution Medicines.
This concludes today's conference call. Thank you for participating. You may now disconnect.