01—Abstract
Summary
Summary of the 8-K filed December 2, 2024. Cited figures are marked; the original filing is the authoritative source.
On December 2, 2024, Revolution Medicines, Inc. furnished pipeline updates under Item 8.01 (Other Events) covering its RAS(ON) inhibitors RMC-6236 and RMC-6291.
For RMC-6236 monotherapy at 300 mg daily in previously treated RAS-mutant pancreatic ductal adenocarcinoma (data cutoff July 23, 2024; 76 patients), the company reported rash and gastrointestinal events as the most common treatment-related adverse events, one Grade 4 TRAE (platelet count decreased) and no Grade 5 TRAEs. In 2L metastatic PDAC, the objective response rate was 36%a (8 of 22) for KRAS G12X tumors and 27% (10 of 37) for G12X, G13X, or Q61X tumors, with median progression-free survival of 8.8 months and 8.5 months, respectively. Preliminary median overall survival was not estimable for either group.
In NSCLC (data cutoff September 30, 2024; 124 patients across 120 mg to 300 mg daily), the company stated RMC-6236 was generally well tolerated at 120 mg to 220 mg daily, with more TRAEs at 300 mg daily, and reported one Grade 4 pneumonitis at 300 mg daily. In RAS G12X NSCLC efficacy-evaluable patients who had received one or two prior lines of therapy, the ORR was 38%b (15 of 40), median PFS was 9.8 months and median OS was 17.7 months. The company said these data support plans for a global, randomized Phase 3 trial of RMC-6236 versus docetaxel.
The filing also reported early combination data: RMC-6236 with pembrolizumab in 20 patients (October 28, 2024 cutoff), RMC-6236 with RMC-6291 in 74 patients, including 25%c ORR (3 of 12) in previously treated colorectal cancer, and RMC-6291 with pembrolizumab in 15 patients. The company described these combinations as generally well tolerated and as supporting further evaluation, including a possible chemotherapy-sparing triplet in first-line NSCLC.
02—Key points
Key Highlights
- RMC-6236 at 300 mg daily in 2L metastatic PDAC: ORR of 36% (8 of 22) in KRAS G12X tumors and 27% (10 of 37) in G12X, G13X, or Q61X tumors, as of a July 23, 2024 cutoff.
- Interim median PFS in 2L PDAC was 8.8 months for KRAS G12X and 8.5 months for G12X, G13X, or Q61X tumors; median OS was not estimable for either group.
- RAS G12X NSCLC efficacy-evaluable patients (1–2 prior lines) had an ORR of 38% (15 of 40), median PFS of 9.8 months and median OS of 17.7 months as of a September 30, 2024 cutoff.
- Safety in 124 NSCLC patients: RMC-6236 was described as generally well tolerated at 120–220 mg daily, with higher TRAE rates at 300 mg daily and one Grade 4 pneumonitis at that dose.
- The company plans to initiate a global, randomized Phase 3 trial comparing RMC-6236 with docetaxel in RAS-mutated NSCLC after one or two prior lines of therapy.
- RMC-6236 plus RMC-6291 in previously treated KRAS G12C-inhibitor-experienced colorectal cancer showed a 25% ORR (3 of 12) and 92% disease control rate (11 of 12) in preliminary data.
- Early combination data with pembrolizumab in first-line-oriented NSCLC cohorts (20 patients with RMC-6236, 15 patients with RMC-6291) were described as generally well tolerated, supporting further evaluation of a chemotherapy-sparing triplet.
03—Questions
Frequently Asked Questions
What were the most common treatment-related adverse events with RMC-6236 in pancreatic cancer?
In 76 patients with PDAC treated at 300 mg daily (data cutoff July 23, 2024), the most common TRAEs were rash, which occurred in 91% of patients, and gastrointestinal events such as diarrhea in 53%, nausea in 38% and vomiting in 36%. One Grade 4 TRAE (platelet count decreased) was observed and no Grade 5 TRAEs were reported. TRAEs led to dose interruption in 40% of patients and to dose discontinuation in none.
How did patients with pancreatic cancer respond to RMC-6236 in the second-line setting?
The objective response rate was 36% (8 of 22 patients) for KRAS G12X-mutant tumors and 27% (10 of 37 patients) for tumors with G12X, G13X, or Q61X mutations, among patients whose first dose was at least 14 weeks before the July 23, 2024 cutoff. Preliminary median PFS was 8.8 months and 8.5 months, respectively, and median OS was not estimable in both groups.
What did the NSCLC data show, and what is the company's next step?
In RAS G12X NSCLC patients who had received one or two prior lines of therapy and had not received docetaxel, the ORR was 38% (15 of 40) as of September 30, 2024. Median PFS was 9.8 months and median OS was 17.7 months. The company said these data support plans to initiate a global, randomized Phase 3 trial comparing RMC-6236 with docetaxel.
What safety signals did the company report at the higher RMC-6236 dose in NSCLC?
Across 124 NSCLC patients treated from 120 mg to 300 mg daily, 33 patients (27%) had Grade 3 or higher TRAEs overall. At 300 mg daily (51 patients), 21 (41%) had Grade 3 or higher TRAEs, compared with 12 (16%) in the 120–220 mg group. One Grade 4 pneumonitis occurred at 300 mg daily in a patient with concomitant pneumocystis pneumonia. The company said the drug was generally well tolerated at 120–220 mg daily.
What did the company report about combinations with RMC-6291 and pembrolizumab?
In 74 patients treated with RMC-6236 plus RMC-6291, the combination was generally well tolerated across all dose levels, with one Grade 4 TRAE (hypokalemia) associated with Grade 3 diarrhea. In colorectal cancer patients previously treated with a KRAS(OFF) G12C inhibitor, the ORR was 25% (3 of 12). Early pembrolizumab combination data in 20 RMC-6236 patients and 15 RMC-6291 patients were described as generally well tolerated, and the company said they support exploring a triplet combination in first-line NSCLC.
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