Total Revenue (USD, thousands)

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Earnings Per Share (EPS) - Diluted (USD)

7564db7954d4992e72d7d54705437ace2cbe996915157ddcaa4c57992aa62245

Adjustments for Non-Cash Items (USD, thousands)

Stock-Based Compensation (USD, thousands)

Changes in Working Capital (USD, thousands)

Capital Expenditures (CapEx) (USD, thousands)

Proceeds from / Repayments of Debt (USD, thousands)

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Dividend Payments (USD, thousands)

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61d73eb0bcf0262f4a194b5b9c4423d82294b55199c4d8d5be8e4f3e69875b65

| Name                  | Position                                      | Start Date         | Short Bio                                                                                                                                                                                                                     |
|-----------------------|-----------------------------------------------|--------------------|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Mark A. Goldsmith    | Chief Executive Officer, President, and Chair | November 2014      | Mark A. Goldsmith, M.D., Ph.D., has served as CEO, President, and Chair of RVMD since **November 2014**. He has extensive experience in biopharma, including roles at Constellation Pharmaceuticals and Global Blood Therapeutics.  **[0000950170-24-048380_rvmd-20240425.htm:16]** **[0000950170-24-048380_rvmd-20240425.htm:31]** **[0001193125-23-118577_d479013ddef14a.htm:12]**  |
| Jack Anders          | Chief Financial Officer                       | September 2022     | Jack Anders joined RVMD in **August 2018** as VP, Finance, was promoted to SVP, Finance in **March 2021**, and became CFO in **September 2022**. He previously held finance roles at Depomed, Elan Pharmaceuticals, and Yahoo!.  **[0000950170-24-048380_rvmd-20240425.htm:31]** **[0001193125-23-118577_d479013ddef14a.htm:30]**  |
| Steve Kelsey         | President, Research and Development           | March 2017         | Steve Kelsey, M.D., has served as President, R&D at RVMD since **March 2017**. He previously held leadership roles at Onkaido Therapeutics, Medivation, and Geron Corporation, and serves on scientific advisory boards.  **[0000950170-24-048380_rvmd-20240425.htm:31]**        |
| Margaret Horn        | Chief Operating Officer                       | October 2018       | Margaret Horn, J.D., has served as COO since **October 2018**. She was previously General Counsel (2014–2022) and EVP (2014–2018) at RVMD, and COO at ProLynx LLC from 2010 to 2014.  **[0000950170-24-048380_rvmd-20240425.htm:31]** **[0001193125-23-118577_d479013ddef14a.htm:30]**                                      |
| Wei Lin              | Chief Medical Officer                         | April 2023         | Wei Lin, M.D., has served as CMO since **April 2023**. He has oncology expertise from roles at Erasca, Nektar Therapeutics, and Genentech, where he led global approvals for TECENTRIQ® and other therapies.  **[0000950170-24-048380_rvmd-20240425.htm:32]** **[0000950170-23-018785_rvmd-ex99_1.htm:3]** **[RVMD_3250091_3]**             |
| Xiaolin Wang         | Executive Vice President, Development         | March 2021         | Xiaolin Wang, Sc.D., has served as EVP, Development since **March 2021**. She previously held leadership roles at Acerta Pharma, Geron Corporation, and Genentech.  **[0000950170-24-048380_rvmd-20240425.htm:32]** **[0001193125-23-118577_d479013ddef14a.htm:30]**                                                        |
| Jeff Cislini         | SVP, General Counsel, and Secretary           | September 2022     | Jeff Cislini has served as SVP, General Counsel, and Secretary since **September 2022**. He previously held legal roles at Atara Biotherapeutics, O’Melveny & Myers LLP, and Wilson Sonsini Goodrich and Rosati.  **[0000950170-24-048380_rvmd-20240425.htm:32]** **[0001193125-23-118577_d479013ddef14a.htm:31]** **[0001193125-23-118577_d479013ddef14a.htm:30]**        |
| Frank Clyburn        | Board Member (Class II Director)              | August 5, 2024     | Frank K. Clyburn, Jr. was appointed as a Class II Director on **August 5, 2024**. He has extensive experience in pharma, including as CEO of IFF and EVP at Merck, where he led the global launch of Keytruda.  **[0000950170-24-092735_rvmd-20240805.htm:2]** **[0000950170-24-092735_rvmd-ex99_1.htm:3]**              |
| Mary Pinder-Schenck  | SVP, Head of Medical Affairs                  | August 2024        | Mary Pinder-Schenck, M.D., serves as SVP, Head of Medical Affairs. She was appointed as part of strategic leadership hires announced in **August 2024**.  **[0000950170-24-092735_rvmd-ex99_1.htm:3]**                                                                    |
| Ryan Asay            | SVP, Corporate Affairs                        | August 2024 (est.) | Ryan Asay serves as SVP, Corporate Affairs. He was appointed as part of strategic leadership hires announced in **August 2024**, though the specific start date is not provided.  **[0000950170-24-092735_rvmd-ex99_1.htm:3]**                                            |
| Mason Shih           | SVP, Head of Drug Safety                      | August 7, 2024     | Mason Shih, M.D., serves as SVP, Head of Drug Safety. He was appointed as part of strategic leadership hires announced on **August 7, 2024**.  **[0000950170-24-092735_rvmd-ex99_1.htm:3]**                                                                              |
| Jing Yi              | SVP, Head of Program Leadership               | August 2024        | Jing Yi, Ph.D., serves as SVP, Head of Program Leadership. She was appointed as part of strategic leadership hires announced in **August 2024**.  **[0000950170-24-092735_rvmd-ex99_1.htm:3]**                                                                           |
```

28fe240b805b04469d061ba4e43b9c0d7b879ef3a8dbd50fc167e8c51b8afcd0

Current Assets (USD, thousands)

Cash and Cash Equivalents (USD, thousands)

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Common Stock (USD, thousands)

Additional Paid-in Capital (USD, thousands)

cba5b1ed991b220beeb739ec74a334ff4e9b86bb3e134ed3709418a9c6082944

1. Can you explain the specific reasons behind the delay in initiating the Phase III registrational study for RMC-6236 in non-small cell lung cancer, and what challenges remain before regulatory alignment can be achieved?
2. Given that you initiated the Phase III trial for pancreatic cancer but not yet for lung cancer, can you discuss the differences in data or strategic considerations that have led to the divergence in timelines between these two programs?
3. With your cash runway projected to fund operations into 2027, can you clarify what is included in your financial projections, specifically how potential future pivotal trials beyond the two disclosed Phase III second-line studies are factored into your probability-adjusted model?
4. In the RAS(ON) inhibitor doublet study combining RMC-6236 with RMC-6291, can you provide more details on the patient population, including prior treatments and tumor types, and what specific qualitative evidence are you seeking to assess the combination's effectiveness over monotherapy?
5. Regarding your clinical collaboration with Tango Therapeutics, what strategic considerations led you to choose their PRMT5 inhibitor over other programs, and how does this collaboration align with your broader combination strategy for RMC-6236?

88c9dc311cb23bb7ac6426b0cd7024a781a2121f55555699acaf8af76bc7d78c

Median PFS (Months)

Median OS (Months)

ORR 14 weeks (%)

ORR 20 weeks (%)

ORR (%)

DCR (%)

Grade 3+ TRAE Rash (%)

Grade 3+ TRAE Diarrhea (%)

Grade 3+ TRAE Stomatitis (%)

Grade 3+ TRAE PDAC (%)

b03345b3b70d24be83c2c18423709c3cd30738c251a65fe3d6d2605cdeb7b9c4

Collaboration Revenue

Total Revenue

f947816cc119fdd4935379160201b210385921f98cba6ca1bce6c647fd51aa78

Revolution Medicines, Inc. (RVMD) is a clinical-stage precision oncology company specializing in the development of targeted therapies for RAS-addicted cancers. The company leverages advanced drug discovery technologies to create small molecules that address unconventional binding sites in cancer cells. RVMD's offerings include a pipeline of RAS(ON) inhibitors and companion inhibitors, designed for use as monotherapies or in combination regimens to combat genetic drivers and resistance mechanisms in cancer.  **[0000950170-24-122303_rvmd-20240930.htm:27]** **[0000950170-24-092783_rvmd-20240630.htm:26]** **[0000950170-24-020145_rvmd-20231231.htm:6]** 

1. **RAS(ON) Inhibitors** - Develops small molecules that directly bind to active, GTP-bound RAS variants, suppressing cancer cell growth and survival. Includes clinical-stage candidates such as **RMC-6236**, **RMC-6291 (G12C)**, and **RMC-9805 (G12D)**, as well as preclinical candidates like **RMC-5127 (G12V)**, **RMC-0708 (Q61H)**, and **RMC-8839 (G13C)**.  **[0000950170-24-122303_rvmd-20240930.htm:27]** **[0000950170-24-092783_rvmd-20240630.htm:26]** **[0000950170-24-020145_rvmd-20231231.htm:6]** 

2. **RAS Companion Inhibitors** - Targets key nodes in the RAS pathway or associated pathways to enhance the efficacy of RAS(ON) inhibitors, primarily for combination treatment strategies.  **[0000950170-24-122303_rvmd-20240930.htm:27]** **[0000950170-24-092783_rvmd-20240630.htm:26]** **[0000950170-24-020145_rvmd-20231231.htm:6]** 

3. **Combination Therapies** - Evaluates RAS(ON) inhibitors in combination regimens, including doublet therapies with other investigational drugs, to address adaptive resistance mechanisms in cancer.  **[0000950170-24-122303_rvmd-20240930.htm:27]** **[0000950170-24-092783_rvmd-20240630.htm:26]** **[0000950170-24-020145_rvmd-20231231.htm:6]**

010ef42797d4b5d78c4a15aa7f73c3d1dd39e902c3ef662c7bdaa99c3a61ef84

23794d91c53ae875c8e247d72561e35d9d06ee07c70c9e0dbcc977a6d161504a

### Q3 2024 Earnings Call
- **Issued Period**: Q3 2024  
- **Guided Period**: FY 2024  
- **Guidance**:  
  1. **Full-Year 2024 GAAP Net Loss**: Expected to be between **$560 million and $600 million**, including estimated non-cash stock-based compensation expense of **$70 million to $80 million**.  **[RVMD_3406308_4]**   
  2. **Cash Runway**: Ended Q3 2024 with **$1.55 billion in cash and investments**, projected to fund planned operations into **2027**.  **[RVMD_3406308_4]**   
  3. **2025 Expense Outlook**: Expenses expected to **increase** due to initiation of two Phase III trials, organizational build-out for commercial preparation, and other opportunities outside of pivotal trials.  **[RVMD_3406308_14]**   

---

### Q2 2024 Earnings Call
- **Issued Period**: Q2 2024  
- **Guided Period**: FY 2024  
- **Guidance**:  
  1. **Full-Year 2024 GAAP Net Loss**: Expected to be between **$560 million and $600 million**, including estimated non-cash stock-based compensation expense of **$70 million to $80 million**.  **[RVMD_3397249_0]**   
  2. **Clinical and Pipeline Guidance**:  
     - **RMC-6236**:  
       - Initiation of **Phase III registrational study (RASolute 302)** for second-line metastatic pancreatic cancer planned for 2024.  **[RVMD_3397249_0]**   
       - Updated safety and antitumor activity data, including durability data for non-small cell lung cancer (NSCLC), expected in **Q4 2024**.  **[RVMD_3397249_0]**   
       - Initial data from the combination study of RMC-6236 with pembrolizumab (with or without chemotherapy) in advanced RAS-mutated NSCLC expected in **Q4 2024**.  **[RVMD_3397249_0]**   
     - **RMC-6291**:  
       - Initial data from the combination study of RMC-6291 with RMC-6236 in KRAS G12C solid tumors (primarily NSCLC) expected in **Q4 2024**.  **[RVMD_3397249_0]**   
       - Initial data from the combination study of RMC-6291 with pembrolizumab (with or without chemotherapy) anticipated in the **first half of 2025**.  **[RVMD_3397249_0]**   
     - **RMC-9805**:  
       - Initial safety, tolerability, and antitumor activity data from the first-in-human monotherapy study expected in **Q4 2024**.  **[RVMD_3397249_0]**   

---

### Q1 2024 Earnings Call
- **Issued Period**: Q1 2024  
- **Guided Period**: FY 2024  
- **Guidance**:  
  1. **Full-Year 2024 GAAP Net Loss**: Expected to be between **$480 million and $520 million**, including estimated non-cash stock-based compensation expense of **$70 million to $80 million**.  **[RVMD_3387633_4]**   
  2. **RMC-6236 Clinical Trials**:  
     - Launch of **first registrational trials** for RMC-6236 as a second-line treatment in **advanced pancreatic cancer** and **advanced non-small cell lung cancer** in the **second half of 2024**  **[RVMD_3387633_1]** ,.  **[RVMD_3387633_3]**   
     - Updated clinical data for RMC-6236 in pancreatic ductal adenocarcinoma and non-small cell lung cancer cohorts, including durability data, to be disclosed near the launch of these trials.  **[RVMD_3387633_1]**   
  3. **RMC-9805 (RAS(ON) G12D-Selective Inhibitor)**:  
     - Initial safety, tolerability, and antitumor activity data for RMC-9805 to be shared in the **second half of 2024**.  **[RVMD_3387633_3]**   
     - Planning for a **combination study** of RMC-6236 and RMC-9805 in patients with advanced RAS G12D-mutated cancers.  **[RVMD_3387633_3]**   
  4. **RAS(ON) Inhibitor Expansion**:  
     - Continued efforts to expand the reach of RMC-6236 into different RAS genotypes and tumor types, with a focus on **first-line treatments** for pancreatic and lung cancers  **[RVMD_3387633_1]** ,.  **[RVMD_3387633_13]**   

---

### Q4 2023 Earnings Call
- **Issued Period**: Q4 2023  
- **Guided Period**: FY 2024  
- **Guidance**:  
  1. **Full-Year 2024 GAAP Net Loss**: Expected to be between **$480 million and $520 million**, including estimated non-cash stock-based compensation expense of **$70 million to $80 million**.  **[RVMD_3375059_3]**   
  2. **Cash and Investments**: Ended 2023 with **$1.85 billion in cash and investments**, expected to fund planned operations into **2027**.  **[RVMD_3375059_3]**   
  3. **Clinical Development Milestones**:  
     - **RMC-6236**:  
       - Plan to initiate **monotherapy pivotal trials** in the second half of 2024 for second-line treatment in **lung and pancreatic cancers**.  **[RVMD_3375059_2]**   
       - Initial clinical PK, safety, tolerability, and activity data from genotype and tumor type cohorts expected in the **second or third quarter of 2024**.  **[RVMD_3375059_2]**   
       - Initial data from combination drug cohorts (e.g., with checkpoint inhibitors) anticipated in the **second half of 2024**.  **[RVMD_3375059_2]**   
     - **RMC-6291**:  
       - Initial clinical PK, safety, tolerability, and activity data from the **RAS inhibitor doublet trial** (with RMC-6236) expected in the **second half of 2024**.  **[RVMD_3375059_2]**   
       - Data from combination studies with checkpoint inhibitors also expected in the **second half of 2024**.  **[RVMD_3375059_2]**   
     - **RMC-9805**:  
       - Initial safety and activity data anticipated in the **second half of 2024**.  **[RVMD_3375059_2]**   

This table summarizes the issued and guided periods alongside the exhaustive guidance provided in each earnings call.

acfb1dd146b8bce1c5fd38f5c39e2603cc9b2104b41a5885c2062341fab81b8a

- **Uncertainty in regulatory interactions and trial designs may cause delays**: The company is not yet able to report on their regulatory interactions with the FDA regarding pivotal trials for RMC-6236, which could imply potential delays or uncertainties in moving forward with their second-line and first-line studies.  **[RVMD_3387633_10]** **[RVMD_3387633_6]**
- **Lack of updated efficacy data raises concerns about progress**: When asked about recent trends in objective response rates for RMC-6236, the CEO declined to comment, indicating they are not reporting any new data at this time, which could suggest that the data may not be as positive as hoped.  **[RVMD_3387633_20]**
- **Dependence on safety data for combination therapies could delay first-line treatments**: The company emphasizes that the initial combination studies with pembrolizumab are focused on safety rather than efficacy, and that progression to first-line treatment will depend on these safety results, which could delay advancement into first-line settings.  **[RVMD_3387633_7]** **[RVMD_3387633_9]**

7f236359cfcc1de0e6a210e6b726dad1178f7155bb101eb4bb529179bb9b0b30

- **Uncertainty and lack of clarity around data updates and timelines**: The company has repeatedly declined to provide clear timelines or detailed guidance on upcoming data disclosures and study designs, stating "we haven't provided any guidance on timing for that" and "I don't think we have anything new to add to that today"  **[RVMD_3397249_10]** ,  **[RVMD_3397249_12]** ,.  **[RVMD_3397249_11]**
- **Lower confidence in efficacy for non-G12X mutations**: Executives expressed less confidence in the efficacy of RMC-6236 in RAS mutations outside of G12X, acknowledging that "the emergence of data in those mutations is going to be somewhat behind... we're a little less confident there".
- **Safety concerns may limit combination therapies**: The company admits RMC-6236 "does have some side effects" and combining it with chemotherapy may pose risks, stating they need to ensure "that combination will not blow up for patients," which could limit its use in first-line treatments.  **[RVMD_3397249_12]**

e84670920735709a37ef76a97ce3e5921ceda164b925d07c7ca5a849648a97e6

- **Uncertainty in clinical trial timelines and data disclosures may lead to delays.** The company acknowledged that it's too early to set out a schedule for data rollouts, which could impact investor confidence.  **[RVMD_3375059_8]**
- **Safety concerns with drug combinations could hinder progress into pivotal trials.** Establishing safety profiles for combinations, especially given past hepatotoxicity issues with other RAS inhibitors, is a primary focus and may slow clinical development.  **[RVMD_3375059_5]**
- **High capital expenditure plans for multiple ambitious projects might strain financial resources.** Despite a strong cash position, the company admitted that at some point it won't feel like that much capital, raising concerns about future funding needs.  **[RVMD_3375059_11]**

690a444b7e2e49f0cffbaae0646945b2523fefc5ec11fde399fd2e3507154b93

1. **First-Line Treatment Strategy**  
   **Q:** Will you pursue first-line lung cancer trials sooner?  
   **A:** We prioritize moving RMC-6236 into first-line settings, leveraging emerging data to enable earlier treatment where benefits are greater. While committed to our second-line monotherapy trial, we are actively exploring first-line options and will adjust plans if necessary.  **[RVMD_3387633_10]** 

2. **Impact of Competing G12C Inhibitors**  
   **Q:** How do other G12C inhibitors affect your trials?  
   **A:** In pancreatic cancer, impact is minimal due to low G12C incidence. In lung cancer, despite crowded G12C space, our RMC-6236 targets both G12C and non-G12C mutations, serving patients without G12C inhibitor options. We expect RMC-6236 to be active on G12C mutations, based on preclinical data.  **[RVMD_3387633_8]** 

3. **FDA Endpoint Requirements**  
   **Q:** Will FDA require overall survival endpoints?  
   **A:** In non-small cell lung cancer, the FDA's stance on requiring overall survival (OS) is unclear. They may accept clinically meaningful progression-free survival (PFS) improvements for approval. The upcoming adagrasib review will provide more insight into FDA's position on OS requirements.  **[RVMD_3387633_18]** 

4. **Combination Therapy Development**  
   **Q:** What will drive further combo therapy development?  
   **A:** We aim to establish safety and combinability for RMC-6236 with mutant-selective inhibitors and pembrolizumab. Efficacy benchmarks include improving response rates over current standards, such as achieving higher than **50% response rate** seen with chemotherapy plus pembrolizumab.  **[RVMD_3387633_12]** **[RVMD_3387633_14]** 

5. **Business Development Plans**  
   **Q:** How are you approaching partnerships?  
   **A:** We plan to commercialize our RAS(ON) inhibitors independently in the U.S., given our integrated portfolio. Outside the U.S., we're open to partnering for marketing and development, seeking alignment to avoid strategic conflicts. We're investing in U.S. commercialization capabilities to field a competitive sales force at the right time.  **[RVMD_3387633_12]** 

6. **Safety Profile and Dose Reductions**  
   **Q:** Does safety vary with mutation profile?  
   **A:** The safety profile of RMC-6236 is consistent across mutation types. Dose reductions observed were not representative of broader tolerability and were chosen to illustrate mechanistic points. Side effects exist, but responses remain strong even after dose adjustments.  **[RVMD_3387633_14]** 

7. **Combination Rationale of RAS Inhibitors**  
   **Q:** Why combine RAS inhibitors with overlapping targets?  
   **A:** Combining mutant-selective inhibitors with our RAS multi-inhibitor addresses tumor escape mechanisms by inhibiting both the original mutation and emergent mutations or wild-type RAS upregulation, potentially enhancing response depth and frequency.  **[RVMD_3387633_16]** 

8. **Data Presentation and Timing**  
   **Q:** Will combination data be presented with monotherapy updates?  
   **A:** Our priority is the second-line monotherapy data for regulatory purposes. Combination data may be presented separately as they inform future studies, but exact timing and context are undecided.  **[RVMD_3387633_11]** 

9. **Patient Demographics in G12D Study**  
   **Q:** Will G12D study reflect real-world patient types?  
   **A:** Yes, the RMC-9805 trial enrolls patients with G12D mutations across all tumor types, primarily gastrointestinal cancers like pancreatic and colorectal cancer, reflecting real-world incidence.  **[RVMD_3387633_21]** 

10. **PFS Data Availability**  
    **Q:** Will PFS data be available in second-half updates?  
    **A:** We expect progression-free survival data to be part of upcoming presentations, which will support the initiation of late-stage trials, particularly for pancreatic cancer. PFS will be an important component of these updates.  **[RVMD_3387633_17]** 

12a062459508673e162f6ceb772b8da7d9e966b532909ec0d896d6cc53af3394

1. **Delay in Lung Cancer Phase III**  
   **Q:** Why is the lung cancer Phase III trial delayed?  
   **A:** The company remains committed to launching the Phase III registrational trial in lung cancer in the near future. However, practical considerations, including completing internal analyses and obtaining regulatory alignment, make it unlikely to initiate the trial before year-end. With the December holiday approaching, it's too much of a stretch to assume all critical activities can be completed to start the study before the end of the year. They will continue pushing to begin the trial as soon as practical.  **[RVMD_3406308_7]** 

2. **First-Line Pancreatic Cancer Strategies**  
   **Q:** What are your plans for first-line pancreatic cancer Phase III?  
   **A:** They are eagerly moving forward with planning a registrational Phase III trial in first-line pancreatic cancer. Based on second-line data showing **progression-free survival** and **overall survival** exceeding first-line benchmarks, they believe the agent as monotherapy is active in the first-line setting. They are considering including monotherapy as well as combinations with standard-of-care regimens like **FOLFIRINOX** and **gemcitabine**. They won't wait for second-line data before starting the first-line study. They believe KRAS is a fundamental driver regardless of therapy line and expect similar efficacy in first-line patients.  **[RVMD_3406308_16]** 

3. **Cash Runway Guidance**  
   **Q:** What's included in your cash runway guidance?  
   **A:** The cash runway guidance fully includes the two Phase III second-line studies in pancreatic and lung cancer that the company is moving ahead with. Beyond that, they use a probability-adjusted model for potential additional programs. While they can't specify what other programs are in the forecast, the two Phase III second-line trials are fully baked in.  **[RVMD_3406308_12]** 

4. **Future Combination Collaborations**  
   **Q:** Will there be more combination studies like with Tango?  
   **A:** They expect to pursue more collaborations combining RMC-6236 with other agents. There is a long list of requests for such collaborations, and they anticipate involving more agents and targets in future studies. Their priorities include combining RMC-6236 with other **RAS(ON) inhibitors**, **pembrolizumab**, and **chemotherapy**, with multiplex combinations. Other combination studies will likely emerge over time.  **[RVMD_3406308_10]** 

5. **Operating Expenses and Spending Outlook**  
   **Q:** How should we think about future spending and OpEx increases?  
   **A:** Expenses are expected to increase as they start two Phase III trials and build out the organization, including preparations for commercial launch. While no specific guidance for 2025 is provided, it's fair to assume expenses will go up due to these activities and opportunities outside the pivotal trials.  **[RVMD_3406308_14]** 

6. **AML and Liquid Tumor Applications**  
   **Q:** Thoughts on applying RAS(ON) platform to AML?  
   **A:** The hematology program has been mostly outsourced to academic collaborators who will present data at ASH. The company has focused on pancreatic cancer, non-small cell lung cancer, and colorectal cancer, and hasn't planned clinical development in less frequent tumors like AML. They recognize the mechanistic basis and unmet medical need and may consider clinical development in the future.  **[RVMD_3406308_11]** 

7. **Patient Background in Doublet Study**  
   **Q:** What's the patient background in the doublet study?  
   **A:** They can't provide much detail about eligibility. The study includes patients with **KRAS-G12C-bearing tumors**, a mixture of solid tumor types, and varied prior treatment backgrounds. This will be best understood when the data is disclosed.  **[RVMD_3406308_7]** 

8. **RMC-6236 and RAS GAP Activity**  
   **Q:** Comments on RMC-6236 increasing RAS GAP activity?  
   **A:** They are aware of this mechanism and discovered it some time ago, first disclosing it at an NCI RAS scientific conference a few years ago. It's quite interesting and may contribute to the therapeutic index of RMC-6236 by affecting RAS signaling more in cancer cells with upregulated **RAS(ON)** signaling than in normal cells with lower levels.  **[RVMD_3406308_15]** 

9. **Triplet Combinations with Pembrolizumab**  
   **Q:** Are you exploring triplet combinations with RMC-6236, pembro, and chemo?  
   **A:** Yes, they are conducting a study combining RMC-6236 with **pembrolizumab** and **platinum-doublet chemotherapy**, effectively a quadruplet regimen. They are initiating this sequentially after identifying the appropriate dose for the doublet of RMC-6236 plus pembrolizumab. Both combinations will ultimately be valuable.  **[RVMD_3406308_13]** 

10. **Choice of Tango Collaboration**  
    **Q:** Why choose Tango's PRMT5 inhibitor for collaboration?  
    **A:** They have done preclinical work with Tango's compound and found the combination encouraging. This doesn't preclude collaborating with other **PRMT5 inhibitors**. They are actively seeking the best combination partners for RMC-6236.  **[RVMD_3406308_17]** 

713b4d89dd7985f5792fd3aa77228f010a159aaca382df93a3bc327c8f8215f7

1. **Data Needed for Phase III Trials**  
   **Q:** How much more data do you need to initiate Phase III?  
   **A:** We need a mature progression-free survival (**PFS**) assessment from more mature observations to finalize trial design and statistical power, along with FDA input. These are key elements for making a final go decision on pivotal trials for **RMC-6236**.  **[RVMD_3375059_7]** 

2. **PFS Improvement in Pancreatic Cancer**  
   **Q:** What PFS bar do you need in PDAC to proceed?  
   **A:** While we've not specified a particular number, we aim to be superior to second-line chemotherapy, where median PFS is around **3 to 3.5 months**. Our goal is to exceed well-accepted benchmarks for second-line pancreatic cancer.  **[RVMD_3375059_14]** 

3. **Capital Allocation Strategy**  
   **Q:** How will you effectively spend your $1.85 billion cash?  
   **A:** Our top priority is advancing **RMC-6236** into pivotal trials for second-line pancreatic and lung cancer, which will receive the lion's share of our capital. We also prioritize expanding the reach of 6236 and advancing our mutant-selective inhibitors **6291** and **9805** into late-stage development.  **[RVMD_3375059_10]** 

4. **Partnership Opportunities**  
   **Q:** How are you thinking about partnering, in the U.S. and abroad?  
   **A:** In the U.S., we plan to build our own franchise and are not keen on partnering. Outside the U.S., we are open to partnerships to handle the complexities of global development and commercialization when the right opportunity arises.  **[RVMD_3375059_17]** 

5. **Confirmed Response Rates Update**  
   **Q:** How are confirmed response rates for 6236 trending post ESMO?  
   **A:** We've seen favorable trends; most responses have been confirmed, except where patients progressed or discontinued treatment. We cannot provide specific confirmed rates today but will share more precise information later in the year.  **[RVMD_3375059_20]** 

6. **Upcoming Data Disclosures**  
   **Q:** What is the sequence and timing of data disclosures?  
   **A:** While we have ideas on how data might roll out, it's too early to set a schedule. The most important event in the second half is the go decision and details about pivotal trial plans. Other information will be disclosed as appropriate.  **[RVMD_3375059_8]** 

7. **KRAS Combo Data Expectations**  
   **Q:** What would be good data from the 6236/6291 combo?  
   **A:** First, we need to ensure the combination is safe and tolerated. We'll then look for clinical activity signals such as increased frequency, depth, or durability of response. Preclinical data suggests benefits, but we need to validate in humans.  **[RVMD_3375059_12]** 

8. **Regulatory Considerations for Trial Design**  
   **Q:** Do you need activity data in G12X/Q61 mutations for FDA buy-in?  
   **A:** We're working with the FDA on final trial design. If we have activity data in these mutations, we'll include it in our discussions. Preclinical data shows all mutant forms of RAS tested show sensitivity to 6236, and we're gathering more information on other genotypes.  **[RVMD_3375059_9]** 

9. **Tumor-Agnostic Development Path**  
   **Q:** What's the regulatory path for 6236 in a tumor-agnostic setting?  
   **A:** We're anchoring on demonstrated activity in non-small cell lung and pancreatic cancers. We're enrolling patients with colorectal cancer, melanoma, and other solid tumors. Our aspiration is to help as many as **30%** of patients with solid tumors carrying RAS mutations. This will drive our decisions on pursuing tissue-agnostic approvals.  **[RVMD_3375059_18]** 

10. **Investigator Trial Enrollment Decisions**  
    **Q:** How do investigators decide between NRAS and RAS-selective trials?  
    **A:** The need for these compounds is high, and there are more patients than our trials can support. Investigators enroll patients based on specific eligibility criteria, and patient availability is not limiting. Demand reflects the significant need in oncology.  **[RVMD_3375059_19]** 

1e10f34cdbb79d7d5c9a51459bad61fb9e060857079293749a37a1a4fc736279

- **Upcoming Data Updates and Registrational Studies for RMC-6236**: Revolution Medicines plans to provide updated safety and antitumor activity data for RMC-6236 in non-small cell lung cancer in the fourth quarter of 2024. They also intend to initiate a second registrational study evaluating RMC-6236 monotherapy for previously treated patients, indicating significant progress in their pipeline.  **[RVMD_3397249_0]**
- **Exploration of Combination Therapies to Expand Treatment Potential**: The company is actively evaluating combination studies, such as RMC-6236 with pembrolizumab in non-small cell lung cancer. This strategy could enable them to move into earlier lines of therapy, including the adjuvant setting, potentially enhancing the efficacy and reach of their treatments.  **[RVMD_3397249_0]**
- **Evidence of Deepening Responses Over Time in Pancreatic Cancer**: Clinical observations have shown that patients with pancreatic cancer treated with RMC-6236 experience **deepening of responses over time**, which may be due to the unique mechanism of action of the drug. This phenomenon could potentially translate to other indications, underscoring the drug's therapeutic potential.  **[RVMD_3397249_0]**

56bf7b7e11134ab5c5065a5858cbbed4017f6aaf7e7601b0399e4aa2b27e975b

- **Revolution Medicines is advancing two Phase III trials**, including the **RASolute 302 study in second-line pancreatic cancer**, which has already started dosing patients, and remains committed to initiating a **Phase III registrational trial in non-small cell lung cancer** in the near future, demonstrating strong progress towards commercialization.  **[RVMD_3406308_12]** **[RVMD_3406308_7]** **[RVMD_3406308_14]**
- **The company is actively engaging in strategic collaborations**, such as with **Tango Therapeutics**, to explore combination therapies with their **RAS(ON) inhibitors**, **RMC-6236** and **RMC-9805**, indicating a robust pipeline and potential for synergistic treatments targeting RAS mutations and MTAP deletions in cancer patients.  **[RVMD_3406308_17]** **[RVMD_3406308_8]** **[RVMD_3406308_10]**
- **Revolution Medicines is prioritizing multiple combination studies** of their lead compound **RMC-6236** with other therapies, including **other RAS(ON) inhibitors**, **pembrolizumab**, and **chemotherapy**, which could expand the treatment potential and address high unmet medical needs in cancers such as pancreatic cancer and non-small cell lung cancer.  **[RVMD_3406308_10]** **[RVMD_3406308_13]** **[RVMD_3406308_6]**

8140dc3a8b14189fd78e4d85bc936f59b32a6bde2110a694a2b2bb06b673d786

- **Revolution Medicines has a strong financial position with approximately $1.85 billion in cash and investments**, expected to fund operations into 2027, enabling advancement of their ambitious pipeline.  **[RVMD_3375059_11]**
- The company is **advancing its lead candidate RMC-6236 into multiple pivotal trials** for second-line lung and pancreatic cancers, with **favorable trends in response rates**, including confirmation of most responses.  **[RVMD_3375059_2]** **[RVMD_3375059_20]**
- Revolution Medicines is exploring **innovative drug combinations**, such as **RMC-6236 with RMC-6291**, potentially enhancing efficacy and enabling movement into first-line treatment settings.  **[RVMD_3375059_19]** **[RVMD_3375059_12]**

5ef941bb6cecb577232699fddb051da186a8ede4aa65b04684470bc8ec18a4eb

- Revolution Medicines ($RVMD) is expanding the potential market for **RMC-6236** by demonstrating activity against a broad range of **RAS mutations**, including **KRAS G12D, G13X, and Q61X variants**, which could address a larger patient population across multiple tumor types.  **[RVMD_3387633_19]** ,  **[RVMD_3387633_3]**
- RVMD is advancing RMC-6236 into its first **registrational trials** in **second-line pancreatic and non-small cell lung cancers** in the second half of the year, with plans to move into **first-line treatments** using combination therapies, potentially expanding its use into earlier lines of therapy where clinical benefit may be more impactful.  **[RVMD_3387633_10]** ,  **[RVMD_3387633_13]** ,  **[RVMD_3387633_2]**
- The company is conducting multiple **combination studies** with RMC-6236, including with **pembrolizumab** and **chemotherapy**, aiming to develop more effective treatment regimens, such as **chemotherapy-free first-line treatments** for RAS-mutated cancers, which could enhance the commercial value and differentiation of its pipeline.  **[RVMD_3387633_12]** ,  **[RVMD_3387633_9]** ,  **[RVMD_3387633_2]**

5b66fafdd849c7cbd1a04864e5dca7a40f28f9c6e4237700487603b41e5bfa7e

- **Delay in Initiation of Phase III Lung Cancer Trial:** The company has pushed back the initiation of their Phase III registrational study in non-small cell lung cancer to the **first quarter of 2025**, citing practical constraints and the need for regulatory alignment. This delay may impact their progress in this important indication.  **[RVMD_3406308_7]**
- **Expected Increase in Expenses Without Specific 2025 Guidance:** While expenses have already increased significantly, the company expects expenses to **increase further in 2025** due to starting two Phase III trials and building out the organization. However, they have not provided specific guidance for 2025, which may affect their cash runway and financial outlook.  **[RVMD_3406308_14]**
- **Limited Focus on Additional Cancer Indications:** The company acknowledges that they have not prioritized clinical development in other potential areas like **acute myeloid leukemia (AML)** due to resource constraints, potentially missing opportunities in other cancer indications.  **[RVMD_3406308_11]**

b68e53fb8d5007f39d1b17554284c7fc5ac022d653b51d2b0e8643a62a2bc813

1. **NSCLC Phase III Trial Design**  
   **Q:** How will KRAZATI approval affect your NSCLC Phase III trial design?  
   **A:** Management acknowledged that KRAS G12C is the most complicated part of their lung cancer trial for **RMC-6236**. They have not yet laid out their plan but noted that potential FDA approval of **KRAZATI** may impact whether KRAZATI becomes the standard of care comparator or if **docetaxel** remains acceptable. They will determine the trial design after further discussion and data disclosure.  **[RVMD_3397249_0]** 

2. **Competitive PFS in NSCLC**  
   **Q:** What PFS data would be competitive for 6236 in NSCLC?  
   **A:** Management emphasized that they need to clear the standard of care bar but did not provide specific numbers. They stated it's difficult to answer while gathering and analyzing data. They have internal target product profiles but prefer to present data in context once available.  **[RVMD_3397249_0]** 

3. **First-Line Pancreatic Cancer Strategy**  
   **Q:** How much more data is needed to move 6236 to first-line pancreatic cancer?  
   **A:** They believe **RMC-6236** monotherapy already qualifies for inclusion in a first-line trial. The main question is how to combine it with chemotherapy, which is a safety and tolerability issue. They are working to ensure that combining with chemotherapy will not cause excessive side effects for patients.  **[RVMD_3397249_0]** 

4. **Combination of 6236 with 6291**  
   **Q:** Who is enrolled in the 6236 and 6291 combo study, and what's the efficacy bar?  
   **A:** The study enrolls patients with previously treated **G12C** tumors, mainly lung and colorectal cancers. They acknowledged that determining efficacy requires large randomized trials and are looking for qualitative differentiation. There is no preset response rate, PFS, or OS number they can ascribe to the combination at this time.  **[RVMD_3397249_0]** 

5. **Timing of Data Updates**  
   **Q:** How will upcoming data disclosures be timed and presented?  
   **A:** Management said that data updates expected in the **fourth quarter** could happen sequentially or be bundled. They did not provide specific timing or venues but will decide the format at the right moment.  **[RVMD_3397249_0]** 

6. **Censoring in Pancreatic Cancer Data**  
   **Q:** Was there unusual censoring in the pancreatic PFS data affecting Phase III relevance?  
   **A:** They explained that the censoring was standard due to patients enrolling later and not having progression events by data cutoff. This does not affect translatability to the registrational trial, as future analyses will be based on prespecified events rather than real-time data cuts.  **[RVMD_3397249_0]** 

7. **Rash Impact on Combinations**  
   **Q:** Could 6236-related rash impact combinations with pembrolizumab or chemo?  
   **A:** They do not think so. The rash associated with **RMC-6236** is acneiform and responds to antibiotics, differing from immune-mediated rashes. Combining 6236 with other treatments is unlikely to mutually enhance rash severity.  **[RVMD_3397249_0]** 

8. **Colorectal Cancer Data Timing**  
   **Q:** When will we see 6236 data in colorectal cancer studies?  
   **A:** They have not provided guidance on timing. They view colorectal cancer as primarily requiring combination strategies and are focusing on that approach.  **[RVMD_3397249_0]** 

9. **G12D Inhibitor Tumor Types**  
   **Q:** Which tumor types are included in the upcoming G12D data?  
   **A:** The study includes patients with solid tumors harboring **G12D** mutations, predominantly gastrointestinal tumors, but also some lung cancers. The representation reflects the prevalence of G12D mutations in these cancers.  **[RVMD_3397249_0]** 

10. **Fixed Dose Combinations**  
    **Q:** Are you planning any fixed dose combinations of your molecules?  
    **A:** They consider it possible in the future but need to establish doses first. Fixed dose combinations may be complex due to different dosing schedules (e.g., **once daily** vs **twice daily**). They will pursue it if it adds convenience without unnecessary complexity.  **[RVMD_3397249_0]** 

bedffe7189113537ffafdc9feabb442cc33615eb1991ec7e8d864169fe9e5c93

Revolution Medicines Inc (RVMD)

Financials