Revolution Medicines Inc (RVMD) 2024 Q3 法說會逐字稿

Good day. And thank you for standing by. Welcome to the Revolution Medicines Q3 2024 earnings conference call. (Operator Instructions) Please be advised that today's conference is being recorded.

再會。感謝您的支持。歡迎參加 Revolution Medicines 2024 年第三季財報電話會議。（操作員指示）請注意，今天的會議正在錄製中。

I would now like to hand the conference over to your first speaker today, Ryan Asay, Senior Vice President of Corporate Affairs. Please go ahead.

現在我想將會議交給今天的第一位發言人，企業事務資深副總裁 Ryan Asay。請繼續。

Thank you and welcome everyone to the third-quarter 2024 earnings call. Joining me on today's call are Dr. Mark Goldsmith, Revolution Medicine's Chairman and Chief Executive Office; Dr. Steve Kelsey, our President of R&D; and Jack Andrews, our Chief Financial Officer; Dr. Wei Lin, our Chief Medical Officer will join us for the Q&A portion of today's call. I'd like to inform you that certain statements we make during this call will be forward-looking because such statements deal with future events and are subject to many risks and uncertainties.

感謝並歡迎大家參加 2024 年第三季財報電話會議。參加今天電話會議的還有 Revolution Medicine 董事長兼執行長 Mark Goldsmith 博士； Steve Kelsey 博士，我們的研發總裁；和我們的財務長傑克安德魯斯；我們的首席醫療官林偉醫師將參加今天電話會議的問答部分。我想通知您，我們在本次電話會議中所做的某些陳述將具有前瞻性，因為此類陳述涉及未來事件，並受到許多風險和不確定性的影響。

Actual results may differ materially from those in the forward-looking statements. For a full discussion of these risks and uncertainties, please review our annual report on Form 10-K and our quarterly report on Form 10-Q that are filed with the US Securities and Exchange Commission.

實際結果可能與前瞻性陳述中的結果有重大差異。如需對這些風險和不確定性進行全面討論，請查看我們向美國證券交易委員會提交的 10-K 表年度報告和 10-Q 表季度報告。

This afternoon, we released financial results for the quarter ended September 30, 2024 and recent corporate updates. The press release is available on the investors section of our website at revmed.com. With that, I'll turn the call over to Dr. Mark Goldsmith, Revolution Medicine's Chairman and Chief Executive Officer. Mark?

今天下午，我們發布了截至 2024 年 9 月 30 日的季度財務業績以及最近的公司更新。新聞稿可在我們網站 revmed.com 的投資者部分取得。接下來，我會將電話轉給 Revolution Medicine 董事長兼執行長 Mark Goldsmith 博士。標記？

Thanks Ryan. It's good to be with you this afternoon. At Revolution Medicines, we are committed to revolutionizing treatment for patients with RAS addicted cancers through the discovery, development and delivery of innovative targeted medicines. We believe that we have increasingly been able to demonstrate that our portfolio of RAS(ON) inhibitors has the potential to provide meaningful impact for patients living with some of the most difficult to treat cancers.

謝謝瑞安。今天下午很高興能和你在一起。在 Revolution Medicines，我們致力於透過發現、開發和提供創新標靶藥物，徹底改變 RAS 成癮癌症患者的治療方法。我們相信，我們越來越能夠證明我們的 RAS(ON) 抑制劑組合有潛力為患有一些最難治療的癌症的患者提供有意義的影響。

At the start of the year, we provided a road map of strategic development priorities for 2024, focused on our three pioneering grass on inhibitors in clinical development RMC-6236, RMC-6291 and RMC-9805. The highest priority has been to advance RMC-6236, our first in class RAS(ON) multi selective inhibitor into its first pivotal trials. One in pancreatic ductal adenocarcinoma, which we refer to as PDAC and one in non-small cell lung cancer.

年初，我們提供了2024年策略發展重點路線圖，重點在於我們臨床開發的三款先鋒草抑制劑RMC-6236、RMC-6291和RMC-9805。當務之急是將我們的首款 RAS(ON) 多選擇性抑制劑 RMC-6236 推進其首次關鍵試驗。一種是胰臟導管腺癌，我們稱為 PDAC，另一種是非小細胞肺癌。

Our second priority aims to begin defining the path to expanding the reach of RMC-6236 into earlier lines of therapy particularly in PDAC. Our third priority aimed to qualify our mutant selective inhibitors RMC-6291, a RAS(ON) G12C selective inhibitor and RMC-9805, a RAS(ON) G12D selective inhibitor for late stage development. We have made substantial progress against these priorities.

我們的第二個優先任務是開始確定將 RMC-6236 的應用範圍擴大到早期治療系列（特別是 PDAC）的路徑。我們的第三個優先事項旨在使我們的突變選擇性抑制劑RMC-6291（一種RAS(ON) G12C 選擇性抑制劑）和RMC-9805（一種RAS(ON) G12D 選擇性抑制劑）進行後期開發。我們在這些優先事項方面取得了實質進展。

We demonstrated compelling durability data, specifically progression free survival and overall survival in a cohort of patients with previously treated metastatic PDAC treated with RMC-6236. Based on these results, we initiated our first global randomized Phase 3 study in second line treatment of patients with metastatic PDAC and are now actively dosing patients in this study.

我們展示了令人信服的耐久性數據，特別是一組先前接受 RMC-6236 治療的轉移性 PDAC 患者的無進展生存期和總生存期。基於這些結果，我們啟動了第一項針對轉移性 PDAC 患者二線治療的全球隨機 3 期研究，目前正在積極對本研究中的患者進行給藥。

Last month, we shared encouraging safety, tolerability and anti tumor activity with RMC-9805 in patients with KRAS G12D PDAC. We continue to advance and extend our pipeline including RMC-9805 and RMC-6291 by exploring new combinations to inform the design of future pivotal studies in earlier lines of therapy and across multiple tumor types including PDAC and non-small cell lung cancer.

上個月，我們分享了 RMC-9805 在 KRAS G12D PDAC 患者中令人鼓舞的安全性、耐受性和抗腫瘤活性。我們透過探索新的組合，繼續推進和擴展包括RMC-9805 和RMC-6291 在內的產品線，為早期療法以及包括PDAC 和非小細胞肺癌在內的多種腫瘤類型的未來關鍵研究設計提供訊息。

And there's more to come, we have a number of disclosure milestones ahead this quarter, when we look forward to sharing updates across our RAS(ON) inhibitor portfolio, including several approaches we're taking in non-small cell lung cancer, including both monotherapy and combinations.

還有更多的事情即將到來，本季度我們將有許多披露里程碑，屆時我們期待分享我們的RAS(ON) 抑製劑產品組合的最新信息，包括我們在非小細胞肺癌方面採取的幾種方法，包括單一療法和聯合療法。

I'd now like to hand the call over to Dr. Steve Kelsey, our President of R&D who will summarize the PDAC results we recently shared from the RMC-6236 and RMC-9805 monotherapy studies at the EORTC-NCI-AACR symposium commonly referred to as the triple meeting.

我現在想將電話轉交給我們的研發總裁 Steve Kelsey 博士，他將總結我們最近在 EORTC-NCI-AACR 研討會上經常提到的 RMC-6236 和 RMC-9805 單藥治療研究中分享的 PDAC 結果至三重會。

They'll also provide a brief overview of our plans in non-small cell lung cancer. Jack Anders, our CFO will then provide a summary of the third-quarter financial results, before I share a few closing remarks and open the call to Q&A. Steve?

他們也將簡要概述我們在非小細胞肺癌方面的計劃。然後，我們的財務長傑克·安德斯 (Jack Anders) 將提供第三季財務業績摘要，然後我將分享一些結束語並開始問答環節。史蒂夫？

Thanks Mark. At the recent Triple meeting in October, we had the opportunity to present data on two of our RAS(ON) inhibitors in PDAC including updated progression free survival and overall survival from our RMC-6236 monotherapy study and initial safety and antitumor activity from our RMC-9885 monotherapy study.

謝謝馬克。在最近於10 月舉行的三重會議上，我們有機會展示了我們的兩種RAS(ON) 抑制劑在PDAC 中的數據，包括我們的RMC-6236 單藥治療研究的最新無進展生存期和總存活期以及我們的RMC 的初始安全性和抗腫瘤活性-9885 單一療法研究。

Before I review these results, I would like to provide some perspective into RevMed's R&D approach relating to this devastating disease. More than 60,000 pancreatic cancer patients are diagnosed every year in the United States alone with more than half of all cases being diagnosed at the metastatic stage. Over 90% of cases are driven by RAS mutations. With the majority being G12X. G12D is the single most common RAS mutation found in approximately 40% of PDAC. Chemotherapy is the current standard of care for pancreatic cancer.

在回顧這些結果之前，我想先對 RevMed 與這種毀滅性疾病相關的研發方法提供一些看法。光是在美國，每年就有超過 6 萬名胰臟癌患者被診斷出來，其中超過一半的病例在轉移階段被診斷出來。超過 90% 的病例是由 RAS 突變引起的。其中大多數是 G12X。G12D 是在大約 40% 的 PDAC 中發現的最常見的 RAS 突變。化療是目前胰臟癌的標準治療方法。

Based on published clinical trials, median progression free survival or PFS is 2 to 3.5 months for second line patients who have progressed on first line therapy and median overall survival in these patients is six to seven months.

根據已發表的臨床試驗，在第一線治療中出現進展的二線患者的中位無惡化存活期或 PFS 為 2 至 3.5 個月，這些患者的中位總存活期為 6 至 7 個月。

We believe these treatment results indicate a need for improved outcomes for patients. While patients treated with first line combination chemotherapy and initial diagnosis of metastatic PDAC do better. The reported median PFS of approximately seven months and median OS of approximately 11 months still leave room for improvement.

我們相信這些治療結果顯示需要改善患者的治療結果。而接受第一線合併化療並初步診斷為轉移性 PDAC 的患者表現較好。報告的中位 PFS 約為 7 個月，中位 OS 約為 11 個月，仍有改進的空間。

I will now provide a brief summary of the results recently presented for our oral RAS(ON) multiselective inhibitor RMC-6236 and our oral RAS(ON) G12D selective inhibitor RMC-9805.

我現在將簡要總結我們的口服 RAS(ON) 多選擇性抑制劑 RMC-6236 和口服 RAS(ON) G12D 選擇性抑制劑 RMC-9805 最近提出的結果。

The details can be found on the events and presentations page of our corporate website at revmed.com. Beginning with RMC-6236, as the data have matured and as of the data cut off of the July 23, 2024, we can now report that patients who had received one prior chemotherapy regimen for metastatic PDAC with G12X mutations and who received RMC-6236 monotherapy across the dose levels of 160 to 300 mg daily, achieved a median PFS of 8.5 months with a median OS of 14.5 months.

詳細資訊可以在我們公司網站 revmed.com 的活動和演示頁面上找到。從 RMC-6236 開始，隨著數據的成熟，截至 2024 年 7 月 23 日的數據截止，我們現在可以報告先前接受過一種針對 G12X 突變的轉移性 PDAC 化療方案並接受 RMC-6236 治療的患者每日160 至300 mg 劑量水平的單藥治療實現了8.5 個月的中位PFS 和14.5 個月的中位OS。

For all second line patients with RAS mutant PDAC at these dose levels, the median PFS was 7.6 months and median OS was 14.5 months. At these doses including the highest dose of 300 mg daily. The safety and tolerability profile was manageable and the average dose intensity of RMC-6,236 was 92%. The overall response rate for patients with G12X tumors in the second line setting at these doses was 29%, also reflecting increasing maturation of the data.

對於這些劑量等級的所有患有 RAS 突變 PDAC 的二線患者，中位 PFS 為 7.6 個月，中位 OS 為 14.5 個月。這些劑量包括每日 300 毫克的最高劑量。RMC-6,236 的安全性和耐受性狀況可控，平均劑量強度為 92%。在這些劑量下，二線治療中 G12X 腫瘤患者的整體緩解率為 29%，也反映了數據的日益成熟。

This clinical profile is clearly encouraging and the robustness of these data continue to justify our optimism about RASolute 302, our Phase 3 registrational study in patients who have received one prior line of therapy for metastatic pancreatic cancer. This study is actively recruiting patients as highlighted in last month's press release announcing the first patient dosed in the study.

這項臨床概況顯然令人鼓舞，這些數據的穩健性繼續證明我們對 RASolute 302 持樂觀態度，RASolute 302 是我們針對先前接受過一種轉移性胰腺癌治療的患者進行的 3 期註冊研究。正如上個月的新聞稿中所強調的那樣，該研究正在積極招募患者，該新聞稿宣布了該研究中第一位患者的用藥。

Moving to RMC-9805, our RAS(ON) G12D selective inhibitor. At the Triple meeting last month, we presented the initial clinical data from the Phase 1 monotherapy study of RMC-9805 with a main focus on patients with PDAC. As of the September 2, 2024 data cutoff date RMC-9805 demonstrated encouraging preliminary clinical antitumor activity.

轉向 RMC-9805，我們的 RAS(ON) G12D 選擇性抑制劑。在上個月的三方會議上，我們展示了 RMC-9805 單藥治療 1 期研究的初步臨床數據，主要關注 PDAC 患者。截至 2024 年 9 月 2 日的數據截止日期，RMC-9805 表現出令人鼓舞的初步臨床抗腫瘤活性。

We reported a 30% objective response rate and an 80% disease control rate for patients treated with 200 milligrams daily, which is the candidate recommended Phase 2 dose. RMC-9805 was well tolerated at this dose level with manageable and predominantly low grade treatment related adverse events.

我們報告稱，每天接受 200 毫克（候選者建議的 2 期劑量）治療的患者的客觀緩解率為 30%，疾病控制率為 80%。RMC-9805 在此劑量水準下具有良好的耐受性，且不良事件可控制且主要為低度治療相關不良事件。

One grade three adverse event was reported amongst 179 patients. While the data are early, the safety and tolerability profile, as well as the initial read on antitumor activity are clearly encouraging. Based on our experience with RMC-6236, it will take more time for the RMC-9805 data to mature sufficiently to characterize the true overall response rate and the durability of the RMC-9805 antitumor activity as represented by the more relevant outcome measures of progression free survival and overall survival.

179 名患者中報告了一項三級不良事件。雖然數據仍處於早期階段，但安全性和耐受性概況以及抗腫瘤活性的初步研究顯然令人鼓舞。根據我們在 RMC-6236 方面的經驗，RMC-9805 數據需要更多時間才能充分成熟，以表徵真正的總體緩解率和 RMC-9805 抗腫瘤活性的持久性（以更相關的進展結果指標為代表）自由生存和整體生存。

The initial profile of 9805 is also consistent with potential use in combinations which continues to be an important strategic priority for us. The encouraging data from both RMC-6236 and RMC-9805, provide us with several options for development in RAS G12D PDAC including the RAS(ON) doublet combination of RMC-6236 with RMC-9805, which is currently undergoing clinical evaluation.

9805 的初始特徵也與組合的潛在用途一致，這仍然是我們的重要策略重點。RMC-6236 和 RMC-9805 的令人鼓舞的數據為我們提供了 RAS G12D PDAC 開發的多種選擇，包括 RMC-6236 與 RMC-9805 的 RAS(ON) 雙聯組合，目前正在進行臨床評估。

Ultimately, we hope that these agents will provide important optionality for pancreatic cancer patients with tumors harboring KRAS G12D, the largest genetically defined subset of PDAC patients. Switching gears, I'd like to share a brief overview of our work in non-small cell lung cancer.

最終，我們希望這些藥物將為攜帶 KRAS G12D 腫瘤的胰臟癌患者提供重要的選擇，KRAS G12D 是 PDAC 患者最大的基因定義子集。換個主題，我想分享我們在非小細胞肺癌領域的工作的簡要概述。

We anticipate a number of upcoming disclosures for both RMC-6236 and RMC-6291, our RAS(ON) G12C selective inhibitor. We remain fully committed and look forward to sharing the remaining 2024 data disclosures in the remaining part of the fourth quarter.

我們預期 RMC-6236 和 RMC-6291（我們的 RAS(ON) G12C 選擇性抑制劑）即將揭露。我們仍然全力以赴，並期待在第四季度的剩餘時間內分享 2024 年剩餘的數據揭露。

When we plan to share updated RMC-6236 monotherapy activity data in non-small cell lung cancer, as well as initial data from our exploratory combination studies including RMC-6236 plus pembrolizumab and the RAS(ON) inhibitor doublet of RMC-6236 plus RMC-6291.

當我們計劃分享更新的RMC-6236 單藥治療非小細胞肺癌活性數據，以及我們探索性聯合研究的初始數據時，包括RMC-6236 加派姆單抗以及RMC-6236 加RMC 的RAS(ON)抑制劑雙藥-6291。

We expect to reach regulatory alignment and initiate a Phase 3 registrational study evaluating RMC-6236 as monotherapy in patients with previously treated advanced RAS mutant non-small cell lung cancer in the first quarter of 2025.

我們預計在 2025 年第一季達成監管協調並啟動一項 3 期註冊研究，評估 RMC-6236 作為既往治療過的晚期 RAS 突變非小細胞肺癌患者的單一療法。

Now, I'd like to turn the call over to our CFO, Jack Anders to provide a financial update. Jack?

現在，我想將電話轉給我們的財務長 Jack Anders，以提供最新的財務資訊。傑克？

Thanks Steve. We ended the third quarter of 2024 with $1.55 billion in cash and investments which we project can fund planned operations into 2027 based on our current operating plan. Turning to expenses, R&D expenses for the third quarter of 2024 were $151.8 million compared to $107.7 million for the third quarter of 2023.

謝謝史蒂夫。截至 2024 年第三季度，我們擁有 15.5 億美元的現金和投資，我們預計這些現金和投資可以根據我們目前的營運計畫為 2027 年的計畫營運提供資金。說到費用，2024 年第三季的研發費用為 1.518 億美元，而 2023 年第三季的研發費用為 1.077 億美元。

The increase in R&D expenses was primarily due to increases in clinical trial related expenses for a first wave of RAS(ON) inhibitors personnel related expenses associated with additional head count and stock based compensation expense. G&A expenses for the third quarter of 2024 were $24.0 million compared to $15.5 million for the third quarter of 2023.

研發費用的增加主要是由於第一波 RAS(ON) 抑制劑臨床試驗相關費用的增加，人員相關費用與額外人員和股票補償費用相關。2024 年第三季的一般管理費用為 2,400 萬美元，而 2023 年第三季為 1,550 萬美元。

The increase in G&A expenses was primarily due to increases in personnel related expenses associated with additional headcount, commercial preparation activities and stock based compensation expense. Net loss for the third quarter of 2024, was $156.3 million compared to $108.4 million for the third quarter of 2023. The increase in that loss was due to higher operating expenses.

一般及行政費用的增加主要是由於與人員增加、商業準備活動和股票補償費用相關的人事相關費用的增加。2024 年第三季的淨虧損為 1.563 億美元，而 2023 年第三季的淨虧損為 1.084 億美元。此虧損的增加是由於營運費用增加。

We are reiterating our 2024 financial guidance and continue to expect projected full-year 2024 GAAP net loss to be between $560 million and $600 million, which includes estimated non cash stock based compensation expense of between $70 million and $80 million. That concludes the financial update.

我們重申 2024 年財務指引，並繼續預計 2024 年全年 GAAP 淨虧損將在 5.6 億美元至 6 億美元之間，其中包括估計的 7,000 萬美元至 8,000 萬美元的非現金股票補償費用。財務更新到此結束。

I'll now turn the call back over to Mark.

我現在將把電話轉回給馬克。

Thank you, Jack. Revolution Medicines continues to make substantial progress across our portfolio. The recent triple meeting presentations for RMC-6236 and RMC-9805 underscore the compelling opportunities we have to meaningfully impact outcomes among patients with PDAC based on the profiles demonstrated so far, we are advancing both programs with intensity and speed.

謝謝你，傑克。Revolution Medicines 在我們的產品組合中繼續取得實質進展。最近針對RMC-6236 和RMC-9805 的三重會議演示強調了我們擁有的令人信服的機會，根據迄今為止展示的情況，我們必須對PDAC 患者的結果產生有意義的影響，我們正在以強度和速度推進這兩個項目。

As Steve shared the PFS and OS results for RMC-6236 and previously treated PDAC patients support our optimism that if we produced in the ongoing global randomized controlled Phase 3 study, RMC-6236 could become a potential new standard of care in this setting.

正如Steve 分享的RMC-6236 的PFS 和OS 結果以及先前接受治療的PDAC 患者支持我們的樂觀態度，即如果我們在正在進行的全球隨機對照3 期研究中進行生產，RMC-6236 可能成為這種情況下潛在的新護理標準。

These data also position us well to move into evaluation in the front line PDAC setting. The initial RMC-9805 monotherapy data in PDAC are also very encouraging. We recognize it will take time for the data to mature sufficiently to provide clarity about the optimal development approach and portfolio strategy including understanding the potential for combinations.

這些數據也使我們能夠很好地進入前線 PDAC 設定的評估。PDAC 中最初的 RMC-9805 單藥治療數據也非常令人鼓舞。我們認識到，數據需要一段時間才能充分成熟，以明確最佳開發方法和投資組合策略，包括了解組合的潛力。

Nonetheless, based on their differentiated clinical profiles, we believe there should be a place for both compounds in a potential emerging targeted therapy paradigm for patients with PDAC. We're very pleased that RMC-9805 is the third RAS(ON) inhibitor from our portfolio to achieve proof of concept with an acceptable safety profile, representing important validation of our innovation engine and a significant milestone for Revolution Medicines as an organization.

儘管如此，基於它們不同的臨床特徵，我們相信這兩種化合物應該在針對 PDAC 患者的潛在新興標靶治療範例中佔有一席之地。我們非常高興RMC-9805 是我們產品組合中第三種實現概念驗證並具有可接受的安全性的RAS(ON) 抑制劑，這代表了對我們創新引擎的重要驗證，也是Revolution Medicines 作為一個組織的一個重要里程碑。

Our tricomplex platform has delivered three distinct oral inhibitors with compelling clinical profiles. This work has started new territory and oncology by targeting the oncogenic RAS(ON) protein state, an extraordinary achievement. These three investigational drugs include two covalent RAS(ON) inhibitors and one non covalent RAS(ON) inhibitor.

我們的三複合物平台提供了三種不同的口服抑制劑，具有令人信服的臨床特徵。這項工作透過針對致癌 RAS(ON) 蛋白狀態開啟了腫瘤學的新領域，這是一項非凡的成就。這三種研究藥物包括兩種共價 RAS(ON) 抑制劑和一種非共價 RAS(ON) 抑制劑。

One RAS(ON) inhibitor designed for BRET; and two designed for mutation selectivity and one RAS(ON) inhibitor that covalently irreversibly and selectively engages aberrant aspartic acid at amino acid position 12 in RAS. To our knowledge, a chemistry first in a clinical stage investigational drug.

一種專為 BRET 設計的 RAS(ON) 抑制劑；兩種設計用於突變選擇性，一種 RAS(ON) 抑制劑以共價不可逆方式選擇性地結合 RAS 氨基酸位置 12 處的異常天門冬胺酸。據我們所知，這是臨床階段研究藥物中首次出現的化學反應。

Importantly, the strength of the clinical data we've obtained with the first wave of RAS(ON) inhibitor programs highlights the clinical translatability of our discovery and pre-clinical efforts and encourages us to continue driving progress in this space.

重要的是，我們透過第一波 RAS(ON) 抑制劑計畫獲得的臨床數據的強度凸顯了我們的發現和臨床前工作的臨床可轉化性，並鼓勵我們繼續推動這一領域的進展。

In conclusion, we are successfully executing and making significant progress on our key 2024 priorities and laying the foundation for long term sustainable progress supporting our goal of revolutionizing treatment for patients with RAS addicted cancers. Initiating our first Phase 3 clinical study and second line pancreatic cancer is a significant milestone in this company's evolution and an important step in our mission to improve outcomes for patients with RAS addicted cancers.

總之，我們正在成功執行 2024 年關鍵優先事項並取得重大進展，並為長期可持續進展奠定基礎，支持我們徹底改變 RAS 成癮癌症患者治療的目標。啟動我們的第一個 3 期臨床研究和二線胰臟癌是該公司發展的一個重要里程碑，也是我們改善 RAS 成癮癌症患者治療結果的使命的重要一步。

We anticipate it will be the first of many registrational studies in patients with RAS addicted cancers. Our non-small cell lung cancer monotherapy and combination studies are ongoing and we look forward to sharing an update with you this quarter and we remain well capitalized, enabling us to continue to advance our pipeline in these high unmet need cancers.

我們預計這將是針對 RAS 成癮癌症患者的眾多註冊研究中的第一項。我們的非小細胞肺癌單藥治療和聯合治療正在進行中，我們期待在本季度與您分享最新進展，我們仍然資本充足，使我們能夠繼續推進我們在這些未滿足的高需求癌症領域的研發管線。

I'd like to take a moment to recognize and thank the patients and caregivers, clinical investigators, scientific and business collaborators, advisers and shareholders and the tireless efforts of RevMed employees on behalf of patients. Without their commitment and support, the progress we've made wouldn't be possible.

我想花一點時間向患者和照護者、臨床研究人員、科學和商業合作者、顧問和股東以及 RevMed 員工代表患者所做的不懈努力表示認可和感謝。沒有他們的承諾和支持，我們就不可能有今天的進步。

This concludes our prepared remarks for today and I'll now turn the call over to the operator for the Q&A session.

我們今天準備好的演講到此結束，現在我將把電話轉給接線生進行問答環節。

(Operator Instructions)

（操作員說明）

Peter Lawson, Barclays.

彼得·勞森，巴克萊銀行。

Great. Thanks so much. Thanks for taking the questions. I guess the first one would just be around what we should be looking for in the combination data sets that we get over the next few months to six months in terms of the combination with pembro and then the combinations between the multi and the G12C and kind of how we should be thinking about those in terms of side effect profiles versus any efficacy signals?

偉大的。非常感謝。感謝您提出問題。我想第一個是我們應該在未來幾個月到六個月內獲得的組合資料集中尋找的內容，其中包括與 pembro 的組合，然後是 multi 與 G12C 和 kind 之間的組合我們應該如何從副作用與任何功效訊號的角度來考慮這些問題？

Thank you, Peter. I appreciate the question. Well, I think there is a difference between the pembro studies and the RAS(ON) inhibitor doublet study. The pembro study is primarily a safety study. And they are the most important signal that we are zeroed in on is the hepatotoxicity signal that was seen with the first generation RAS(OFF) G12C inhibitors.

謝謝你，彼得。我很欣賞這個問題。嗯，我認為 pembro 研究和 RAS(ON) 抑制劑雙峰研究之間存在差異。pembro 研究主要是一項安全性研究。我們關注的最重要訊號是第一代 RAS(OFF) G12C 抑制劑觀察到的肝毒性訊號。

We want to clear that issue. As we've mentioned a number of times in the past, we did have data reported actually about 12 months ago that referred to patients who had recently come off of pembrolizumab, it started RMC-6236 and those patients were considered to be at high risk for hepatotoxicity, if there was a combination problem, did not really show any evidence of significant hepatotoxicity.

我們想澄清這個問題。正如我們過去多次提到的，我們確實有大約 12 個月前報告的數據，這些數據涉及最近停止使用派姆單抗的患者，開始使用 RMC-6236，這些患者被認為處於高風險對於肝毒性，如果存在組合問題，並沒有真正顯示出任何顯著肝毒性的證據。

So that gives us some level of preview. But what we have underway now is concurrent administration of the two compounds. And that's primarily what we're looking for.

這給了我們一定程度的預覽。但我們現在正在進行的是兩種化合物的同時給藥。這就是我們主要尋找的。

With the RMC-6236 plus RMC-6291 combination, we're less focused on tolerability, because we don't really have a particular issue that we anticipate needing to clear. But there we're looking for some sort of qualitative evidence that the activity that we saw, the characteristics, the profile that we saw in preclinical models in which the combination outstripped and really distinguished itself even qualitatively from the monotherapy agents that we see something that translates that into people.

透過 RMC-6236 和 RMC-6291 組合，我們不再那麼關注耐受性，因為我們實際上沒有預期需要解決的特定問題。但我們正在尋找某種定性證據，證明我們在臨床前模型中看到的活性、特徵和概況，在這些模型中，該組合超越了單一療法，甚至在定性上確實與單一療法藥物區分開來，我們看到了一些東西將其轉化為人。

And that's about the best that I can tell you today about those two studies obviously, we're getting closer to disclosing those and from here to that point, I think, we'll just have to leave it open.

這就是我今天能告訴你們的關於這兩項研究的最好信息，顯然，我們越來越接近披露這些研究，從這裡到那一點，我認為，我們只能保持開放狀態。

Great. Thank you so much.

偉大的。太感謝了。

Thank you. Michael Schmidt, Guggenheim Securities.

謝謝。邁克爾·施密特，古根漢證券公司。

Hey, guys, thanks for taking my questions. Just to follow up on the RAS(ON) inhibited doublet combination. Could you just remind us of the patient background, the patient population in that study? Is that exclusively lung cancer patients or are there other histologies included as well?

嘿，夥計們，謝謝你回答我的問題。只是為了跟進 RAS(ON) 抑制雙聯體組合。您能否提醒我們研究中的患者背景和患者群體？這僅僅是肺癌患者還是還包括其他組織學類型？

And what about prior treatment with the covalent G12C inhibitor? And then a question on the plant Phase 3 study in lung cancer, I know you sort of slightly pushed that timing out. Can you just comment on what some of the items are that you have to align with the FDA before?

那麼先前使用共價 G12C 抑制劑進行的治療又如何呢？然後是關於肺癌植物三期研究的問題，我知道你稍微推遲了這個時間。您能否簡單評論一下您之前必須與 FDA 協調的一些項目？

Sort of faded out. A little bit at the end there? But I think you were asking about the timing. What drove the timing of the of the Phase 3 lung cancer trial? Is that the second part of your question?

有點淡出。最後還有一點嗎？但我認為你問的是時間安排。是什麼推動了肺癌 3 期試驗的時機？這是你問題的第二部分嗎？

Yeah. What are some of the things that you need to align with us still with the FDA on that front?

是的。在這方面，您需要與我們和 FDA 保持哪些一致？

Yeah, so on the first question, we can't provide a lot of detail about that -- about the eligibility. Obviously, it's patients with KRAS G12C varying tumors. It's a mixture of solid tumor types, it's a mixture of prior treatment backgrounds and it'll be best understood when you see the data.

是的，所以關於第一個問題，我們無法提供有關資格的許多細節。顯然，這是患有 KRAS G12C 變異腫瘤的患者。它是實體瘤類型的混合體，是先前治療背景的混合體，當您看到數據時就會得到最好的理解。

And with regard to the lung cancer trial, I want to make it really clear that we remain committed to launching a Phase 3 registrational trial in lung cancer in the near future. And we fully expect as Steve pointed out to complete our analysis and our internal deliberations on an updated Phase 1 data set and to share these discord.

關於肺癌試驗，我想明確表示，我們仍然致力於在不久的將來啟動肺癌的第三期註冊試驗。正如史蒂夫指出的那樣，我們完全期望完成我們對更新的第一階段數據集的分析和內部審議，並分享這些不和諧之處。

But practically speaking with the December holiday, just around the corner, it's just become too much of a stretch to assume that on top of these activities, all of which are critical path to the program that we could also obtain regulatory alignment on the study details and initiate the trial before the end of the year. And simply having recognized this reality, we wanted to be transparent about it.

但實際上，十二月假期即將來臨，假設除了這些活動之外，所有這些都是該計劃的關鍵路徑，我們還可以獲得研究細節的監管一致性，這實在是太牽強了。啟動試驗。在認識到這一現實後，我們希望對此保持透明。

I do want to point out that we were able to accelerate the launch of the Phase 3 pancreatic cancer trial. We call that the RASolute 302 study. But apparently we were a bit too optimistic on the timing for the lung cancer study initiation. We will certainly continue pushing hard to achieve a lift off on this second pivotal trial as soon as practical.

我確實想指出，我們能夠加速胰臟癌三期試驗的啟動。我們稱之為 RASolute 302 研究。但顯然我們對肺癌研究啟動的時機有點過於樂觀。我們肯定會繼續努力推動第二次關鍵試驗盡快啟動。

Again, let me just emphasize that we do expect to be able to move forward, but I can't provide any more detail today. Just ask everybody to stay tuned for the promised data disclosure this quarter.

我再次強調，我們確實希望能夠取得進展，但今天我無法提供更多細節。請大家繼續關注本季承諾的數據揭露。

Great. Thanks for clarifying, Mark.

偉大的。感謝您的澄清，馬克。

Jay Olsen, Oppenheimer.

傑·奧爾森，奧本海默。

Hey, congrats on all the progress and thanks for taking the questions. Since you have a clinical collaboration with Tango Therapeutics, evaluating the combination of 6236 and 9805 with their PRMT5 inhibitor. Can you provide some color on the clinical development strategy there and indications that you're focusing on? Thank you.

嘿，祝賀所有的進展，並感謝您提出問題。由於您與 Tango Therapeutics 進行了臨床合作，因此正在評估 6236 和 9805 與其 PRMT5 抑制劑的組合。您能否提供一些有關臨床開發策略的資訊以及您關注的適應症？謝謝。

Thanks Jay. Unfortunately, no, we can't really provide any more information than what the Tango reported. We're obviously happy to be participating, but we're providing clinical drug supply to Tango who will sponsor the studies. Can't really give you more information. Other than that, we have done some pre-clinical work with that combination.

謝謝傑伊。不幸的是，我們無法提供比 Tango 報導更多的資訊。我們顯然很高興參與，但我們正在向贊助這些研究的 Tango 提供臨床藥物供應。實在無法給你更多資訊。除此之外，我們也對該組合進行了一些臨床前工作。

Each of these two agents addresses a different signaling component that may be contributing to oncogenesis in those patients who have both the RAS mutation and MTAP deletion. And so it certainly makes sense to try to suppress both of those signaling contributors and the pre-clinical results were encouraging in that regard. So we're excited to be able to help support the combination study.

這兩種藥物中的每一種都針對不同的訊號成分，這些訊號成分可能有助於同時具有 RAS 突變和 MTAP 缺失的患者的腫瘤發生。因此，嘗試抑制這兩種訊號傳導因素當然是有意義的，並且在這方面的臨床前結果令人鼓舞。因此，我們很高興能夠幫助支持聯合研究。

Great. Thank you.

偉大的。謝謝。

Thank you.

謝謝。

Marc Frahm, TD Cowen.

馬克·弗拉姆，TD·考恩。

Hi, thanks for taking my questions. I'm just following up on Michael's earlier question. Just, about a year ago, you put out the kind of initial statement that you intended to start Phase 3 for pancreatic and lung, so that kind of decision seems like it was made kind of in parallel.

您好，感謝您回答我的問題。我只是在跟進邁克爾之前的問題。就在大約一年前，您發表了最初的聲明，表示打算啟動胰臟和肺部的第三階段，因此這種決定似乎是同時做出的。

Can you just kind of explain why, how the questions you still needed to answer to actually move forward from that decision you made a year ago to starting the trial differed and kind of what, how the timelines have seem to have diverged for the two?

您能否解釋為什麼，從一年前做出的決定到開始審判，您仍然需要回答的問題有何不同，以及兩者的時間表似乎有何不同？

I don't really think there's much color we can get to that. I mean, the steps that we have to go through for those are essentially the same.

我真的認為我們沒有太多的色彩可以做到這一點。我的意思是，我們必須執行的步驟本質上是相同的。

And enrollment phases can differ. It's just a practical reality, it's very hard to predict a year ago exactly what they will be able to start a study. I don't think there's really much more to be able to provide than that.

且註冊階段可能有所不同。這只是一個現實的現實，很難在一年前準確預測他們將能夠開始一項研究。我認為沒有什麼比這更能提供的了。

Okay. And then maybe not so much about the Tango collaboration itself, but just talk through kind of your strategy moving forward with kind of novel combinations. Just how are you approaching that with 6,236? Should we see a lot more of these deals or these types of collaborations or is this more of a one off?

好的。然後，也許不會過多談論 Tango 合作本身，而只是談談你們以新穎的組合推進的策略。你是如何用 6,236 來達成這個目標的？我們是否應該看到更多這樣的交易或此類類型的合作，或者這只是一次性的？

I doubt it's going to be a one-off. We have a long list of requests for collaboration for accommodation with RMC-6236. It almost overwhelms us just in terms of reviewing the list, but -- so I do expect there will be other agents, other targets, other things for which we'll do collaborative studies. Of course, we prioritized the studies that we feel we need to do as priority studies.

我懷疑這將是一次性的。我們有一長串與 RMC-6236 合作住宿的請求。就審查清單而言，它幾乎讓我們不知所措，但是——所以我確實預計還會有其他藥物、其他目標、其他我們將進行合作研究的東西。當然，我們優先考慮我們認為需要做的研究作為優先研究。

And you know what those are. We're combining RMC-6236 with other RAS(ON) inhibitors. We're combining RMC-6236 with pembrolizumab. We're combining RMC-6236 with chemotherapy and various combinations -- multiplex combinations of those. So those are our near-term priorities, but I do expect there will be other combination studies that will emerge over time.

你知道那些是什麼。我們將 RMC-6236 與其他 RAS(ON) 抑制劑結合。我們將 RMC-6236 與 pembrolizumab 結合。我們將 RMC-6236 與化療和各種組合結合—這些組合的多重組合。因此，這些是我們近期的優先事項，但我確實預計隨著時間的推移將會出現其他組合研究。

Okay. Thank you.

好的。謝謝。

Thank you. Alec Stranahan, Bank of America.

謝謝。亞歷克·斯特拉納漢，美國銀行。

Hey guys, thanks for taking our questions. Just looking ahead to the preclinical AML data. We should expect that at ASH. Curious to hear your thoughts around the application of the RAS(ON) platform to liquid tumors and maybe what you'd want to see to proceed to clinical studies here and any color around combinations in the setting seems like fedratinib and venetoclax or maybe some options being considered based on the abstract. Thank you.

嘿夥計們，感謝您提出我們的問題。展望臨床前 AML 數據。我們應該在 ASH 上期待這一點。很想聽聽您對RAS(ON) 平台在液體腫瘤中的應用的想法，也許您希望看到什麼以繼續進行臨床研究，以及該設置中組合周圍的任何顏色似乎是fedratinib 和Venetoclax 或者可能是一些選擇根據摘要進行考慮。謝謝。

To be true, Alex. The hematology component of our program has almost been completely outsourced to academic collaborators up to now and they're going to be the ones that will be presenting data at ASH and other meetings going forward. We have been so focused on pancreatic cancer, non-small cell lung cancer and colorectal cancer that we have not really had an opportunity to plan any clinical development in some of the more infrequent tumors that carry RAS mutations like AML.

說實話，亞歷克斯。到目前為止，我們計畫的血液學部分幾乎完全外包給學術合作者，他們將在 ASH 和其他會議上展示數據。我們一直如此關注胰腺癌、非小細胞肺癌和結直腸癌，以至於我們沒有真正有機會計劃針對一些攜帶 RAS 突變（如 AML）的罕見腫瘤進行任何臨床開發。

We do appreciate the mechanistic basis there and the unmet medical need and that is increasing, of course, as it becomes clear that one of the major mechanisms by which AML escapes from targeted therapies like FLT3 inhibitors is through acquisition of RAS mutation.

我們確實欣賞那裡的機制基礎和未滿足的醫療需求，當然，這種需求正在增加，因為很明顯，AML 逃避 FLT3 抑制劑等標靶治療的主要機制之一是透過獲得 RAS 突變。

But right now for a relatively medium sized biotech company on the west coast of the United States, it's not a top priority for us, but we do very much appreciate the work that's being done by the academic collaborators that might set us up for a clinical development at some point in the not too distant future.

但目前對於美國西海岸一家相對中等規模的生物技術公司來說，這不是我們的首要任務，但我們非常感謝學術合作者所做的工作，這些工作可能會為我們的臨床研究奠定基礎。的將來的某個時刻發展。

Makes sense. Thank you.

有道理。謝謝。

Thank you. Jonathan Chang, Leerink Partners.

謝謝。喬納森·張 (Jonathan Chang)，Leerink 合夥人。

Hi guys. Thanks for taking the question. Just one for me. On cash runway guidance, can you provide some color on what's baked into the runway guidance specifically? What's baked in terms of the different ways you could proceed in pancreatic cancer and lung cancer across your pipeline? Thank you.

嗨，大家好。感謝您提出問題。只給我一個。關於現金跑道指南，您能否具體說明跑道指南中包含的內容？您在治療胰臟癌和肺癌方面有哪些不同的方法？謝謝。

Thanks, Jonathan. I think Jack can comment on that.

謝謝，喬納森。我認為傑克可以對此發表評論。

Yes. With regards to the cash guidance, what's baked in there is the two Phase 3 second line studies that we've disclosed that we are moving ahead with. Beyond that, we use a probability adjusted model with regards to costs and each -- there is a multitude of potential opportunities and programs that we push forward in additional pivotal trials.

是的。關於現金指導，其中包括我們已經揭露的兩項三期二線研究，我們正在推進這些研究。除此之外，我們使用關於成本和每一項的機率調整模型——我們在額外的關鍵試驗中推進了許多潛在的機會和計劃。

But we use the probability adjusted model. So we don't -- we can't really describe specifically what additional programs are in the cash runway forecast. But what's fully baked in there are those two Phase 3 second long trials.

但我們使用機率調整模型。所以我們不能真正具體描述現金跑道預測中有哪些額外項目。但其中完全成熟的是那兩個第三階段的第二次長期試驗。

Understood. Thank you.

明白了。謝謝。

Thank you. (Operator Instructions) Eric Joseph, J.P. Morgan.

謝謝。（操作員說明）Eric Joseph，J.P. Morgan。

Yeah, thank you. Thanks for taking the questions. Just on the combination work of 6236 with pembrolizumab, I'm curious to know if you're also looking at combinations of triplets 6236 pembro and chemotherapy. I guess, how do you think about the strategic utility of that triplets regimen potentially as you look to expand in frontline opportunities in non-small cell lung cancer?

是的，謝謝。感謝您提出問題。關於 6236 與 pembrolizumab 的聯合治療，我很想知道您是否也在考慮三聯體 6236 pembro 與化療的聯合治療。我想，當您希望擴大非小細胞肺癌的第一線機會時，您如何看待三胞胎療法的潛在策略效用？

Wei, you want to comment on that?

魏，你想對此發表評論嗎？

Yeah. Within the study, the, what you refer to as triplet, really, it's a quadruplet of our 6236 plus pembro plus platinum doublet chemotherapy that's actually go into the protocol itself. So, the we're actually doing it sequentially after clearing, identifying the appropriate dose for the doublet of 6236 plus pembro and we'll initiate the combination with the chemotherapy, not at all. So both will be ultimately (inaudible)

是的。在這項研究中，你所說的三聯療法，實際上是我們的 6236 加 pembro 加鉑雙聯化療的四聯療法，實際上已納入方案本身。因此，我們實際上是在清除後按順序進行，確定 6236 加 pembro 的雙聯體的適當劑量，我們將開始與化療聯合使用，而不是根本。所以兩者最終都會（聽不清楚）

Okay. Got it. And just with -- just on the OpEx side, pretty significant jump this past quarter, but you're keeping full year, spend guidance intact. I'm just wondering whether there's any one time items or non-recurring items you should keep in mind and I guess how should we think about sort of the sequential ramp from here into the early part of 2025 in spend?

好的。知道了。只是在營運支出方面，上個季度出現了相當大的跳躍，但你保持了全年支出指導不變。我只是想知道是否有任何一次性項目或非經常性項目您應該記住，我想我們應該如何考慮從現在到 2025 年初支出的連續增長？

So with regards to one-time items or potential one-time items within the historical results within what we've reported to date in 2025, nothing that stands out as one-time items. If you kind of take a look at the midpoint of our guidance for 2024 and look at where we are year-to-date.

因此，就我們迄今為止報告的 2025 年歷史結果中的一次性項目或潛在一次性項目而言，沒有什麼是突出的一次性項目。如果您看一下我們 2024 年指導的中點，並看看我們今年迄今為止的情況。

So we probably are about $405 million net loss year-to-date in our -- the midpoint of our guidance is (inaudible) million, so that assumes a little bit of a ramp going into Q4 from a net loss perspective. And with regards to 2025, we haven't guided to any specific guidance and we will likely do that in the future.

因此，今年迄今為止，我們的淨虧損可能約為4.05 億美元——我們的指導中位數是（聽不清楚）100 萬美元，因此，從淨虧損的角度來看，假設進入第四季度會有一點增長。至於 2025 年，我們還沒有提供任何具體指導，但我們將來可能會這樣做。

However, I think that it's fair to assume that our expenses are going to go up. Obviously, we plan on starting two Phase 3 -- we start one Phase 3 trial and we plan on starting another. We are also kind of building out the organization, at least from a -- preparing from a commercial launch perspective. And we have a lot of opportunities outside of those two pivotal trials that we've said that we're going to be launching. So no specific guidance of 2025 outside, we do expect expense to increase.

然而，我認為假設我們的開支將會增加是公平的。顯然，我們計劃開始兩個第 3 階段——我們開始一個第 3 階段試驗，我們計劃開始另一個階段。我們也在某種程度上建立了這個組織，至少從商業發布的角度來看是如此。除了我們說過要啟動的這兩項關鍵試驗之外，我們還有很多機會。因此，外界沒有 2025 年的具體指導，我們確實預期費用會增加。

Okay, got it. Thanks for taking the questions.

好的，明白了。感謝您提出問題。

Thank you, Eric.

謝謝你，埃里克。

Thank you. Laura Prendergast, Raymond James.

謝謝。勞拉·普倫德加斯特，雷蒙德·詹姆斯。

Hey, guys, quick question regarding the nature paper that was published last week out of MSK that show proof of concept that 6236 actually increases RAS G12X CCPA activity is just a mechanism that you guys have also been looking at internally. And just, generally any comments on how you're thinking about this especially in regards to potential combinations or just in general. Thank you.

嘿，夥計們，關於 MSK 上週發表的自然論文的一個簡單問題，該論文顯示了 6236 實際上增加 RAS G12X CCPA 活性的概念證明，這只是你們內部也一直在研究的一種機制。只是，一般來說，關於您如何看待這個問題的任何評論，特別是在潛在組合或一般情況下。謝謝。

Yeah, hi. Thanks, Laura. Yeah, of course, we're very aware of this additional mechanism and in fact, we discovered it some time ago and we first disclosed it ourselves at an NCI RAS scientific conference a few years ago.

是的，嗨。謝謝，勞拉。是的，當然，我們非常清楚這個額外的機制，事實上，我們不久前就發現了它，並且我們在幾年前的 NCI RAS 科學會議上首次披露了它。

So, yes, we're quite familiar with it. We think it's quite interesting. It may in fact 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 that have a lower level of RAS(ON) signaling. So we were happy to see it. We were familiar with the work for sure and helped lay the foundation for it. And we think it is likely to be a contributor to RMC-6236.

所以，是的，我們對此非常熟悉。我們認為這很有趣。事實上，與 RAS(ON) 訊號水平較低的正常細胞相比，它可能透過在 RAS(ON) 訊號上調的癌細胞中更多地影響 RAS 訊號，從而有助於 RMC-6236 的治療指數。所以我們很高興看到它。我們確實熟悉這項工作並為其奠定了基礎。我們認為它很可能是 RMC-6236 的貢獻者。

Great. Thank you.

偉大的。謝謝。

Thank you. Eliana Merle, UBS.

謝謝。埃利安娜梅爾，瑞銀。

Hey guys, It's Sam on for Eli guess, just as you're thinking about a potential Phase 3 study in first line PDAC, I guess, what are the different potential strategies that you could be kind of looking for here? And then like in terms of timing, would this be something where you would potentially wait for second line data?

嘿夥計們，我是 Sam，Eli 猜想，正如您正在考慮一線 PDAC 的潛在 3 期研究一樣，我想您可能會在這裡尋找哪些不同的潛在策略？然後就像在時間方面一樣，您是否可能會等待第二行資料？

Or could we potentially see the second line and first line studies being run in parallel and related to this. And moving into the first line, just like mechanistically is graphic like more or less of a driver and like, I guess how it might we expect efficacy to translate into this earlier setting? Thanks.

或者我們可能會看到二線和第一線研究並行並與此相關。進入第一行，就像機械上是圖形一樣，或多或少是一個驅動程式之類的，我想我們如何期望將功效轉化為這個早期的設定？謝謝。

Okay, thank you for the questions. I think there were three questions in there and I think I remember two of them. So the one I remember most is are we waiting for results from the Phase 3 second line study before launching a first line study. That one's the easiest one.

好的，謝謝你的提問。我想裡面有三個問題，我想我記得其中兩個。所以我記得最清楚的是，我們在啟動第一線研究之前等待第三階段二線研究的結果。這是最簡單的一個。

No, we'll move into that first line study as soon as we have the regimen sorted out, the optimized regimen and overall trial design that I think sets up. What do we have to -- what's going to be in that study and how are we going to get there? Maybe, Wei can talk to us a little bit about the various things that we have going on, helping us determine what we might include in that.

不，一旦我們整理出治療方案、優化的治療方案和我認為建立的整體試驗設計，我們就會進入第一線研究。我們必須做什麼——這項研究將包括什麼以及我們如何實現這一目標？也許，魏可以和我們談談我們正在進行的各種事情，幫助我們確定我們可以在其中包含哪些內容。

Yeah, happy to answer that. So right now, I think we believe the second line data with the PFS, OS exceeding the first line benchmark or the established the proof-of-concept in our mind of this agent as a monotherapy being active in the first line setting. So I think -- so we are eagerly moving forward with planning for a registrational Phase 3 with a single agent monotherapy as one of the potential therapy arms.

是的，很高興回答這個問題。因此，現在，我認為我們相信二線數據的 PFS、OS 超過了一線基準，或者在我們心中建立了該藥物作為單一療法在一線環境中發揮作用的概念驗證。所以我認為，我們正在熱切地推進註冊第三階段的計劃，以單藥單一療法作為潛在的治療手段之一。

We're also actively developing in combination with standard-of-care that includes a five review based regimen, as well as gemcitabine based regimen. And those potentially can be enabled as additional treatment arms expandable investigation arms in that Phase 3 trial. So that's kind of the way we're thinking about the first line phase. I think expanding on, I think your question, I'm going to rephrase it. Please let me know if I address it correctly.

我們也積極開發與護理標準相結合的方案，包括基於五次審查的方案以及基於吉西他濱的方案。這些可能可以在第三階段試驗中作為額外的治療組和可擴展的研究組來啟用。這就是我們考慮第一線階段的方式。我想擴展一下你的問題，我將重新表達它。如果我的地址正確，請告訴我。

I think what you're trying to ask is, do we believe that RAS is a driver across different lines of therapy, whether that changes or not and whether the efficacy could potentially change or not. I think, number one, I think we do believe that RAS is a fundamental driver regardless of line of therapy and without providing selective pressure with a RAS inhibitor in any line of therapy, then the sensitivity to remain the same across lines because there has not been a selective pressure resistance at all. Therefore, we do believe the second line proof-of-concept should be able to translate to the first line.

我想你想問的是，我們是否相信 RAS 是不同療法的驅動因素，無論這種變化是否發生變化，以及療效是否可能改變。我認為，第一，我認為我們確實相信RAS 是一個基本驅動因素，無論採用何種治療方案，並且在任何治療方案中不使用RAS 抑制劑提供選擇性壓力，那麼跨系列的敏感性保持相同，因為沒有根本就是選擇性壓力抵抗。因此，我們確實相信第二行概念驗證應該能夠轉化為第一行。

We have also shown data for third line, which really demonstrate that it's also active in the third line plus patients and so validating that scientific concept. And in that comparison between second line and third line data, we've shown that we're more than double the PFS in either line.

我們也展示了第三線的數據，這確實顯示它在第三線及患者中也很活躍，因此驗證了這個科學概念。在第二行和第三行資料之間的比較中，我們表明，任一行的 PFS 都增加了一倍以上。

And I think among target therapy, there's this concept of treatment effect built in terms of measure by hazard ratio, right. So proportionally, we actually have a greater than 50% risk reduction in progression in second and third line. So we hope that -- if that basic concept holds, then we can expect similar treatment effect applying to first line as well, meaning a reduction of risk for progression in first line of 50% or greater. So those are the kind of our current thinking.

我認為在標靶治療中，有一種治療效果的概念，是根據風險比來衡量的，對吧。因此，按比例計算，我們實際上將二線和三線疾病進展風險降低了 50% 以上。因此，我們希望——如果這個基本概念成立，那麼我們可以預期類似的治療效果也適用於一線用藥，這意味著一線用藥的進展風險降低 50% 或更多。這就是我們目前的想法。

Thank you so much.

太感謝了。

Thank you. Kelly Shi, Jeffries.

謝謝。凱莉·施，杰弗里斯。

Hi, this is Clara on for Kelly. Thanks for taking our questions. So we just a quick follow up question on Tango's clinical collaboration. Wondering if you can add any color on the reason for the choice of collaboration partner among other clinical PRMT5 programs? Thank you.

大家好，我是凱莉的克拉拉。感謝您回答我們的問題。我們只是快速跟進一下 Tango 的臨床合作問題。想知道您是否可以補充一下在其他臨床PRMT5計畫中選擇合作夥伴的原因？謝謝。

Yes. So you're asking about our choice, not Tango's choice of us, but our choice of Tango's compound. Sure. It looks like an interesting compound. There certainly are other compounds in the field. We've done some preclinical work with the Tango compound, as I mentioned earlier, and they've done some preclinical work with our compounds. So we have some visibility into what that combination looks like in preclinical model systems.

是的。所以你問的是我們的選擇，不是Tango選擇我們，而是我們選擇Tango的大院子。當然。它看起來是一個有趣的化合物。該領域當然還有其他化合物。正如我之前提到的，我們已經用 Tango 化合物做了一些臨床前工作，他們也用我們的化合物做了一些臨床前工作。因此，我們對這種組合在臨床前模型系統中的表現有了一定的了解。

But that doesn't mean that we wouldn't do a collaboration study with another PRMT5 inhibitor. We are actively trying to find the best combination partners for RMC-6236 and it's far too early for us to make any declarations about that. But we're happy to be in the collaboration and it's one of, as I mentioned earlier, probably many different combination studies we'll do with agents across many different disease targets.

但這並不意味著我們不會與另一種 PRMT5 抑制劑進行合作研究。我們正在積極努力尋找 RMC-6236 的最佳組合合作夥伴，現在對此做出任何聲明還為時過早。但我們很高興能夠參與合作，正如我之前提到的，這可能是我們將針對許多不同疾病目標的藥物進行的許多不同的組合研究之一。

Appreciate the color.

欣賞顏色。

I'm showing no further questions at this time. I would now like to turn it back to Mark Goldsmith, Chairman and Chief Executive Officer for closing remarks.

我目前沒有提出任何進一步的問題。現在我想請董事長兼執行長馬克‧戈德史密斯 (Mark Goldsmith) 致閉幕詞。

Thank you operator. And thank you to everyone for participating today and for your continued support of Revolution Medicines.

謝謝運營商。感謝大家今天的參與以及對 Revolution Medicines 的持續支持。

Thank you for your participation in today's conference. This does conclude the program. You may now disconnect.

感謝您參加今天的會議。這確實結束了該程式。您現在可以斷開連線。