Revolution Medicines Inc (RVMD) 2023 Q3 法說會逐字稿

Good day, and thank you for standing by. Welcome to the Revolution Medicines Q3 2023 Earnings Conference Call. (Operator Instructions). Please be advised that today's conference is being recorded.

美好的一天，感謝您的支持。歡迎參加 Revolution Medicines 2023 年第三季財報電話會議。 （操作員說明）。請注意，今天的會議正在錄製中。

I would now like to hand the conference over to your speaker, Erin Graves, Senior Director of Corporate Communications and Investor Relations. Please go ahead.

現在我想將會議交給您的演講者，企業傳播和投資者關係高級總監艾琳·格雷夫斯 (Erin Graves)。請繼續。

Thank you, and welcome, everyone, to the third quarter 2023 earnings call. Joining me on today's call are Dr. Mark Goldsmith, Revolution Medicine's Chairman and Chief Executive Officer; and Jack Anders, our Chief Financial Officer. Dr. Steve Kelsey, our President of R&D, will join us for the Q&A portion of today's call.

謝謝大家，歡迎大家參加 2023 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；和我們的財務長傑克·安德斯。我們的研發總裁 Steve Kelsey 博士將參加我們今天電話會議的問答部分。

As we begin, I would like to note that our presentation will include statements regarding the current beliefs of Revolution Medicines with respect to our business and the proposed acquisition of EQRx, including statements regarding our development plans and time lines for our portfolio and pipeline and the expected timing and benefits of the proposed acquisition, all of which are intended to be covered by the safe harbor provisions of the Private Securities Litigation Reform Act of 1995 for forward-looking statements.

在我們開始時，我想指出，我們的簡報將包括有關 Revolution Medicines 目前對我們業務和擬議收購 EQRx 的信念的聲明，包括有關我們的發展計劃以及我們的投資組合和管道的時間表以及擬議收購的預期時機和收益，所有這些都旨在涵蓋1995 年《私人證券訴訟改革法案》中前瞻性陳述的安全港條款。

These statements are subject to a number of assumptions, risks and uncertainties. Actual results may differ materially from these statements, and except as required by law, the company undertakes no obligation to revise or update any forward-looking statements.

這些陳述受到許多假設、風險和不確定性的影響。實際結果可能與這些陳述有重大差異，除非法律要求，否則本公司不承擔修改或更新任何前瞻性陳述的義務。

I encourage you to review the legal disclaimer slide of our corporate presentation, our earnings press release and all of our filings with the SEC concerning these and other matters.

我鼓勵您查看我們公司簡報的法律免責聲明幻燈片、我們的收益新聞稿以及我們向 SEC 提交的所有有關這些問題和其他事項的文件。

With that, I will turn the call over to Dr. Mark Goldsmith, Revolution Medicine's Chairman and Chief Executive Officer. Mark?

接下來，我將把電話轉給 Revolution Medicine 董事長兼執行長 Mark Goldsmith 博士。標記？

Thank you for joining us. I'd like to focus first on our remarkable headline investigational drug, RMC-6236, and try to paint the picture we see based on a couple of important weeks of data updates an extensive dialogue with investigators and clinical experts.

感謝您加入我們。我想首先關注我們引人注目的研究藥物 RMC-6236，並嘗試根據幾週重要的數據更新以及與研究人員和臨床專家的廣泛對話來描繪我們所看到的情況。

First, objectively and by hands-on investigator experience treating over 131 patients so far, RMC-6236 is well tolerated at clinically active doses, including 300 milligrams QD as reported to us by investigators. These observations with the first-ever RASMULTI inhibitor in the clinic are dogma-breaking and demonstrate clearly that this compound has a very sound therapeutic window.

首先，客觀地說，根據迄今為止治療超過 131 名患者的研究人員實際經驗，RMC-6236 在臨床活性劑量下具有良好的耐受性，包括研究人員向我們報告的 300 毫克 QD。這些對臨床上首個 RASMULTI 抑制劑的觀察結果打破了教條，清楚地表明該化合物具有非常合理的治療窗口。

Second, this profile is enabling continuity of dosing, which we believe is critical in treating RAS-addicted cancers. Patients receiving RMC-6236 have required few dose interruptions and even fewer discontinuations for intolerability. This differentiating feature of RMC-6236 is a core lever for evaluating meaningful clinical benefit.

其次，這種情況可以實現給藥的連續性，我們認為這對於治療 RAS 成癮性癌症至關重要。接受 RMC-6236 治療的患者幾乎不需要中斷劑量，甚至更少因不耐受而停藥。 RMC-6236 的這種差異化特徵是評估有意義的臨床益處的核心槓桿。

Third, despite the inter-patient variability that is typical for oral anticancer agents, RMC-6236 showed dose-dependent increase in exposure at every dose escalation tested up to and including 400 milligrams daily.

第三，儘管口服抗癌藥物存在典型的患者間差異，但 RMC-6236 在每次劑量遞增測試中顯示暴露量呈劑量依賴性增加，直至每日 400 毫克（包括每日 400 毫克）。

Fourth, RMC-6236 has shown objective anti-tumor activity, both by radiographic imaging and ctDNA quantitation against 3 oncogenic RAS genotypes for which no other targeted therapy is available, RAS-G12D, G12V and G12R. G12D and V alone account for more than half of all RAS solid tumors. And G12D, V and R mutations are the 3 most common RAS drivers of pancreatic ductal adenocarcinoma, accounting for nearly 90%.

第四，透過放射成像和 ctDNA 定量，RMC-6236 針對 3 種致癌 RAS 基因型（RAS-G12D、G12V 和 G12R，尚無其他標靶治療可用）顯示出客觀的抗腫瘤活性。僅 G12D 和 V 就佔所有 RAS 實體瘤的一半以上。 G12D、V和R突變是胰臟導管腺癌最常見的3個RAS驅動因素，佔近90%。

The results with each of these genotypes individually represents a first-in-class clinical validation for a direct RAS inhibitor and the breadth of activity is simply unique, a true RASMULTI inhibitor. It is not possible to discern any obvious relationship between dose and objective response rate by RECIST at this stage in the study, probably due to small numbers at each dose level and the bias towards short follow-up at the high dose levels. With increased numbers of patients now enrolled and ongoing maturation of the data, we expect to be able to conduct a robust exposure efficacy analysis using several outcome measures.

每種基因型的結果分別代表了直接 RAS 抑制劑的一流臨床驗證，並且活性的廣度是獨一無二的，是真正的 RASMULTI 抑制劑。在研究的這個階段，不可能透過 RECIST 辨別劑量和客觀緩解率之間的任何明顯關係，可能是由於每個劑量水平的人數較少以及高劑量水平的短期隨訪偏差。隨著現在入組患者數量的增加和數據的不斷成熟，我們期望能夠使用多種結果指標進行穩健的暴露功效分析。

The blended objective response rate in non-small cell lung cancer is already solid at 38% in the data we shared in October. Some patients are expected to develop a partial response after the first scan, we anticipate this number settling out in the 40% to 50% range at recommended Phase II dose. And objective response rate in lung cancer generally correlates with progression-free survival, so we plan to select a candidate dose to discuss with the regulators and execute the foundational work to enable a pivotal Phase III trial in second-line RAS-mutant non-small cell lung cancer to begin in 2024 while we continue collecting durability data.

根據我們 10 月分享的數據，非小細胞肺癌的綜合客觀緩解率已經穩定在 38%。預計一些患者在第一次掃描後會出現部分緩解，我們預計在建議的 II 期劑量下，這一數字將穩定在 40% 至 50% 的範圍內。肺癌的客觀緩解率通常與無惡化存活期相關，因此我們計劃選擇候選劑量與監管機構討論並執行基礎工作，以實現二線 RAS 突變非小細胞肺癌的關鍵 III 期試驗細胞肺癌將於2024 年開始，同時我們將繼續收集耐久性數據。

The blended objective response rate in pancreatic ductal adenocarcinoma in the data we shared in October was a respectable 20%, which may change as we gather more data at higher doses, follow patients on treatment longer and hone in on a go-forward dose.

我們在10 月分享的數據中，胰臟導管腺癌的綜合客觀緩解率為相當可觀的20%，隨著我們以更高劑量收集更多數據、更長時間地追蹤患者治療並不斷磨練前進劑量，這一數字可能會改變。

One relevant benchmark for comparison we've highlighted is the objective response rate for cytotoxic chemotherapy that has been reported across many studies in second-line pancreatic cancer, which hovers in the 7% to 11% range. Notably, most patients treated in the RMC-6236 study so far have had 2 or more lines of treatment previously, making them third-line or later by definition.

我們強調的一個相關比較基準是細胞毒性化療的客觀緩解率，許多二線胰臟癌研究報告的客觀緩解率徘徊在 7% 至 11% 的範圍內。值得注意的是，到目前為止，在 RMC-6236 研究中接受治療的大多數患者之前都接受過 2 種或更多線治療，根據定義，他們屬於三線或更晚的治療。

In the context of third-line or later, the reported objective response rate has been 0% to 4% while the response rate for such patients in our study was as high or higher than the overall 20% number. For all of these reasons, our expert advisers, and we believe, that RMC-6236 is performing well by this standard for patients who are facing grim prospects with standard of care.

在三線或更高級別的情況下，報告的客觀緩解率為 0% 至 4%，而我們研究中此類患者的緩解率與總體 20% 的數字一樣高或更高。基於所有這些原因，我們的專家顧問並且我們相信，對於那些在標準護理方面面臨嚴峻前景的患者來說，按此標準，RMC-6236 表現良好。

While these objective response rate observations are encouraging, we continue to emphasize that objective response rate is not the key clinical endpoint for pancreatic ductal adenocarcinoma since rapid progression with short overall survival is the norm even in those who respond initially to established treatments. We expect that doctors, patients, regulators and payers will be driven by durability of clinical benefit as indicated by progression-free survival and overall survival.

雖然這些客觀緩解率觀察結果令人鼓舞，但我們繼續強調，客觀緩解率並不是胰腺導管腺癌的關鍵臨床終點，因為即使對於那些最初對既定治療有反應的患者來說，快速進展和總生存期短也是常態。我們預計醫生、患者、監管機構和付款人將受到無惡化存活期和總存活期所顯示的臨床效益持久性的驅動。

Median progression-free survival for standard second-line pancreatic ductal adenocarcinoma treatment consistently has been reported to be approximately 3 months and may be shorter for patients beyond second-line. It's too early for us to project these parameters for RMC-6236 and it will take some time into 2024 for us to be able to establish a true median PFS.

據報道，標準二線胰臟導管腺癌治療的中位無惡化存活期約為 3 個月，二線以外的患者可能會更短。現在為 RMC-6236 預測這些參數還為時過早，到 2024 年我們還需要一些時間來建立真正的中位 PFS。

But here, there are also encouraging signs. The disease control rate we shared in October was 87%, significantly higher than most reports for salvage chemotherapy in pancreatic cancer. Many patients on study have already crossed the median PFS threshold mentioned above and remain on treatment, including as far out as 48 weeks.

但這裡也出現了令人鼓舞的跡象。我們10月分享的疾病控制率為87%，顯著高於大多數胰臟癌挽救性化療的通報。許多接受研究的患者已經超過了上述中位 PFS 閾值並繼續接受治療，包括長達 48 週的治療。

This statement is true even for patients who have not yet shown an objective response. 20% of patients without a partial response were still on drug at 18 weeks with many of these 20% having reached 21 or more weeks while continuing on drug, well past the short duration benchmark for second-line pancreatic ductal adenocarcinoma. Even the few patients with a partial response who progressed did so at 18 weeks or later. These are highly encouraging findings.

即使對於尚未表現出客觀反應的患者，這種說法也是正確的。沒有部分緩解的患者中有 20% 在 18 週時仍在用藥，其中許多 20% 的患者在繼續用藥期間已達到 21 週或更長，遠遠超過了二線胰腺導管腺癌的短期基準。即使是少數部分緩解的患者也會在 18 週或之後出現病情進展。這些都是非常令人鼓舞的發現。

Finally, we believe we have a proposed recommended Phase II dose for lung cancer in hand now, and expansions are underway to develop a robust data set we think is needed to satisfy Project Optimus. We have strong conviction about the potential clinical impact of RMC-6236 [in] serving the real unmet needs in lung cancer and with continuing consultation with advisers and engaging as appropriate with regulators. In 2024, we expect to initiate a pivotal Phase III monotherapy second-line non-small cell lung cancer trial focused on achieving full regulatory approval and with a potential accelerated approval opportunity built in via an interim analysis. Investigators globally are highly interested in participating in this study.

最後，我們相信我們現在手頭上有一個建議的肺癌 II 期建議劑量，並且正在進行擴展以開發我們認為滿足 Optimus 項目所需的強大數據集。我們堅信 RMC-6236 在滿足肺癌真正未滿足的需求方面的潛在臨床影響，並繼續與顧問協商並視情況與監管機構合作。 2024 年，我們預計將啟動一項關鍵的 III 期單一療法二線非小細胞肺癌試驗，重點是獲得監管機構的全面批准，並透過中期分析建立潛在的加速批准機會。全球研究人員對參與這項研究非常感興趣。

We are likewise excited about the potential for RMC-6236 in pancreatic cancer, where unmet needs are certainly profound. Here, PFS is the gating parameter for advancing into late-stage development since ORR is an unreliable predictor of durability. We expect to establish RMC-6236's durability profile via median PFS and identify a recommended Phase II dose in 2024.

我們同樣對 RMC-6236 在胰腺癌中的潛力感到興奮，胰腺癌的未滿足需求肯定是巨大的。在這裡，PFS 是進入後期開發的門控參數，因為 ORR 是耐久性的不可靠預測指標。我們預計透過中位 PFS 建立 RMC-6236 的耐久性概況，並在 2024 年確定建議的 II 期劑量。

With that in hand and continuing consultation with advisers and engaging as appropriate with regulators, we are designing a pivotal monotherapy trial in pancreatic cancer potentially to be initiated in 2024. Our base plan currently is a Phase III randomized trial for second-line treatment, but we are also evaluating options that could accelerate our reach into first-line. Investigators globally are highly interested in participating in this study or studies as well.

有了這些信息，並繼續與顧問協商並酌情與監管機構接觸，我們正在設計一項可能於 2024 年啟動的胰腺癌關鍵單一療法試驗。我們的基本計劃目前是二線治療的 III 期隨機試驗，但我們還在評估可以加速我們進入一線的選擇。全球的研究人員也對參與這項或多項研究非常感興趣。

Next, I'd like to comment on our exciting second investigational drug to show clinical activity, RMC-6291 for RAS G12C cancers and try to paint the picture we see based on the recent update and extensive dialogue with investigators and clinical experts.

接下來，我想評論我們令人興奮的第二種研究藥物，即RMC-6291，用於顯示臨床活性，用於RAS G12C 癌症，並嘗試根據最近的更新以及與研究人員和臨床專家的廣泛對話來描繪我們所看到的情況。

First, objectively and by investigators who have treated more than 63 patients so far, RMC-6291, is well tolerated across a wide range of clinically active doses, and so far, investigators report that it is well tolerated. Asymptomatic prolongation of QTc on electrocardiogram has been seen in some patients only infrequently exceeding the 500-millisecond threshold. Investigators broadly do not consider this laboratory finding a key limiter to clinical development of this compound.

首先，客觀地說，根據迄今為止已治療超過63 名患者的研究人員的說法，RMC-6291 在各種臨床活性劑量下具有良好的耐受性，並且到目前為止，研究人員報告其耐受性良好。在某些患者中，心電圖顯示 QTc 無症狀延長，僅偶爾超過 500 毫秒閾值。研究人員普遍認為實驗室並未發現該化合物臨床開發的關鍵限制因素。

Second, good tolerability enables continuity of treatment and patients receiving RMC-6291 have required few dose interruptions and even fewer discontinuations for intolerability.

其次，良好的耐受性可以實現治療的連續性，接受 RMC-6291 的患者幾乎不需要中斷劑量，甚至更少因不耐受而停藥。

Third, 6291 has shown objective antitumor activity, both by radiographic imaging and ctDNA quantitation in both non-small cell lung cancer and colorectal cancer.

第三，透過放射成像和 ctDNA 定量，6291 在非小細胞肺癌和結直腸癌中顯示出客觀的抗腫瘤活性。

Notably, in lung cancer, the ORR in the data we shared in October was 50% in patients who had recently progressed on prior treatment with an approved KRAS G12C(OFF) inhibitor. The only comparable reported data in similar patients using a G12C(OFF) inhibitor showed an objective response rate of 7%. Similarly, the ORR for single-agent RMC-6291 was 43% in colorectal cancer patients who had not yet experienced a RAS inhibitor, similar to reported data from G12C(OFF) inhibitors when used in combination with anti-eGFR antibodies.

值得注意的是，在肺癌方面，我們在 10 月分享的數據中，對於最近使用已獲批准的 KRAS G12C(OFF) 抑制劑進行先前治療而取得進展的患者，ORR 為 50%。使用 G12C(OFF) 抑制劑的類似患者中唯一可比較的報告數據顯示客觀緩解率為 7%。同樣，在尚未接受 RAS 抑制劑治療的結直腸癌患者中，單藥 RMC-6291 的 ORR 為 43%，與 G12C(OFF) 抑制劑與抗 eGFR 抗體聯合使用時報告的數據相似。

These results indicate 2 dimensions of clinically meaningful differentiation from other KRAS G12C inhibitors. This differentiation is highly encouraging for the potential of RMC-6291 itself as a drug, and it supports our preclinical prediction that inhibition of the RAS(ON) state in a human tumor may be biologically differentiated relative to inhibition of the RAS(OFF) state. Further, we believe this paradigm likely applies across our portfolio of RAS(ON) inhibitors boosting the probabilities of success across our entire deep pipeline.

這些結果顯示與其他 KRAS G12C 抑制劑具有臨床意義的差異的兩個維度。這種差異對於RMC-6291 本身作為藥物的潛力是非常令人鼓舞的，並且它支持我們的臨床前預測，即人類腫瘤中RAS(ON) 狀態的抑制可能相對於RAS(OFF) 狀態的抑制在生物學上有所不同。此外，我們相信這種範式可能適用於我們的 RAS(ON) 抑制劑組合，從而提高我們整個深層管道的成功機率。

Fourth, based on these findings, we believe that RMC-6291 is an investigational drug with a profile that deserves to be evaluated in a late-stage development program. There remains several options to be considered and strategic decisions will need to be made among them based on further data we are collecting. These include monotherapy approaches built directly upon the differentiated response profile described above, and we are currently conducting monotherapy dose optimization with the goal of selecting the single-agent recommended Phase II dose with a Project Optimus data package that supports it.

第四，基於這些發現，我們認為 RMC-6291 是一種研究藥物，值得在後期開發計劃中進行評估。仍有幾個選項需要考慮，並且需要根據我們收集的進一步數據在其中做出策略決策。其中包括直接建立在上述差異化反應特徵基礎上的單一療法，我們目前正在進行單一療法劑量優化，目標是選擇單藥推薦的 II 期劑量以及支持它的 Project Optimus 數據包。

We are also committed to evaluating several compelling combination options very soon, and indeed, have already begun recruiting for the exciting pairing of RMC-6236 plus RMC-6291 based on compelling preclinical observations.

我們也致力於很快評估幾種令人信服的組合選項，事實上，基於令人信服的臨床前觀察，我們已經開始招募 RMC-6236 與 RMC-6291 的令人興奮的配對。

In aggregate, these findings are highly encouraging and point to large opportunities ahead for these first 2 compounds. Based on this momentum, we look forward to completing the acquisition of EQRx.

總的來說，這些發現非常令人鼓舞，並指出前兩種化合物面臨著巨大的機會。基於這一勢頭，我們期待完成對 EQRx 的收購。

Let me summarize the status briefly. We expect to acquire EQRx in an all-stock transaction to gain an estimated $1.1 billion in additional net capital after estimated post-closing EQRx wind-down and transition costs, a significant quantum of capital that can be deployed for Rev Med programs and more than we had estimated conservatively when we signed the deal. Our strengthened balance sheet is intended to enable the larger investments needed to support the parallel data-driven, late-stage development for our RAS(ON) inhibitor pipeline focused initially on RMC-6236, -6291 and -9805.

讓我簡單總結一下現狀。我們預計透過全股票交易收購 EQRx，在估計交割後 EQRx 逐步縮減和過渡成本後，將獲得估計 11 億美元的額外淨資本，這是可用於 Rev Med 項目的大量資本，並且超過我們在簽署協議時進行了保守估計。我們強化的資產負債表旨在實現更大的投資，以支持我們最初專注於 RMC-6236、-6291 和 -9805 的 RAS(ON) 抑制劑管道的平行數據驅動後期開發。

Our shareholder meeting to vote on the transaction is scheduled for November 8, 2023, at 11:00 a.m. Eastern Time and the deal is expected to close shortly following the shareholder vote, subject to satisfaction of customary closing conditions.

我們定於東部時間 2023 年 11 月 8 日上午 11:00 召開股東大會，就該交易進行投票，預計該交易將在股東投票後不久完成，但須滿足慣例成交條件。

The stock exchange ratio determined and announced last week was as follows: each common share of EQRx outstanding will be exchanged for 0.1112 common shares of Rev Med. We estimate we will be issuing approximately 55 million new shares to EQRx shareholders as part of this merger, thus acquiring approximately $20 in estimated net capital per share of the common stock issued in connection with the merger based on our updated net cash projection.

上週確定並公佈的換股比例如下：每股已發行的 EQRx 普通股將兌換 0.1112 股 Rev Med 普通股。我們估計，作為此次合併的一部分，我們將向 EQRx 股東發行約 5,500 萬股新股，從而根據我們更新的淨現金預測，獲得與合併相關發行的普通股每股約 20 美元的淨資本。

Revolution Medicines will continue to focus on our mission to revolutionize treatment for patients with RAS-addicted cancers through the discovery, development and delivery of innovative targeted medicines.

Revolution Medicines 將繼續專注於我們的使命，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。

Now let's hear from Jack Anders, our CFO, regarding our Q3 financials. Jack?

現在讓我們聽聽我們的財務長傑克·安德斯 (Jack Anders) 講述我們第三季度的財務狀況。傑克？

Thank you, Mark. Turning to our third quarter financials. We ended the quarter with $813.2 million in cash, cash equivalents and investments. Please note, this balance does not include any net proceeds from the anticipated acquisition of EQRx, which is expected to add approximately $1.1 billion in net cash proceeds should the transaction close.

謝謝你，馬克。轉向我們第三季的財務狀況。本季結束時，我們的現金、現金等價物和投資為 8.132 億美元。請注意，該餘額不包括預期收購 EQRx 帶來的任何淨收益，如果交易完成，預計將增加約 11 億美元的淨現金收益。

Total operating expenses for the third quarter of 2023 were $123.2 million. The increase in operating expenses over the prior year period was largely due to clinical trial and manufacturing expenses for RMC-6236 and RMC-6291, an increase in research expenses associated with our preclinical portfolio and an increase in personnel-related expenses resulting from additional head count.

2023 年第三季的總營運費用為 1.232 億美元。營業費用較上年同期增加主要是由於 RMC-6236 和 RMC-6291 的臨床試驗和製造費用、與我們的臨床前產品組合相關的研究費用的增加以及因額外負責人而導致的人員相關費用的增加數數。

GAAP net loss for the third quarter of 2023 was $108.4 million or $0.99 per share.

2023 年第三季 GAAP 淨虧損為 1.084 億美元，即每股 0.99 美元。

We are updating our financial guidance and expect full year 2023 GAAP net loss to be between $385 million and $415 million, which includes estimated noncash stock-based compensation expense of $45 million to $50 million. The increase in GAAP net loss guidance is largely due to the anticipated acceleration of a portion of RMC-6236 manufacturing spend originally planned for 2024. This spend was accelerated as a result of the progress in our RMC-6236 program.

我們正在更新我們的財務指引，預計 2023 年全年 GAAP 淨虧損將在 3.85 億美元至 4.15 億美元之間，其中包括估計的 4500 萬美元至 5000 萬美元的非現金股票補償費用。 GAAP 淨虧損指引的增加主要是由於原計劃於 2024 年進行的部分 RMC-6236 製造支出的預期加速。由於我們的 RMC-6236 計劃取得進展，該支出加速。

We reiterate cash runway guidance into 2025 based on our current plan.

我們根據目前計畫重申 2025 年的現金跑道指引。

Please note that our current financial guidance excludes the impact of the proposed EQRx transaction.

請注意，我們目前的財務指引不包括擬議的 EQRx 交易的影響。

And with that, I'll now turn the call back over to Mark.

現在，我將把電話轉回給馬克。

Thank you, Jack. We believe Revolution Medicines has an unprecedented opportunity to deliver high-impact benefit to patients through our pipeline. And toward that goal, the deal with EQRx will markedly enhance our ability to bring the most out of these exciting compounds. We have heard broad and strong support for the Rev Med portfolio, approach and proposed transaction. The Board and management of Rev Med encourage all of our shareholders to vote in favor of the EQRx transaction. The employees of Revolution Medicines renew our deep commitment to outsmart cancer on behalf of patients and to build share value for our investors.

謝謝你，傑克。我們相信，Revolution Medicines 擁有前所未有的機會，可以透過我們的產品線為患者帶來高影響力的益處。為了實現這一目標，與 EQRx 的交易將顯著增強我們充分利用這些令人興奮的化合物的能力。我們聽到了對 Rev Med 投資組合、方法和擬議交易的廣泛而強有力的支持。 Rev Med 的董事會和管理層鼓勵所有股東投票支持 EQRx 交易。 Revolution Medicines 的員工重申了我們的堅定承諾：代表病患戰勝癌症，並為投資者創造股票價值。

(Operator Instructions) Our first question will come from Marc Frahm of TD Cowen.

（操作員說明）我們的第一個問題將來自 TD Cowen 的 Marc Frahm。

Recognize there's not been a lot of time since the data cuts that were presented back at ESMO and EMA, but there were a few patients who were unconfirmed but ongoing in partial responses at that time. I'm not sure if you're able to update if some of those have been able to have subsequent scans and that can actually confirm.

認識到自 ESMO 和 EMA 提交數據削減以來時間並不長，但當時有一些患者尚未得到證實，但正在進行部分緩解。我不確定您是否能夠更新其中一些是否能夠進行後續掃描並且實際上可以確認。

And then maybe a bigger philosophical question. Over those meetings, we also saw and in the last few months, we've seen a handful of trials take on docetaxel in the second-line setting in lung cancer -- a handful of different settings within lung cancer. And often, drugs that look pretty promising have struggled a bit to or even failed to beat docetaxel. Just philosophically, since the safety profile looks really good, why be aggressive and take docetaxel straight on instead of trying to combine with docetaxel since that would seem to be a much easier hurdle on the efficacy side.

然後也許是一個更大的哲學問題。在這些會議上，我們也看到，在過去的幾個月裡，我們看到了一些關於多西他賽在肺癌二線治療中的試驗——肺癌中的一些不同情況。通常，看起來很有前途的藥物很難甚至無法擊敗多西紫杉醇。從哲學上講，既然安全性看起來非常好，為什麼要積極主動地直接服用多西他賽，而不是嘗試與多西他賽聯合使用，因為這在功效方面似乎是一個更容易的障礙。

Thanks a lot, Marc. Appreciate your questions. Let me comment first on the question of confirmations. A number of those patients really had just squeaked in, in the advanced period we required in order to report them, which means that they just had one scan and it's only been a couple of weeks since then. So I think for most patients, we just don't have any more information, so I can't really provide an update today.

非常感謝，馬克。感謝您的提問。我先談談確認問題。其中一些患者確實是在我們報告所需的晚期階段才勉強進來的，這意味著他們只進行了一次掃描，而從那時起僅過了幾週。所以我認為對於大多數患者來說，我們只是沒有更多信息，所以我今天無法提供更新。

The question of docetaxel as a comparator versus -- for a monotherapy trial versus waiting for a combination, well, I think in part the question answers itself a little bit, but maybe Steve Kelsey can give you a little bit more philosophy on that.

多西紫杉醇作為比較劑與單一療法試驗與等待聯合療法的問題，嗯，我認為這個問題在一定程度上回答了自己，但也許史蒂夫·凱爾西可以給你更多關於這一點的哲學。

I think, Marc, the principle, which we're trying to carry through the whole portfolio irrespective of lines of therapy is we would like to get chemotherapy out of the equation if we possibly can. And so a good starting point would be a single-agent study against docetaxel to try and beat it, really. I think leaving chemotherapy like docetaxel in the sort of therapeutic armamentarium for patients is suboptimal, and I think that we would just rather try and beat it hands down and relegate the docetaxel to a later line of therapy, frankly.

馬克，我認為，無論採用哪種治療方案，我們都試圖在整個投資組合中貫徹的原則是，如果可能的話，我們希望將化療排除在外。因此，一個很好的起點是針對多西他賽的單藥研究，以嘗試真正擊敗它。我認為將多西他賽這樣的化療留在患者的治療設備中並不是最理想的，坦率地說，我認為我們寧願嘗試輕而易舉地擊敗它，並將多西他賽降級為後來的治療方案。

I appreciate that it is certainly an option to do -- to have docetaxel in both arms, but that's not really the philosophical basis of our portfolio.

我很欣賞，雙臂使用多西紫杉醇當然是一種選擇，但這並不是我們投資組合的真正哲學基礎。

Our next question will be coming from Eric Joseph of JPMorgan.

我們的下一個問題將來自摩根大通的埃里克約瑟夫。

I just wanted to try and get a little bit -- a little more incremental color on the tolerability profile that you're observing at the 400-milligram cohort and whether you see room to further dose escalate [and if] 500 milligrams is something that you were contemplating.

我只是想嘗試獲得一點——您在 400 毫克隊列中觀察到的耐受性概況的更多增量顏色，以及您是否認為劑量進一步增加的空間[以及如果] 500 毫克是您正在沉思。

And just as we think about your backfilling of some of the previous dose cohorts, can you just kind of elaborate a little bit on your sort of strategy there? What cohorts you're prioritizing? Perhaps whether you're opening the criteria up for patients with G12C mutation? And perhaps also just sort of how colorectal cancer patients might sort of fall within that scope? Is that a histology you're keen on sort of revisiting here within the Phase I study?

正如我們考慮您對先前的一些劑量組的回填一樣，您能否詳細說明您的策略？您優先考慮哪些群體？也許您是否正在開放 G12C 突變患者的標準？也許大腸直腸癌患者也可能屬於這個範圍？您是否熱衷於在第一階段研究中重新審視這種組織學？

Thanks a lot, Eric. I'll take the first question and Steve can comment on the second. The first about tolerability, we don't really have any incremental information compared to what we just reported 2 weeks ago. And as you know, once we have the information, we'll submit it to the dose-selection committee and they'll determine where we are with it and whether or not it's a good dose, whether or not we should advance the dose. Those determinations will be made in the right time frame with the right data.

非常感謝，埃里克。我將回答第一個問題，史蒂夫可以評論第二個問題。首先是關於耐受性，與兩週前報告相比，我們實際上沒有任何增量資訊。如你所知，一旦我們掌握了信息，我們就會將其提交給劑量選擇委員會，他們將確定我們的進展情況以及劑量是否合適，是否應該提前劑量。這些決定將在正確的時間範圍內利用正確的數據做出。

The second question, I think the question really was how are we -- what are the -- what's the range of options that we're looking at for combinations in the -- over the next 12 months? And how would we prioritize those?

第二個問題，我認為真正的問題是，在接下來的 12 個月裡，我們正在尋找哪些組合選項？我們將如何優先考慮這些？

Really, it was sort of -- it's actually more about as you are backfilling some of the prior dose cohorts to sort of take into consideration when thinking about or deflecting the Phase II recommended dose. I guess, really, it's a matter of what dose cohorts, what dose levels are you perhaps [pursuing] more aggressively prioritizing and whether sort of the patient mix going in is either perhaps being more concentrated to certain histologies or perhaps even being opened up as well.

事實上，這實際上更多的是當你回填一些先前的劑量組時，在考慮或偏離第二階段建議劑量時要考慮到這一點。我想，實際上，這取決於什麼劑量組、您可能[追求]更積極地優先考慮什麼劑量水平以及進入的患者組合是否可能更集中於某些組織學，或者甚至可能被開放為出色地。

Got it, okay. So it's about monotherapy and dose-selection. Steve, if you can comment.

明白了，好吧。所以這是關於單一療法和劑量選擇。史蒂夫，如果你能發表評論的話。

For pragmatic reasons, Eric, which are related to, firstly, the number of patients queuing up to get on the study; and secondly, the relative paucity of guidance coming from the FDA about the specific requirements for -- to fulfill the Project Optimus initiative. We are aggressively backfilling most of the dose levels actually at 300 milligrams and below. And the priority right now is to backfill it with patients who have non-small cell lung cancer and pancreatic cancer because those are the ones that the FDA are going to be interested in, in the exposure-response analysis that we submit them for when we recommend a go-forward dose into Phase III.

Eric 表示，出於務實的原因，這首先與排隊參加研究的患者數量有關；其次，FDA 相對缺乏關於實現 Optimus 計畫計畫的具體要求的指導。我們正在積極回填大部分劑量水平，實際劑量為 300 毫克及以下。現在的首要任務是用患有非小細胞肺癌和胰腺癌的患者進行回填，因為這些是 FDA 在我們提交這些患者進行的暴露反應分析中感興趣的患者。建議將劑量推進到 III 期。

There is an amendment to this protocol, which has now been approved, it's on ClinicalTrials.gov, which allows us to expand in several different histologies, including colorectal cancer and other tumor types. And it also includes -- does include G12C-mutant tumors. But that's completely separate from the exercise to select the recommended Phase II dose for both non-small cell lung cancer and pancreatic cancer, the kind of parallel activities at the moment.

該方案有一項修正案，現已在 ClinicalTrials.gov 上獲得批准，該修正案允許我們擴展到幾種不同的組織學，包括結直腸癌和其他腫瘤類型。它還包括——確實包括 G12C 突變腫瘤。但這與為非小細胞肺癌和胰腺癌選擇推薦的 II 期劑量的活動完全分開，目前這種活動是並行的。

Our next question will be coming from Jonathan Chang of Leerink Partners.

我們的下一個問題將來自 Leerink Partners 的 Jonathan Chang。

First question, how should investors be thinking about time lines for next data updates across your pipeline?

第一個問題，投資人應該如何考慮管道中下一次數據更新的時間表？

I don't have much specificity on that right now. Obviously, we've been asked that a lot over the last couple of weeks. We just need to see how things play out. I think it's pretty clear what we're trying to do in the near term, it's largely around dose selection and acquiring more durability data, and to some degree, more ORR data at higher doses.

我現在對此沒有太多具體資訊。顯然，過去幾週我們經常被問到這個問題。我們只需要看看事情會如何發展。我認為我們近期想要做的事情非常清楚，主要是圍繞劑量選擇和獲取更多的耐久性數據，以及在某種程度上，更高劑量下的更多 ORR 數據。

So I don't think we're talking years out, but I can't give you specificity. The most sort of narrow question we get asked is, will we make a presentation at ASCO and I just don't know. In order for us to do that, we'd have to submit an abstract in February, which means we have to know what it is we're going to present in May to do so. So we'll just have to see.

所以我不認為我們會討論多年，但我無法給你具體的資訊。我們被問到的最狹隘的問題是，我們是否會在 ASCO 上演講，但我不知道。為了做到這一點，我們必須在二月提交一份摘要，這意味著我們必須知道我們將在五月提交什麼內容才能這樣做。所以我們只能看看。

But we'll try to provide more clarity once we sort of get past these next couple of months and give some more specificity about expected milestones in the coming year.

但是，一旦我們度過了接下來的幾個月，我們將嘗試提供更多的清晰度，並對來年的預期里程碑提供更多具體資訊。

Understood. And second question, what do you see as the duration of disease control and PFS benchmarks in previously treated PDAC? And what do you see as sufficiently good duration of disease control and PFS data relative to those benchmarks?

明白了。第二個問題，您認為先前接受治療的 PDAC 的疾病控制持續時間和 PFS 基準是多少？相對於這些基準，您認為疾病控制持續時間和 PFS 數據夠好？

Yes, I think Steve can comment mostly on the first part of that question because that's objective information. And then as to what we consider an improvement is -- will be the subject of ongoing conversation with experts in the FDA.

是的，我認為史蒂夫可以主要評論該問題的第一部分，因為這是客觀資訊。至於我們認為的改進是什麼——將是與 FDA 專家持續對話的主題。

Yes. The benchmark right now is pretty universally set at around 3 months. There are a few series where the PFS is 2 months and one or two where it's longer than that. But the vast majority of studies that have been done in that second-line salvage setting show a 3-month PFS. And frankly, that's when the scans are done, and there's a very dramatic drop-off in freedom from progression at the point at which that second scan is done. So I think that's the key -- that's definitely the benchmark to beat.

是的。目前的基準普遍設定在 3 個月左右。有幾個系列的 PFS 為 2 個月，還有一兩個系列的 PFS 更長。但在二線挽救環境中進行的絕大多數研究均顯示 3 個月的 PFS。坦白說，當掃描完成時，在第二次掃描完成時，進展自由度急劇下降。所以我認為這是關鍵——這絕對是要超越的基準。

Your question about how good is good, I mean there are 3 constituencies that we have to satisfy here. Those are the regulators, those are the prescribers and then there's the payers and those exist in multiple geographic jurisdictions. So I think the consultations that are ongoing with those constituencies will ultimately decide what is good enough, and then we'll be able to benchmark our actual data against that and decide if that's a meaningful important improvement and decide whether to go forward and how.

你問的問題是多好才算好，我的意思是我們必須滿足三個面向的要求。這些是監管者，那些是處方者，然後是付款者，這些人存在於多個地理管轄區。因此，我認為與這些選民正在進行的磋商最終將決定什麼是足夠好的，然後我們將能夠根據我們的實際數據進行基準測試，並確定這是否是一項有意義的重要改進，並決定是否繼續以及如何繼續。

And our next question will come from Chris Shabutani of Goldman Sachs.

我們的下一個問題將來自高盛的克里斯沙布塔尼。

This is Charlie on for Chris. Just to start, wondering if you could provide some clarity on the 6236-6291 combination trial that's enrolling. Who are you actively recruiting in terms of G12C experience versus naive patients in that study?

這是查理為克里斯代言的。首先，想知道您是否可以提供一些關於正在註冊的 6236-6291 組合試用的說明。在該研究中，您正在積極招募哪些具有 G12C 經驗的患者與未接受過治療的患者？

And then my second question is just regarding the potential for tissue-agnostic approval. What does the team see as the clinical bar to reach there in terms of ORR?

然後我的第二個問題是關於與組織無關的批准的潛力。團隊認為達到 ORR 目標的臨床標準是什麼？

Just a clarification on your second question, Charlie. Were you asking about for the combination or for either of those compounds individually or just more generically?

只是澄清你的第二個問題，查理。您是詢問組合還是單獨或更一般地詢問這些化合物中的任何一種？

I guess more generically.

我想更籠統一些。

Okay. All right. Thanks.

好的。好的。謝謝。

The 6236-6291 combination protocol right now is enrolling both lung cancer and colorectal cancer patients. And the colorectal cancer cohort will prioritize patients who have not had a G12C inhibitor. The lung cancer cohort right now allows either. And we're not at the point where we're biasing in any one direction or the other right now because we're still in the dose escalation, dose finding, dose exploration mode. And it doesn't really matter, frankly, what disease or prior treatment the patient has for that purpose.

6236-6291組合方案目前正在招募肺癌和大腸癌患者。大腸直腸癌隊列將優先考慮未服用 G12C 抑制劑的患者。現在的肺癌隊列允許其中任何一種。我們現在還沒有處於任何一個方向或另一個方向上存在偏見的地步，因為我們仍然處於劑量遞增、劑量發現、劑量探索模式。坦白說，患者患有什麼疾病或之前接受過什麼治療並不重要。

So as soon as we've got a dose for that combo, then I think we'll be a little bit more selective about the patients that we want to encourage into the study and that will, to some extent, depend on what we've seen during the dose-escalation period.

因此，一旦我們獲得了該組合的劑量，那麼我認為我們會對我們想要鼓勵參與研究的患者更有選擇性，這在某種程度上取決於我們的目標在劑量遞增期間見過。

I think everybody knows accelerated approval is getting a little bit harder. The gloss is coming off at a little bit. The bar moves around depending on the indication, frankly. But accelerated approvals traditionally have been given for single agents with response rates in the sort of 25% to 30% range. And I don't expect it to be any different for a RAS inhibitor and RAS-mutant disease, particularly as the precedent that has essentially been set by the accelerated approvals of sotorasib and adagrasib.

我想每個人都知道加速批准變得有點困難。光澤有點脫落。坦白說，該條根據指示移動。但傳統上，單一藥物的加速審批反應率在 25% 至 30% 範圍內。我預期 RAS 抑制劑和 RAS 突變疾病不會有任何不同，尤其是在索托拉西和阿達格拉西的加速批准所開創的先例。

I think he was asking specifically about the tissue-agnostic, tumor-agnostic strategy.

我認為他具體詢問的是與組織無關、與腫瘤無關的策略。

Yes. I think though -- but I think the -- in the core indication -- if you pursue a tissue-agnostic strategy, there's going to be a couple of indications that are going to dominate that cohort. And I think the response rate has to be in that sort of 30% range, I think, in order for anyone to take that seriously.

是的。我認為，但我認為，在核心適應症中，如果你追求與組織無關的策略，那麼將會有幾個適應症將主導該群體。我認為回覆率必須在 30% 的範圍內，才能讓任何人認真看待這個問題。

Clearly, the point of the tissue-agnostic strategy is there are going to be some indications which are so uncommon, there's only going to be a handful of patients and you won't be able to compute a response rate with any degree of certainty. So we're really talking about the confidence intervals around the overall response rate for lead indications within that cohort.

顯然，組織不可知策略的要點是，將會有一些非常不常見的適應症，只有少數患者，您將無法以任何確定性計算緩解率。因此，我們實際上討論的是該隊列中先導適應症的總體反應率的置信區間。

One moment for our next question. It will be coming from Ami Fadia of Needham.

請稍等一下我們的下一個問題。它將來自尼達姆的 Ami Fadia。

With regards to the pivotal trial you're planning in lung, do you believe that you need to generate data in G12C patients before you begin the trial? And perhaps give us a sense of the number of patients you think you need to enroll for this type of a nested trial design.

關於您計劃在肺部進行的關鍵試驗，您是否認為在開始試驗之前需要在 G12C 患者中產生數據？也許可以讓我們了解您認為需要招募此類嵌套試驗設計的患者數量。

Thanks, Ami. I think Steve can comment on that.

謝謝，阿米。我認為史蒂夫可以對此發表評論。

I didn't quite understand the first part of your question is?

我不太明白你問題的第一部分是？

It's do we need to validate G12C in humans before...

我們是否需要先在人體驗證 G12C...

Before we include in a pivotal trial. The validation is obviously -- validation is a sort of a fairly hard-baked word. I think we want some experience in those patients before including them as a significant part of a pivotal trial. But everything that we have learned from the preclinical models would lead us to expect the activity in G12C-mutant lung cancer to be very similar to the activity in G12D- and G12V-mutant lung cancer for RMC-6236. And so I don't think we'll validate, but we're going to try and get some information that will help reassure us that what we've seen in the preclinical levels is also true in the clinic.

在我們參與關鍵試驗之前。驗證顯然是一個相當生硬的詞。我認為，在將這些患者納入關鍵試驗的重要組成部分之前，我們需要在這些患者身上獲得一些經驗。但我們從臨床前模型中了解到的一切將使我們預期 RMC-6236 在 G12C 突變型肺癌中的活性與 G12D 和 G12V 突變型肺癌中的活性非常相似。因此，我認為我們不會進行驗證，但我們將嘗試獲取一些信息，這些信息將有助於讓我們放心，我們在臨床前水平中看到的情況在臨床中也是如此。

With regards to numbers, again, we're still refining the study design. We have -- we obviously have to design that study, we have to discuss it with the regulators. And we're still debating whether the G12C mutation should be in the [nest or the anti-nest], frankly. So as soon as we have finalized, I suppose, then I think we'll be in a better position to explain what it is and what we've -- and why we've done that. Right now, there are just a little too many moving parts to be able to be as clear as we might like to be with you right now.

關於數字，我們仍在完善研究設計。我們顯然必須設計這項研究，我們必須與監管機構進行討論。坦白說，我們仍在爭論 G12C 突變是否應該在[巢或反巢]中。因此，我想，一旦我們最終確定，我們就能更好地解釋它是什麼、我們已經做了什麼——以及我們為什麼這樣做。目前，有太多的活動部件，無法像我們現在希望與您一起了解的那樣清楚。

Yes. And if I could add to that on that last point. What Steve's alluding to is sort of regardless of our confidence in the activity against G12C, there still are operational issues associated with having approved G12C inhibitors available and dozens of G12C inhibitors -- G12C(OFF) inhibitors in clinical studies.

是的。如果我可以補充最後一點的話。 Steve 所指的是，無論我們對 G12C 活性的信心如何，仍然存在與已批准的 G12C 抑制劑和數十種 G12C 抑制劑（臨床研究中的 G12C(OFF) 抑制劑）相關的操作問題。

And so there are risks associated with that cohort regardless of the performance of 6291, and so managing that is part of what we're thinking through. And that will probably have more impact on whether G12C ends up in the core nest or on the periphery because we want to make sure to protect the entirely unserved -- the population that's entirely unserved by targeted therapy today, which is the G12X without C. But we're interested in both, and we'll have to sort that out.

因此，無論 6291 的表現如何，該群體都存在風險，因此管理風險是我們正在考慮的一部分。這可能會對 G12C 最終是在核心巢還是在外圍產生更大的影響，因為我們希望確保保護完全沒有得到服務的人群——今天完全沒有得到靶向治療的人群，也就是沒有 C 的 G12X。但我們對兩者都感興趣，我們必須解決這個問題。

If I may just ask a quick follow-up. And maybe if you could sort of just explain the concept of the nested trial design. The way I understood it was you would power each subset to be able to sort of -- so okay, if you could just clarify.

我可以要求快速跟進嗎？也許您可以解釋一下嵌套試驗設計的概念。我的理解是，你將為每個子集提供動力，使其能夠某種程度 - 好吧，如果你能澄清一下的話。

Yes. No, the way it works is the core nest gets evaluated statistically first. So you enroll patients however they enroll. It has nothing to do with the sequence of enrollment. But then statistically, you test the core group that you predesignated as the core group. If that scores positively, then that permits you to go on to evaluating a larger group that still includes the core but also now includes additional patients.

是的。不，它的工作方式是首先對核心巢進行統計評估。因此，您可以按照患者的註冊方式來註冊患者。與錄取順序無關。但從統計上來說，您測試了您預先指定為核心組的核心組。如果得分為正，那麼您就可以繼續評估更大的組，該組仍然包括核心患者，但現在也包括其他患者。

And then you can keep -- I mean you could do that 100 times if you want it, you can keep recycling the statistical power. But if at any point -- you have to make sure you do it in the right order because if at any point you don't see positivity, then you no longer can go on and test even larger groups because it would be futile to do so.

然後你可以繼續——我的意思是，如果你願意的話，你可以這樣做 100 次，你可以繼續回收統計能力。但如果在任何時候——你必須確保以正確的順序進行，因為如果在任何時候你看不到積極性，那麼你就無法再繼續測試更大的群體，因為這樣做是徒勞的所以。

And our last question will come from Alec Stranahan of Bank of America.

我們的最後一個問題將來自美國銀行的亞歷克·斯特拉納漢（Alec Stranahan）。

Just a couple. At a high level, could you maybe talk about anticipated expense ramp to support the multiple mid- and late-stage studies you have planned for -6236 and the new candidates from the RAS innovation engine? I guess asked another way, how do you continue to be judicious in your spending despite having almost $2 billion in cash on the balance sheet, assuming the EQRx deal closes.

只是一對。在較高層面上，您能否談談預期的費用成長，以支持您為 -6236 計劃的多項中期和後期研究以及來自 RAS 創新引擎的新候選藥物？我想換個方式問，假設 EQRx 交易完成，儘管資產負債表上有近 20 億美元的現金，您如何繼續明智地支出。

And just quickly to clarify for non-small cell, is it safe to assume that 500 mg will not be pursued since you said that the pivotal monotherapy dose has been selected? And if so, is the reason just in terms of speed to start the registrational studies? Or was there something in the clinical data that you think makes the 500 dose a nonstarter?

快速澄清一下，對於非小細胞，既然您說已經選擇了關鍵的單藥治療劑量，那麼可以安全地假設不會採用 500 毫克嗎？如果是這樣，原因只是因為註冊研究的啟動速度嗎？或者您認為臨床數據中是否存在某些因素導致 500 劑不可能成功？

Thanks, Alec, for your questions. On the second question, let me just take care of that one and then come back to the expenses. The comment that we believe we have a recommended Phase II dose, candidate dose in hand, was specifically with regard to lung cancer where we already have a response rate that's in the zone of where it needs to be and where that is generally better correlated with durability. So we can make some good assumptions now, continue planning and kind of pre-execution and then allow the data to catch up with it in 2024.

謝謝亞歷克的提問。關於第二個問題，我先解決這個問題，然後再談談費用。我們認為我們有建議的 II 期劑量、候選劑量，特別是針對肺癌，我們已經有一個反應率，該反應率處於需要的範圍內，並且通常與肺癌相關性更好。耐用性。因此，我們現在可以做出一些很好的假設，繼續規劃和預先執行，然後讓資料在 2024 年趕上。

The question about 500 milligrams and higher really -- or 400 milligrams and higher really has to do with pancreatic ductal adenocarcinoma, but we haven't really declared that we have a recommended Phase II dose in hand. In fact, we've made it pretty clear we want to see what happens not only at 300, but at 400 milligrams. And then as we commented earlier, if we clear that dose level and dose-selection committee wants to advance to 500 milligrams, well, then that's what we'll do.

關於 500 毫克或更高的劑量，或 400 毫克或更高的劑量，確實與胰臟導管腺癌有關，但我們還沒有真正宣布我們手邊有建議的 II 期劑量。事實上，我們已經非常明確地表示，我們不僅想看看在 300 毫克濃度下會發生什麼，而且在 400 毫克濃度下會發生什麼。然後，正如我們之前評論的那樣，如果我們明確劑量水平和劑量選擇委員會希望提高到 500 毫克，那麼我們就會這麼做。

So just to separate the 2 statements, they really -- they don't go together. They're on different concepts.

因此，只是為了分開這兩個陳述，它們實際上——它們並不在一起。他們有不同的概念。

Expense ramp. Jack, you want to comment on it?

費用斜坡。傑克，你想對此發表評論嗎？

Yes. We haven't necessarily given out any specifics on forward-looking expense guidance outside of our 2023 GAAP net loss guidance. But it is fair to say that our expenses will increase from current levels. We are going to be making investments in these programs. We do need some more data in order to fully understand what those investments are.

是的。除了 2023 年 GAAP 淨虧損指引之外，我們不一定會給出任何有關前瞻性費用指引的具體細節。但可以公平地說，我們的開支將比目前的水平有所增加。我們將對這些項目進行投資。我們確實需要更多數據才能充分了解這些投資是什麼。

And I think your question is whether we're going to be judicious and -- with our spend. I mean, we obviously -- we need to make investments, but we're going to be wise about the spend on a go-forward basis. But we haven't given any specifics.

我認為你的問題是我們是否會明智地對待我們的支出。我的意思是，我們顯然需要進行投資，但我們會在未來的基礎上明智地對待支出。但我們沒有給出任何具體細節。

Yes. If I could just build on Jack's last comment there. The whole point of the transaction is to give us the capital to make the investments in '24 and '25 and beyond that we really need to make in order to maximize value creation by evaluating these first 2, 3 compounds in the right settings and to evaluate them aggressively in a competitive environment, taking into account also all the downstream commercial considerations and regulatory context, exclusivity and pricing and so on. So we will be increasing our spending, there's no doubt, but I think it will increase our productivity and maximize value creation.

是的。如果我能以傑克最後的評論為基礎就好了。交易的重點是為我們提供資金，以便在 24 年和 25 年及以後進行投資，我們確實需要進行這些投資，以便透過在正確的環境中評估前 2、3 種化合物來最大化價值創造，並在競爭環境中積極評估它們，同時考慮所有下游商業考慮和監管環境、排他性和定價等。因此，毫無疑問，我們將增加支出，但我認為這將提高我們的生產力並最大限度地創造價值。

Our focus is not immediately on [hoarding] the capital, but at the same time, obviously, we'll make data-driven decisions and we have lots of internal checks and balances to make sure that if we do so and that we do so in close alignment with a compelling strategy.

我們的重點不是立即[囤積]資本，但同時，顯然，我們將做出數據驅動的決策，並且我們有大量的內部製衡，以確保我們這樣做以及我們這樣做與令人信服的戰略緊密結合。

And I would now like to turn the conference back to Dr. Mark Goldsmith for closing remarks.

現在我想請馬克‧戈德史密斯 (Mark Goldsmith) 博士致閉幕詞。

Thank you, operator. Thanks to everyone for participating today. We appreciate your continued support of Revolution Medicines.

謝謝你，接線生。感謝大家今天的參與。我們感謝您對 Revolution Medicines 的持續支持。

This concludes today's conference. Thank you for participating. You may now disconnect.

今天的會議到此結束。感謝您的參與。您現在可以斷開連線。