Summit Therapeutics Inc (SMMT) 2024 Q3 法說會逐字稿

Good morning, and welcome to Summit Therapeutics third-quarter 2024 earnings and update call. (Operator Instructions) Please note that today's call is being recorded. (Operator Instructions)

早安，歡迎參加 Summit Therapeutics 2024 年第三季財報和更新電話會議。（操作員說明）請注意，今天的通話正在錄音。（操作員說明）

Thank you. At this time, I would like to turn the call over to Dave Gancarz, Summit Therapeutics Chief Business and Strategy Officer. You may proceed.

謝謝。現在，我想將電話轉給 Summit Therapeutics 首席業務和策略長 Dave Gancarz。您可以繼續。

Good morning and thank you for joining us. Our press release was issued earlier this morning and is available on the homepage of our website. Our Form 10-Q was also filed earlier this morning and is available on our website. Today's call is being simultaneously webcast and an archived replay will also be made available later today on our website, www.smmttx.com.

早安，感謝您加入我們。我們的新聞稿於今天早上早些時候發布，可在我們網站的主頁上找到。我們的 10-Q 表格也在今天早上早些時候提交，並可在我們的網站上取得。今天的電話會議同時進行網路直播，存檔重播也將於今天稍晚在我們的網站 www.smmttx.com 上提供。

Joining me on the call today is Bob Duggan, our Chairman of the Board and Chief Executive Officer; Dr. Maky Zanganeh, our Chief Executive Officer and President; Manmeet Soni, our Chief Operating Officer and Chief Financial Officer; and Dr. Allen Yang, our Chief Medical Officer.

今天和我一起參加電話會議的是我們的董事會主席兼執行長 Bob Duggan； Maky Zanganeh 博士，我們的執行長兼總裁； Manmeet Soni，我們的營運長兼財務長；和我們的首席醫療官楊艾倫博士。

Before we get started with the rest of the call, I would like to note that some of the statements made by our management team today and some responses to questions that we will make may be considered forward-looking statements based on our current expectations. Summit caution that these forward-looking statements are subject to risks and uncertainties that may cause actual results to differ materially from those indicated in the forward-looking statements. Please refer to our SEC filings for information about these risks and uncertainties.

在我們開始電話會議的其餘部分之前，我想指出，我們的管理團隊今天發表的一些聲明以及我們將做出的一些對問題的答复可能會被視為基於我們當前預期的前瞻性聲明。Summit 警告稱，這些前瞻性陳述存在風險和不確定性，可能導致實際結果與前瞻性陳述中所示的結果有重大差異。請參閱我們向 SEC 提交的文件，以了解有關這些風險和不確定性的資訊。

Summit undertakes no obligation to update these forward-looking statements except as required by law. Following comments from Bob, Maky and Manmeet, we will take questions. And with that, I'd like to turn the call over to Bob.

除法律要求外，Summit 不承擔更新這些前瞻性聲明的義務。根據 Bob、Maky 和 ​​Manmeet 的評論，我們將回答問題。說到這裡，我想把電話轉給鮑伯。

Thank you, Dave. Good morning, everyone. Thank you for joining us today. I'm very proud of the recent accomplishment of Team Summit and the continuing positive information to be shared surrounding Ivonescimab, our lead investigational asset. There have been several meaningful achievements around the progress of Ivonescimab since our last earnings call, both with our partners in China as well as here in the US, and Western markets.

謝謝你，戴夫。大家早安。感謝您今天加入我們。我對團隊高峰會最近的成就以及圍繞我們的主要研究資產 Ivonescimab 持續分享的積極訊息感到非常自豪。自從上次財報電話會議以來，我們與中國以及美國和西方市場的合作夥伴在 Ivonescimab 的進展方面取得了一些有意義的成就。

We continue to progress towards our mission of building an organization, making a significant positive difference in serious unmet medical needs, specifically. We intend to amend the protocol for our multi-regional Phase 3 trial, HARMONi-3, to now evaluate patients with first-line treatment for metastatic non-small cell lung cancer with both squamous and non-squamous histologies.

我們繼續朝著建立一個組織的使命邁進，特別是在嚴重的未滿足的醫療需求方面做出重大積極的改變。我們打算修改多區域 3 期試驗 HARMONi-3 的方案，以評估接受第一線治療的鱗狀和非鱗狀組織學轉移性非小細胞肺癌患者。

The prior trial design previously included only tumors or squamous histology. This is a significant immediate expansion of total addressable market of our current Phase 3 clinical trial portfolio.

先前的試驗設計先前僅包括腫瘤或鱗狀組織學。這是我們目前 3 期臨床試驗組合的總目標市場的重大立即擴張。

We will provide additional context in a few moments around HARMONi-3's expanded patient population. We have completed enrollment of our global Phase 3 HARMONi trial in patients with EGFR mutated advanced non-small cell lung cancer, who have progressed after treatment with the third-generation EGFR tyrosine kinase inhibitor or TKI. As previously announced, we expect HARMONi top line Data in mid-2025. In addition, we received Fast Track designation from the FDA for this setting in the United States.

我們稍後將提供有關 HARMONi-3 擴大的患者群體的更多背景資訊。我們已經完成了針對 EGFR 突變晚期非小細胞肺癌患者的全球 3 期 HARMONi 試驗的入組，這些患者在使用第三代 EGFR 酪氨酸激酶抑製劑或 TKI 治療後病情出現進展。如同先前所宣布的，我們預計 HARMONi 的營收數據將於 2025 年中期公佈。此外，我們也獲得了 FDA 針對美國這項設定的快速通道指定。

Following the positive results of HARMONi-2, we announced our intentions for launching a third global Phase 3 trial HARMONi-7, studying Ivonescimab monotherapy in patients with first-line metastatic non-small cell lung cancer, whose tumors have high PD-L1 expression.

繼 HARMONi-2 取得正面結果後，我們宣布打算啟動第三項全球 3 期試驗 HARMONi-7，研究 Ivonescimab 單藥治療一線轉移性非小細胞肺癌患者，其腫瘤具有高 PD-L1 表達。

Additionally, encouraging Phase 2 data featuring Ivonescimab from China, was featured at World Lung and the 2024 European Society for Medical Oncology, or ESMO, Annual Meeting in perioperative non-small cell lung cancer, as well as indications outside of non-small cell lung cancer, including advanced triple-negative breast cancer, recurrent metastatic head and neck cancer, and microsatellite-stable metastatic colorectal cancer. Each of these Phase 2 studies were sponsored by Akeso, with data generated and analyzed by Akeso.

此外，來自中國的 Ivonescimab 的令人鼓舞的 2 期數據在世界肺病和 2024 年歐洲腫瘤內科學會 (ESMO) 年會上重點介紹了圍術期非小細胞肺癌以及非小細胞肺癌以外的適應症癌症，包括晚期三陰性乳癌、復發性轉移性頭頸癌和微衛星穩定的轉移性大腸直腸癌。每項二期研究均由康方生物贊助，數據由康方生物生成和分析。

These encouraging data reflect why we are continuing to explore the expansion of our clinical development of Ivonescimab outside of metastatic non-small cell lung cancer. In addition, we raised $235 million from leading biotech investors and individuals, including insiders, extending our cash runway and increasing our resources to execute upon expansive goals. Manmeet will provide more details about our financial position in a few minutes.

這些令人鼓舞的數據反映了我們為何繼續探索將 Ivonescimab 的臨床開發擴展到轉移性非小細胞肺癌之外。此外，我們還從領先的生物技術投資者和個人（包括內部人士）籌集了 2.35 億美元，擴大了我們的現金跑道並增加了我們的資源以實現宏偉的目標。Manmeet 將在幾分鐘內提供有關我們財務狀況的更多詳細資訊。

These accomplishments have been foundational to our 2024 goals of successfully executing on our registrational Phase 3 trials while expanding our clinical development plan. Maky will further discuss these accomplishments, including additional strides taken to drive our continued belief and conviction in Team Summit and the potential of Ivonescimab in non-small cell lung cancer and indications beyond lung.

這些成就是我們 2024 年成功執行註冊 3 期試驗同時擴大臨床開發計畫的目標的基礎。Maky 將進一步討論這些成就，包括為推動我們對 Team Summit 的持續信念和信念而採取的額外步驟，以及 Ivonescimab 在非小細胞肺癌和肺癌以外適應症中的潛力。

We are a mission-driven organization with the collective goal to improve quality of life, increase potential duration of life, and resolve serious medical needs. We believe we have the right team and the right molecule in Ivonescimab to help us realize this goal.

我們是一個以使命為導向的組織，其共同目標是提高生活品質、延長潛在壽命並解決嚴重的醫療需求。我們相信 Ivonescimab 擁有合適的團隊和合適的分子來幫助我們實現這一目標。

With that, I will turn the call over to Maky for additional context and recent highlights for consideration.

至此，我將把電話轉給 Maky，以了解更多背景資訊和最近的亮點以供考慮。

Thank you, Bob, and good morning, everyone. As Bob said, I remain incredibly enthusiastic about the accomplishments of Team Summit and our partnership with Akeso. Before providing on some of the highlights, as Bob mentioned, I would like to discuss the clinical work that has been conducted with Ivonescimab.

謝謝你，鮑勃，大家早安。正如鮑伯所說，我對團隊高峰會的成就以及我們與康方的合作關係仍然充滿熱情。正如 Bob 所提到的，在介紹一些要點之前，我想先討論一下 Ivonescimab 所進行的臨床工作。

There are more than 25 clinical trials around the globe evaluating Ivonescimab across 17 tumor settings, including 9 Phase 3 trials planned, ongoing or completed, either in China or globally. While 6 of the Phase 3 programs across Summit and Akeso are currently focused in non-small cell lung cancer, 3 additional Phase 3 clinical trials have been announced by Akeso, evaluating our lead candidate in solid tumor settings beyond non-small cell lung cancer.

全球有超過 25 項臨床試驗在 17 個腫瘤環境中評估 Ivonescimab，包括在中國或全球規劃、正在進行或已完成的 9 項 3 期試驗。雖然Summit 和康方生物的6 個3 期項目目前專注於非小細胞肺癌，但康方生物也宣布了另外3 項3 期臨床試驗，評估我們在非小細胞肺癌以外的實體瘤環境中的主要候選藥物。

This includes BTC, head and neck cancer and pancreatic cancer. At Summit, we are sponsoring 2 ongoing Phase 3 clinical trials, HARMONi and HARMONi-3. We are planning to initiate HARMONi-7 in early 2025. Based on the data Bob mentioned that was released at ESMO, that I will speak more to it in a moment, we are excited to and are actively exploring expanding our Summit-led clinical development plan beyond metastatic non-small cell lung cancer. As a reminder, Ivonescimab is a only PD-1 VEGF bispecific antibody in Phase 3 in our licensed territories.

這包括 BTC、頭頸癌和胰腺癌。在 Summit 上，我們贊助了兩項正在進行的 3 期臨床試驗：HARMONi 和 HARMONi-3。我們計劃於 2025 年初啟動 HARMONi-7。根據 Bob 提到的 ESMO 上發布的數據（我稍後會詳細介紹），我們很高興並正在積極探索將我們的峰會主導的臨床開發計劃擴展到轉移性非小細胞肺癌之外。提醒一下，Ivonescimab 是我們許可地區唯一處於 3 期階段的 PD-1 VEGF 雙特異性抗體。

Ivonescimab brings these 2 highly validated mechanism of action together into one novel molecule targeting simultaneously both PD-1 and VEGF. Next, I would like to review the many achievements completed as well as discussed, some upcoming catalysts for the remainder of this year.

Ivonescimab 將這 2 種經過高度驗證的作用機制結合在一起，形成一種同時靶向 PD-1 和 VEGF 的新型分子。接下來，我想回顧一下已完成和討論的許多成就，以及今年剩餘時間的一些即將到來的催化劑。

The third quarter of 2024 was a landmark moment for Ivonescimab and its development with significant catalyst events in the form of data releases in September at the World Lung and ESMO conferences. Last month at the World Lung conference, HARMONi-2 results were featured as part of the Presidential Symposium and received a tremendous response from leading KOLs.

2024 年第三季對於 Ivonescimab 及其發展來說是一個具有里程碑意義的時刻，9 月份世界肺臟會議和 ESMO 會議上以數據發布的形式發生了重大催化事件。上個月的世界肺臟會議上，HARMONi-2 結果作為總統研討會的一部分進行了專題報道，並得到了領先 KOL 的熱烈反響。

In this head-to-head trial comparing Ivonescimab versus pembro, both as monotherapy, HARMONi-2 met its primary endpoint of progression-free survival with Ivonescimab achieving a 49% reduction in the risk of disease progression or death compared to pembro.

在這項比較 Ivonescimab 與 pembro 單一療法的頭對頭試驗中，HARMONi-2 達到了無進展生存期的主要終點，與 pembro 相比，Ivonescimab 使疾病進展或死亡風險降低了 49%。

Ivonescimab showed consistent clinically meaningful benefit across key subgroups, including patients with either PD-L1 low or PD-L1 high expressing tumors and in [squamous] and non-squamous histologies. Consistent with previous studies, Ivonescimab demonstrated an acceptable and manageable safety profile.

Ivonescimab 在關鍵亞組中顯示出一致的具有臨床意義的益處，包括 PD-L1 低表達或 PD-L1 高表達腫瘤以及[鱗狀]和非鱗狀組織學的患者。與先前的研究一致，Ivonescimab 表現出可接受且可控的安全性。

With the additional Phase 2 data released in the third quarter at both World Lung and ESMO, we continue to expand a meaningful data that has been generated with Ivonescimab in various solid tumor settings, beyond non-small cell lung cancer. We are fortunate to have created such a strong partnership in our ongoing collaboration with Akeso, as we leverage data from multiple solid tumor studies, supporting and informing Summit's own late-stage clinical development strategy in our licensed territories.

隨著第三季 World Lung 和 ESMO 發布的額外 2 期數據，我們繼續擴展 Ivonescimab 在各種實體瘤環境中生成的有意義的數據，超越非小細胞肺癌。我們很幸運能夠在與康方生物的持續合作中建立如此牢固的合作夥伴關係，因為我們利用多項實體瘤研究的數據，支持並告知 Summit 在我們許可地區的後期臨床開發策略。

In addition to touching on our current clinical development plans, we initiated our strategic alliances with the University of Texas MD Anderson Cancer Center this quarter, providing additional opportunities to evaluate Ivonescimab in tumor types and settings, in which, we have not yet tested its potential.

除了涉及我們目前的臨床開發計劃外，我們本季度還啟動了與德克薩斯大學 MD 安德森癌症中心的戰略聯盟，提供了在腫瘤類型和環境中評估 Ivonescimab 的額外機會，其中我們尚未測試其潛力。

Patients are expected to soon begin treatment and clinical development efforts will soon begin via this collaboration. After the HARMONi-2 data was announced, we have received inbound interest from physicians regarding approximately 75 proposed investigator-sponsored trials, or ISTs, in a wide range of cancer types.

預計患者很快就會開始治療，臨床開發工作也將很快透過此次合作開始。HARMONi-2 數據公佈後，我們收到了醫生對大約 75 項擬議的研究者資助試驗 (IST) 的興趣，這些試驗涉及多種癌症類型。

With meaningful updates this past quarter from Akeso's HARMONi-2 study and several Phase 2 studies, we wanted to take the opportunity to review the respective study designs and further highlight key results. We will start with HARMONi-2. HARMONi-2 is a randomized double-blind clinical trial, evaluating frontline monotherapy Ivonescimab as compared to monotherapy pembro in patients with locally advanced or metastatic non-small cell lung cancer, with positive PD-L1 expression.

隨著上個季度康方生物的 HARMONi-2 研究和多項 2 期研究的有意義的更新，我們希望藉此機會審查各自的研究設計並進一步強調關鍵結果。我們將從 HARMONi-2 開始。HARMONi-2 是一項隨機雙盲臨床試驗，在 PD-L1 表達陽性的局部晚期或轉移性非小細胞肺癌患者中評估一線單一療法 Ivonescimab 與單一療法 Pembro 的比較。

This is a single-region, multicenter Phase 3 clinical trial conducted and sponsored by Akeso in China. Our partners at Akeso generated and analyzed the data in HARMONi-2.

這是康方生物在中國進行並贊助的單區域、多中心3期臨床試驗。我們康方生物的合作夥伴在 HARMONi-2 中產生並分析了數據。

Here is the primary endpoint of progression-free survival by blinded independent radiologic review committee for the entire study at the time of the first planned interim analysis, with a median follow-up of 8.67 months, demonstrating a significant improvement for Ivonescimab with a hazard ratio of 0.51, corresponding to a 49% improvement over the control arm.

這是在第一次計劃的中期分析時，獨立放射學審查委員會對整個研究得出的無進展生存期的主要終點，中位隨訪時間為 8.67 個月，表明 Ivonescimab 的風險比有顯著改善0.51 ，相當於比控制臂提高了49%。

The median PFS was 11.1 months versus 5.8 months in the Ivonescimab and pembro arms, respectively. Of note, the curves begin to separate at the first point of radiographic assessments and maintain separation over the entire duration of follow-up thus far.

Ivonescimab 組和 pembro 組的 PFS 中位數分別為 11.1 個月和 5.8 個月。值得注意的是，曲線在射線照相評估的第一個點開始分離，並在迄今為止的整個追蹤期間保持分離。

The analysis of PFS subgroups reveals that the PFS benefit with Ivonescimab was observed across nearly all subgroups. Specifically, the benefit is quite comparable across the spectrum of PD-L1 expression with a hazard ratio of 0.54 for patients with PD-L1 low expressing tumors, and 0.46 for patients with tumors of high PD-L1 expression.

PFS 亞組的分析表明，幾乎所有亞組都觀察到 Ivonescimab 帶來的 PFS 獲益。具體而言，在整個 PD-L1 表達範圍內，獲益相當可比，對於 PD-L1 低表達腫瘤患者的風險比為 0.54，對於 PD-L1 高表達腫瘤患者的風險比為 0.46。

As previously discussed, and this is particularly true in the United States and Europe, monotherapy checkpoint inhibitory usage is a standard of care for patients with high PD-L1 expression. With regard to non-small cell lung cancer histology, the benefit was also similar for patients with squamous non-small cell lung cancer, who showed a hazard ratio of 0.48 favoring Ivonescimab, and those patients with tumors of non-squamous histology with a hazard ratio of 0.54 favoring Ivonescimab.

如前所述，單藥療法檢查點抑制的使用是 PD-L1 高表達患者的護理標準，在美國和歐洲尤其如此。關於非小細胞肺癌組織學，鱗狀非小細胞肺癌患者的益處也相似，其風險比為 0.48，有利於 Ivonescimab，而非鱗狀組織學腫瘤患者則有風險0.54 的比率有利於 Ivonescimab。

This slide is a strong indicator that the benefit was seen across clinical subgroups and underscores that the success of the trial overall was not driven by an especially strong performance of a subgroup.

這張投影片有力地表明，臨床亞組都看到了獲益，並強調試驗總體上的成功並不是由亞組特別強勁的表現所驅動的。

For safety, we see that there was a numerically higher rate of serious treatment-related adverse event with Ivonescimab 20.8% compared to 16.1%. This did not translate to greater treatment discontinuation or treatment-related advanced events leading to death, both of which were numerically higher in the pembro arm.

出於安全性考慮，我們發現 Ivonescimab 治療相關的嚴重不良事件發生率在數值上較高，為 20.8%，而 Ivonescimab 為 16.1%。這並沒有轉化為更多的治療中斷或導致死亡的治療相關晚期事件，這兩種情況在 pembro 組中均較高。

This pattern held true in patients with squamous non-small cell lung cancer as well, a place where anti-VEGF therapy has historically demonstrated safety risk, where there were comparable rates of serious treatment-related advanced event. Discontinuation and death in the Ivonescimab are compared with the pembro arm. This is the first randomized Phase 3 clinical trial evaluating the safety profile of Ivonescimab in the squamous population, especially confirming its tolerability in this group.

這種模式也適用於鱗狀非小細胞肺癌患者，抗 VEGF 治療歷來證明有安全風險，且嚴重治療相關晚期事件的發生率相當。將 Ivonescimab 組的停藥和死亡情況與 pembro 組進行比較。這是第一個評估 Ivonescimab 在鱗狀細胞人群中安全性的隨機 3 期臨床試驗，特別是證實了其在該群體中的耐受性。

In more detail, we see that nearly all of the higher rates of treatment-related adverse events were lab-related abnormalities, hypertension and proteinuria, but generally did not lead to discontinuation of dosing. These are conditions that are often seen by oncologists who, in general, are experienced managing this AEs.

更詳細地說，我們發現幾乎所有較高發生率的治療相關不良事件都是實驗室相關異常、高血壓和蛋白尿，但通常不會導致停藥。這些是腫瘤科醫師經常看到的情況，他們通常在處理此類不良事件方面經驗豐富。

Finally, looking at the immune-related and possibly VEGF-related advanced events. In the table to the left, we see comparable immune-related AEs with Ivonescimab compared to pembro. On the right, we see that, as expected, Ivonescimab was associated with more possibly VEGF-related AEs, both in all [grades] and Grade 3 or higher.

最後，關注免疫相關和可能與 VEGF 相關的晚期事件。在左表中，我們看到 Ivonescimab 與 pembro 的免疫相關 AE 相當。在右側，我們看到，正如預期的那樣，Ivonescimab 與更可能與 VEGF 相關的 AE 相關，無論是在所有[級別]還是 3 級或更高級別。

Importantly, however, all Grade 3 or higher AEs were all classified as Grade 3. There were no Grade 4 or Grade 5 AEs that were possibly VEGF-related in either arm of the study. The table in the bottom [right] shows that most of the possible VEGF-related advanced events represented proteinuria and hypertension.

但重要的是，所有 3 級或以上 AE 均被歸類為 3 級。在該研究的任一組中均未出現可能與 VEGF 相關的 4 級或 5 級 AE。底部[右]的表格顯示，大多數可能的 VEGF 相關晚期事件代表蛋白尿和高血壓。

There is no evidence of life threatening or fatal bleeding complications, including among patients with advanced squamous non-small cell lung cancer and in patients with central tumors, cavitary lesions and/or tumor encasing large blood vessels in this Phase 3 study.

在這項 3 期研究中，沒有證據表明存在危及生命或致命的出血併發症，包括晚期鱗狀非小細胞肺癌患者和患有中央腫瘤、空洞病變和/或腫瘤包裹大血管的患者。

As a result of the successful HARMONi-2 study and our analysis of their underlying data, we announced our plan to initiate HARMONi-7 and randomized global Phase 3 study evaluating Ivonescimab versus pembro, both monotherapy in frontline non-small cell lung cancer in the PD-L1 high expressor population.

由於 HARMONi-2 研究的成功以及我們對其基礎數據的分析，我們宣布計劃啟動 HARMONi-7 和隨機全球 3 期研究，評估 Ivonescimab 與 pembro，這兩種藥物均用於一線非小細胞肺癌的單一療法PD-L1 高表達群。

HARMONi-7 is planned with the 2 primary endpoints, progression-free survival and overall survival. We are planning for an estimated 780 patients in this registration-enabling study. Turning to HARMONi-3, as Bob mentioned, we intend to amend this randomized global Phase 3 clinical trial to include patients with tumors of non-squamous histology, in addition to continuing to enroll squamous patient.

HARMONi-7 計畫有 2 個主要終點：無惡化存活期和總存活期。我們計劃在這項註冊研究中招募約 780 名患者。至於 HARMONi-3，如 Bob 所提到的，我們打算修改這項隨機全球 3 期臨床試驗，除了繼續招募鱗狀細胞患者外，還包括非鱗狀組織學腫瘤患者。

As part of the trial amendment, their primary endpoint is intended to be updated to include 2 primary endpoints of progression-free survival and overall survival. The total sample size for this randomized multi-regional Phase 3 clinical trial has been adjusted to include an estimated 1,080 patients.

作為試驗修訂的一部分，其主要終點旨在更新為包括無惡化存活期和總存活期的 2 個主要終點。這項隨機多區域 3 期臨床試驗的總樣本量已調整為包括估計 1,080 名患者。

Expanding HARMONi-3 is the most efficient way to cover all metastatic non-small cell lung cancer patients without driver mutation. HARMONi-3 will now cover metastatic non-small cell lung cancer, both squamous and non-squamous tumors in combination with chemotherapy, and HARMONi-7 intend to cover PD-L1 high expressing tumors via monotherapy, Ivonescimab, now providing the opportunity to capture a significantly broadened addressable market as quickly as possible.

擴大HARMONi-3是涵蓋所有無驅動突變的轉移性非小細胞肺癌患者的最有效方法。HARMONi-3 現在將涵蓋轉移性非小細胞肺癌，包括與化療相結合的鱗狀和非鱗狀腫瘤，而 HARMONi-7 打算透過單一療法 Ivonescimab 覆蓋 PD-L1 高表達腫瘤，現在提供了捕獲的機會盡快顯著拓寬潛在市場。

Supporting this proposed amendment, in part, is both the result of HARMONi-2, showing benefit to patients with both squamous and non-squamous tumors, as well as the Phase 2 data that has been previously presented.

HARMONi-2 的結果在一定程度上支持了這項擬議修正案，它顯示出對鱗狀和非鱗狀腫瘤患者的益處，以及先前提供的 2 期數據。

As a reminder, updated Phase 2 data for this setting was announced at the 2024 European Lung Cancer Conference in March from the AK112-201 clinical trial centered around the cohort of patients in which Ivonescimab is combined with chemotherapy for first-line treatment of squamous and non-squamous advanced or metastatic non-small cell lung cancer in patients without actionable genomic alterations. This data was generated and analyzed by Akeso.

提醒一下，在 3 月的 2024 年歐洲肺癌會議上公佈了 AK112-201 臨床試驗的最新 2 期數據，該試驗以 Ivonescimab 與化療聯合一線治療鱗狀細胞癌和肺癌為中心。的非鱗狀晚期或轉移性非小細胞肺癌患者。此數據由康方生物產生並分析。

First-line patients with advanced or metastatic non-squamous tumors experienced a median progression-free survival of 13.3 months. In addition, first-line advanced or metastatic squamous patients experience median progression-free survival of 11.1 months. Both metrics are encouraging considering the expectation for the current standard of care in this patient population, largely driven by PD-1 inhibitors plus chemotherapy.

一線晚期或轉移性非鱗狀腫瘤患者的中位無惡化存活期為 13.3 個月。此外，第一線晚期或轉移性鱗狀細胞癌患者的中位無惡化存活期為 11.1 個月。考慮到該患者群體目前護理標準的預期（主要是由 PD-1 抑制劑加化療推動），這兩個指標都令人鼓舞。

Median overall survival was not reached in either subset of patients after a median follow-up time of approximately 22.1 months. The frequency of treatment-emergent advanced events leading to the discontinuation of Ivonescimab was 11.1% and 2.8% respectively in patients with squamous and non-squamous tumor.

中位追蹤時間約為 22.1 個月後，兩組患者均未達到中位總存活期。在鱗狀和非鱗狀腫瘤患者中，導致 Ivonescimab 停藥的治療中出現的晚期事件發生率分別為 11.1% 和 2.8%。

We are highly encouraged by the opportunity of Ivonescimab to demonstrate its potential across non-small cell lung cancer in multiple clinical settings. Finally, as we have stated, we are evaluating opportunity to expand our clinical developments beyond metastatic non-small cell lung cancer. We will review the encouraging Phase 2 data announced this past quarter at World Lung and ESMO, starting with an overview of the respective study design.

我們對 Ivonescimab 有機會在多種臨床環境中展示其治療非小細胞肺癌的潛力感到非常鼓舞。最後，正如我們所說，我們正在評估將我們的臨床開發擴展到轉移性非小細胞肺癌以外的機會。我們將回顧上個季度 World Lung 和 ESMO 公佈的令人鼓舞的第二階段數據，首先概述各自的研究設計。

At the World Lung perioperative non-small cell lung cancer, Phase 2 data was featured from AK112-205, a single-region, multicenter, open-label study of patients with Stage 2 or 3 resectable non-small cell lung cancer, with data generated analyzed by Akeso. The study was designed to assess patients receiving either Ivonescimab monotherapy or Ivonescimab plus chemotherapy prior to surgical resection, and then Ivonescimab monotherapy after surgery.

在世界肺癌圍手術期非小細胞肺癌會議上，2 期數據來自AK112-205，這是一項針對2 期或3 期可切除非小細胞肺癌患者的單區域、多中心、開放標籤研究，其中數據由康方科技分析產生。該研究旨在評估手術切除前接受 Ivonescimab 單藥治療或 Ivonescimab 加化療以及手術後接受 Ivonescimab 單藥治療的患者。

Due to the maturity of the data and the timing of the data cutoff, the results were mature for the neoadjuvant portion of the clinical trial. In September 2024, promising anti-tumor activity and safety data for Ivonescimab were presented at ESMO, featuring updated data in advanced triple-negative breast cancer, recurrent/metastatic head and neck squamous cell cancer carcinoma and metastatic microsatellite-stable colorectal cancer.

由於數據的成熟度和數據截止的時間，臨床試驗的新輔助部分的結果已經成熟。2024 年9 月，Ivonescimab 在ESMO 上公佈了有希望的抗腫瘤活性和安全性數據，其中包括晚期三陰性乳腺癌、復發/轉移性頭頸鱗狀細胞癌和轉移性微衛星穩定結直腸癌的最新數據。

The head and neck study assessed patients who receive Ivonescimab map with or without ligufalimab with PD-L1 positive, locally advanced or metastatic recurrent head and neck squamous cell carcinoma. Note that ligufalimab or AK117, is Akeso's proprietary, investigational product that is not approved by any regulatory authority, and to which, Summit does not have any license or ownership rights. The colorectal study was designed to assess patients who were randomly assigned to receive Ivonescimab, plus FOLFOXIRI with or without ligufalimab and investigational anti-CD47 monoclonal antibody.

頭頸研究評估了接受 Ivonescimab 圖譜聯合或不聯合 ligufalimab 治療的 PD-L1 陽性、局部晚期或轉移性復發性頭頸部鱗狀細胞癌患者。請注意，ligufalimab 或 AK117 是康方生物的專有研究產品，未經任何監管機構批准，Summit 不擁有任何許可或所有權。大腸直腸研究旨在評估被隨機分配接受 Ivonescimab 合併 FOLFOXIRI 合併或不合併 ligufalimab 和研究性抗 CD47 單株抗體治療的患者。

The triple-negative breast cancer study assessed patients who received Ivonescimab plus chemotherapy, either paclitaxel or nab-paclitaxel with locally advanced or metastatic TNBC. Turning now to antitumor activity and safety data from these Phase 2 studies.

三陰性乳癌研究評估了接受 Ivonescimab 加化療（紫杉醇或白蛋白結合型紫杉醇）的局部晚期或轉移性 TNBC 患者。現在轉向這些二期研究的抗腫瘤活性和安全性數據。

In preoperative non-small cell lung cancer at the time of data cutoff, 49 patients had been enrolled into the Ivonescimab plus chemotherapy arm in the neoadjuvant setting. Of these 49 patients, 39 went on to complete surgery. Of the 39 patients who received Ivonescimab plus chemotherapy in the neoadjuvant stage and completed surgery, 71.8% of patients experienced a major pathological response and 43.6% of patients experienced a pathological complete response.

截至數據截止時，在術前非小細胞肺癌中，49 名患者已入組 Ivonescimab 加化療組的新輔助治療。在這 49 名患者中，39 名繼續完成手術。在新輔助階段接受Ivonescimab合併化療並完成手術的39例患者中，71.8%的患者出現主要病理緩解，43.6%的患者出現病理完全緩解。

In the 49 patients enrolled in this cohort, median event-free survival was not yet reached after 8.9 months of the median follow-up time. The 12 months event-free survival rate was 80.3%. These results are encouraging compared to the historical data that has been observed in global pivotal studies in a similar setting. The safety profile in this Phase 2 study was acceptable and manageable. No surgeries were delayed or canceled due to the treatment-related advanced events.

在該隊列中入組的 49 名患者中，中位追蹤時間 8.9 個月後尚未達到中位無事件存活期。12個月無事件存活率為80.3%。與類似環境下的全球關鍵研究中觀察到的歷史數據相比，這些結果令人鼓舞。這項第二階段研究的安全性是可以接受且可控的。沒有手術因治療相關的晚期事件而被推遲或取消。

In colorectal cancer, at the time of data cutoff, 22 patients received Ivonescimab plus FOLFOXIRI with a median follow-up time of 9 months. 18 patients received Ivonescimab plus ligufalimab plus FOLFOXIRI, with a median follow-up time of 9.6 months.

在大腸直腸癌方面，截至數據截止時，22 名患者接受了 Ivonescimab 加 FOLFOXIRI 治療，中位追蹤時間為 9 個月。 18 名患者接受 Ivonescimab 加 ligufalimab 加 FOLFOXIRI 治療，中位追蹤時間為 9.6 個月。

All patients in both groups experienced a reduction in their tumor burden compared to their baseline tumor assessment. The overall response rate and DCR for the 39 patients combined from both groups who had at least one post-baseline tumor assessment was 84.6% and 100%, respectively. Median progression-free survival was not reached in either group at the time of this analysis.

與基線腫瘤評估相比，兩組所有患者的腫瘤負荷均減少。兩組中至少進行過一次基線後腫瘤評估的 39 名患者的整體緩解率和 DCR 分別為 84.6% 和 100%。在進行本分析時，兩組均未達中位無惡化存活期。

The safety profile in this Phase 2 study was acceptable and manageable. This response rates are very encouraging considering historical benchmarks in this setting. In addition, these patients have tumors that are considered microsatellite-stable, a setting where PD-1 therapy has not been historically successful. This is another indicator of Ivonescimab potential beyond the current PD-1 landscape.

這項第二階段研究的安全性是可以接受且可控的。考慮到這種情況下的歷史基準，這種回覆率非常令人鼓舞。此外，這些患者的腫瘤被認為是微衛星穩定的，而 PD-1 療法在歷史上並未成功。這是 Ivonescimab 超越當前 PD-1 前景的另一個指標。

In triple-negative breast cancer at the time of data cutoff, 30 patients received Ivonescimab plus chemotherapy with median follow-up time of 10.2 months.

在數據截止時的三陰性乳癌中，30 名患者接受了 Ivonescimab 加化療，中位追蹤時間為 10.2 個月。

60% of patients had previously received taxane-based chemotherapy in either the neoadjuvant or adjuvant settings in this Phase 2 data set. All patients experienced a reduction in their tumor burden compared to their baseline tumor assessment. The overall response rate and DCR for the 29 patients who had at least one post-baseline tumor assessment were 72.4% and 100%, respectively. Median progression-free survival was 9.3 months at the time of this analysis. The safety profile in this Phase 2 study was acceptable and manageable.

在此 2 期資料集中，60% 的患者之前曾在新輔助或輔助治療中接受過以紫杉烷為基礎的化療。與基線腫瘤評估相比，所有患者的腫瘤負荷均減少。至少進行過一次基線後腫瘤評估的 29 名患者的整體緩解率和 DCR 分別為 72.4% 和 100%。進行本分析時，中位無惡化存活期為 9.3 個月。這項第二階段研究的安全性是可以接受且可控的。

The PD-L1 low or negative TNBC is yet another clinical setting without PD-1 therapy as a standard of care. Moving to head and neck. At the time of data cutoff, 10 patients received Ivonescimab with median follow-up of 3.3 months, and 20 patients received Ivonescimab plus ligufalimab, with median follow-up 4.1 months. All patients had tumors with PD-L1 expression. The overall response rate and DCR for the 30 patients combined was 50% and 86.7%, respectively.

PD-L1 低或陰性 TNBC 是另一種沒有 PD-1 治療作為護理標準的臨床情況。移動到頭部和頸部。截至數據截止時，10 名患者接受 Ivonescimab 治療，中位追蹤時間為 3.3 個月，20 名患者接受 Ivonescimab 加 ligufalimab 治療，中位追蹤時間為 4.1 個月。所有患者的腫瘤均表達 PD-L1。30 名患者的整體緩解率和 DCR 分別為 50% 和 86.7%。

The safety profile in this Phase 2 study was acceptable and manageable. The third quarter of 2024 was a pivotal moment in cementing the growing confidence of Ivonescimab. Before I turn it over to Manmeet to provide a financial update, I would like to take a moment to thank our incredible team at Summit.

這項第二階段研究的安全性是可以接受且可控的。2024 年第三季是鞏固 Ivonescimab 信心不斷增長的關鍵時刻。在我將其交給 Manmeet 提供最新財務資訊之前，我想花點時間感謝 Summit 出色的團隊。

As Bob and I have described all of the accomplishments we have achieved over the past 7 quarters with Ivonescimab, this team has done a remarkable job across every team in making our goals a reality and condensing time where and when possible, to accelerate our timeline in bringing additional therapeutic options to patients with cancer. It is a tremendous honor and privilege to work with each member of team Summit, and I would like to express my heartfelt thanks to every one of our phenomenal team members.

正如鮑勃和我描述了我們在過去7 個季度中透過Ivonescimab 取得的所有成就一樣，這個團隊在每個團隊中都做了出色的工作，使我們的目標成為現實，並在可能的情況下壓縮時間，以加快我們的時間表為癌症患者帶來更多的治療選擇。能夠與 Summit 團隊的每一位成員一起工作是一種巨大的榮幸和榮幸，我要向我們每一位傑出的團隊成員表示衷心的感謝。

With that update, I will now ask Manmeet to provide details on our financial position and operational update.

隨著這項更新，我現在將要求 Manmeet 提供有關我們財務狀況和營運更新的詳細資訊。

Thank you, Maky, and good morning, everyone. We issued this morning our earnings release for the third quarter of 2024.

謝謝你，麥基，大家早安。我們今天早上發布了 2024 年第三季的收益報告。

Today, in addition to providing you with an update on our cash position, recent financing and third quarter operating expenses, I will also be providing an update on our clinical operations. On the clinical operations front, I'm really proud of the team Summit for completing the enrollment ahead of schedule for our first registrational global trial, HARMONi, in patients with EGFR mutations post-targeted therapy.

今天，除了向您提供有關我們的現金狀況、最近的融資和第三季營運費用的最新資訊外，我還將提供有關我們臨床營運的最新資訊。在臨床操作方面，我對 Summit 團隊提前完成了我們的第一個註冊全球試驗 HARMONi 的入組感到非常自豪，該試驗針對的是標靶治療後出現 EGFR 突變的患者。

We expect to have the top line data from our HARMONi trial, including patients from US and Europe in mid-2025. Also, since the release of Ivonescimab data during September 2024 at World Conference on Lung Cancer and ESMO Annual Meeting, we have seen an increase in the screening and enrollment activity for the squamous patients at our existing sites in our HARMONi trial. Additionally, we have seen lots of excitement and outreach from both academic and community physicians to participate in the development of Ivonescimab.

我們預計將於 2025 年中期獲得 HARMONi 試驗的主要數據，包括來自美國和歐洲的患者。此外，自 2024 年 9 月在世界肺癌大會和 ESMO 年會上發布 Ivonescimab 數據以來，我們發現 HARMONi 試驗現有站點的鱗狀細胞癌患者篩檢和入組活動有所增加。此外，我們也看到學術界和社區醫生對參與 Ivonescimab 的發展感到興奮和積極主動。

We believe this interest will help us in accelerating activation of additional sites and ultimately enrolling patients faster for the 2 planned trials; HARMONi-3 for addition of non-squamous arm and also for recently announced HARMONi-7 trial, which we had in 2025. On the financials front, let me start with our cash position.

我們相信這種興趣將幫助我們加速激活其他站點，並最終更快地招募患者參加兩項計劃中的試驗； HARMONi-3 用於添加非鱗狀手臂，也用於最近宣布的 HARMONi-7 試驗（我們於 2025 年進行）。在財務方面，讓我從我們的現金狀況開始。

We ended the third quarter of 2024 with a cash position of approximately $487 million. This cash position was strengthened at the end of third quarter with the closing of a $235 million private placement in September 2024 from multiple leading biotech institutional investors and insiders. Turning to operating expenses. I'll provide details to both GAAP and non-GAAP numbers. You can refer to our press release issued this morning for a reconciliation of GAAP to non-GAAP financial measures.

截至 2024 年第三季末，我們的現金部位約為 4.87 億美元。隨著 2024 年 9 月多家領先生技機構投資者和內部人士完成 2.35 億美元的私募，第三季末這一現金狀況得到了加強。轉向營運費用。我將提供 GAAP 和非 GAAP 數字的詳細資訊。您可以參閱我們今天早上發布的新聞稿，以了解 GAAP 與非 GAAP 財務指標的調整表。

To remind, non-GAAP expenses exclude stock-based compensation and onetime charges related to acquired in-process R&D expenses. Our GAAP R&D expenses during the third quarter were $37.7 million compared to $30.8 million for the second quarter of 2024. And non-GAAP R&D expenses were $31.9 million in the second quarter of 2024 compared to $27.3 million for the second quarter of 2024.

需要提醒的是，非公認會計原則費用不包括基於股票的薪酬和與收購的正在進行的研發費用相關的一次性費用。我們第三季的 GAAP 研發費用為 3,770 萬美元，而 2024 年第二季為 3,080 萬美元。2024 年第二季的非 GAAP 研發費用為 3,190 萬美元，而 2024 年第二季為 2,730 萬美元。

Turning to G&A. Our GAAP G&A expenses during the third quarter 2024 totaled $20.4 million compared to $14 million for the second quarter of 2024. And non-GAAP G&A expenses were $6.8 million during the third quarter of 2024 compared to $6.4 million for the second quarter of 2024.

轉向一般行政費用。2024 年第三季我們的 GAAP G&A 費用總計 2,040 萬美元，而 2024 年第二季為 1,400 萬美元。2024 年第三季的非 GAAP 一般管理費用為 680 萬美元，而 2024 年第二季為 640 萬美元。

The increase in GAAP operating expenses was primarily related to the increase in stock-based compensation expense during the quarter related to charges from the achievement of certain market conditions on performance stock option awards, and an increase in R&D expenses due to expansion of clinical study and development costs related to Ivonescimab and increase in people costs as we continue to build our R&D team.

公認會計原則營運費用的增加主要與本季度基於股票的補償費用的增加有關，這些費用與實現績效股票選擇權獎勵的某些市場條件相關的費用以及由於臨床研究和臨床研究的擴展而導致的研發費用的增加有關。

On a non-GAAP basis, which excludes stock-based compensation, our non-GAAP operating expenses during the third quarter 2024 were $38.7 million compared to $33.7 million for the second quarter of 2024. We have been executing efficiently on our 2 registrational studies, HARMONi and HARMONi-3, with quarterly cash burn in our operating activities, keeping it below $35 million.

依照非公認會計原則（不含股票薪酬）計算，我們 2024 年第三季的非公認會計原則營運費用為 3,870 萬美元，而 2024 年第二季為 3,370 萬美元。我們一直在有效執行兩項註冊研究：HARMONi 和 HARMONi-3，我們的經營活動中的季度現金消耗量保持在 3500 萬美元以下。

Finally, to conclude, we believe our current cash balance at quarter end aggregating to $487 million provides us enough cash to continue to invest in the Ivonescimab trials planned to be expanded and initiated in 2025.

最後，總而言之，我們相信我們目前季度末的現金餘額總計為 4.87 億美元，為我們提供了足夠的現金來繼續投資計劃於 2025 年擴大和啟動的 Ivonescimab 試驗。

And with that, I'll hand it back over to Dave.

有了這個，我會把它交還給戴夫。

Thank you, Bob, Maky, and Manmeet. Now we'd like to see if there are any questions that our team can help answer. Operator, would you please open the line for questions?

謝謝鮑勃、麥基和曼米特。現在我們想看看我們的團隊是否可以幫助回答任何問題。接線生，請您撥打電話提問好嗎？

(Operator Instructions) Mitchell Kapoor, H.C. Wainwright.

（操作員說明）Mitchell Kapoor，H.C.溫賴特。

Hey, everyone. Thanks for taking the questions. Just wanted to know on the expansion of the HARMONi-3 trial, who are the likely first-line non-squamous patients that you could likely enroll? And specifically, how do you think about recruiting patients who would otherwise be good candidates for Keytruda? How do you think about getting those patients to participate in this study?

嘿，大家。感謝您提出問題。只是想知道關於 HARMONi-3 試驗的擴展，您可能會招募哪些一線非鱗狀細胞癌患者？具體來說，您如何看待招募本來可以成為 Keytruda 良好候選人的患者？您如何看待讓這些患者參與這項研究？

Yes. Mitchell, for the question. So the expansion is basically similar to the population that was treated in the KEYNOTE-189 study. So these are going to be non-squamous patients following adeno patients. And I think Maky reviewed the trial.

是的。米切爾，請回答這個問題。因此，擴張範圍與 KEYNOTE-189 研究中治療的族群基本相似。因此，這些將是腺病毒患者之後的非鱗狀細胞患者。我認為梅基審查了審判。

I think the key here will be that the chemo will be slightly different. There will be platinum pemetrexed for these patients. However, we have extensive experience with that from the HARMONi studies -- HARMONi-A and HARMONi.

我認為這裡的關鍵是化療會略有不同。這些患者將接受鉑類培美曲塞治療。然而，我們在 HARMONi 研究——HARMONi-A 和 HARMONi 方面擁有豐富的經驗。

And do you have a target enrollment for the split between non-squamous and squamous for this trial?

對於本試驗，您是否有針對非鱗狀細胞和鱗狀細胞癌的入組目標？

We have not disclosed that.

我們還沒有透露這一點。

We're just in the planning phase right now. As we said, we did -- we gave the combined number, 1,080 patients, which we plan to enroll in both squamous and non-squamous. We have not given further splits yet.

我們現在正處於規劃階段。正如我們所說，我們確實這樣做了——我們提供了 1,080 名患者的總人數，我們計劃招募鱗狀和非鱗狀患者。我們還沒有給出進一步的分割。

And then the last one for me is just on HARMONi. Can you talk about the potential for accelerated approval? Could you file on PFS? And how does that differ in terms of the unmet need from the strategy with HARMONi-3 and HARMONi-7?

對我來說最後一個是在 HARMONi 上。能談談加速批准的潛力嗎？您可以在 PFS 上提交嗎？在未滿足的需求方面，這與 HARMONi-3 和 HARMONi-7 的策略有何不同？

HARMONi has always been our fast-to-market strategy. And as you know, we announced that we completed the enrollment earlier this month, and now we expect the data in mid-2025. Obviously, based on the data, right, obviously, we'll be assessing our regulatory strategy and then providing further updates.

HARMONi 一直是我們的快速上市策略。如您所知，我們已於本月初宣布完成註冊，現在我們預計數據將在 2025 年中期公佈。顯然，根據數據，顯然，我們將評估我們的監管策略，然後提供進一步的更新。

Just to clarify, there's 2 parts to that question in terms of the PFS, right? So, there's could you file only on PFS data and then the timing of which could you file with the PFS data before you have the OS readout. And so just for the precedent in this EGFR second-line space, the approval have been on PFS, right? And unfortunately, it is second line, it's a large unmet need. So the time between PFS and OS readouts may not be significantly different, right?

澄清一下，這個問題在 PFS 方面有兩個部分，對吧？因此，您可以只歸檔 PFS 數據，然後在獲得作業系統讀數之前可以歸檔 PFS 數據的時間。因此，僅就 EGFR 二線領域的先例而言，PFS 已獲得批准，對吧？不幸的是，它是第二線，這是一個巨大的未滿足的需求。所以 PFS 和 OS 讀數之間的時間可能沒有顯著差異，對吧？

Yes. The only thing I would add to that, Mitchell, just to round it out, I think you asked the question in terms of the difference between the HARMONi and the HARMONi-3 perspective. So just to reiterate, so HARMONi-3 is when we -- with our intention to expand that population, that is patients already with squamous. So we'll keep that cohort. We'll add patients who are non-squamous, but they'll be without actionable genomic alterations, right?

是的。我唯一要補充的是，Mitchell，為了完善這一點，我認為您提出的問題是關於 HARMONi 和 HARMONi-3 視角之間的差異。重申一下，HARMONi-3 是當我們打算擴大該族群時，即已經患有鱗狀細胞癌的患者。所以我們會保留這個隊列。我們將添加非鱗狀細胞的患者，但他們不會發生可操作的基因組改變，對吧？

So, without driver mutations. Our HARMONi trial will -- is focused on those with EGFR mutant driver -- the driver mutation of EGFR mutations, right? So that is -- they are separate. They're not overlapping populations, HARMONi and HARMONi-3. I just want to make sure that, that's clear.

因此，沒有驅動程式突變。我們的 HARMONi 試驗將聚焦在那些具有 EGFR 突變驅動因子的患者—EGFR 突變的驅動突變，對嗎？也就是說——它們是分開的。HARMONi 和 HARMONi-3 並不是重疊的族群。我只是想確保這一點很清楚。

And just to further clarify, I just want to clarify for the HARMONi-3, as Maky mentioned, now the endpoint is PFS and OS, and the question around PFS filing versus OS timing of filing is relevant for that study.

為了進一步澄清，我只想澄清 HARMONi-3，正如 Maky 所提到的，現在的終點是 PFS 和 OS，並且圍繞 PFS 歸檔與 OS 歸檔時間的問題與該研究相關。

Brad Canino, Stifel.

布拉德·卡尼諾，斯蒂菲爾。

Good morning, and thanks for all the updates. Like on the addition of PFS to the primary endpoint of HARMONi-3, can you talk about what types of regulatory feedback and clinical investigator feedback that went into that decision? And then related -- and sorry to push with a question like this, but we all know that investors are keenly aware and waiting for an OS answer from your partner, Akeso. And a change like this before we get that naturally makes one wonder what the confidence of management is to achieve a clinically meaningful OS benefit in the frontline lung setting. So can you talk about both of those elements?

早上好，感謝所有更新。就像在 HARMONi-3 的主要終點中添加 PFS 一樣，您能否談談做出該決定時受到了哪些類型的監管反饋和臨床研究者反饋？然後是相關的 - 很抱歉提出這樣的問題，但我們都知道投資者敏銳地意識到並等待您的合作夥伴 Akeso 的作業系統答案。在我們得到這一結果之前，這樣的變化自然會讓人想知道管理層對於在前線肺部環境中實現具有臨床意義的 OS 益處的信心有多大。那麼您能談談這兩個要素嗎？

Yes, Brad, so let me answer the last one first. There's no change in our confidence for the HARMONi-2 data around the OS, right? I think the opportunity was -- and it was unrelated, but the magnitude of the PFS benefit in HARMONi-2 was so striking, you don't want to have a therapy that provides such a significant benefit and not make that benefit available to patients, right, just based on that number. Granted, there's a lot of issues that we won't get into about payer reimbursement and the value of OS versus PFS.

是的，布拉德，所以讓我先回答最後一個問題。我們對作業系統周圍的 HARMONi-2 資料的信心沒有改變，對嗎？我認為機會是——而且是不相關的，但 HARMONi-2 的 PFS 益處的幅度是如此驚人，你不希望有一種療法能夠提供如此顯著的益處，但卻不讓患者獲得這種益處，對，就根據這個數字。誠然，有很多關於付款人報銷以及 OS 與 PFS 的價值的問題我們不會討論。

But we think that this is a positive thing, addition of the PFS endpoint as a primary endpoint for the HARMONi-3 study in both timing and availability and benefit to patients.

但我們認為這是一件積極的事情，將 PFS 終點作為 HARMONi-3 研究的主要終點，無論是時間安排、可用性還是對患者的益處。

Yes. And just to answer the other part of your question there, Brad, you asked about regulatory feedback. So, as we've promised from the beginning of this relationship with Akeso and our licensing of Ivonescimab, we would be speaking in particular with the FDA prior to these changes so that we have had communications with the FDA here.

是的。布拉德，為了回答你問題的另一部分，你詢問了監管回饋。因此，正如我們從與 Akeso 建立合作關係以及 Ivonescimab 許可之初就承諾的那樣，我們將在這些變化之前特別與 FDA 進行溝通，以便我們與 FDA 進行溝通。

Especially for such an important change.

尤其是對於這樣一個重要的改變。

Yes.

是的。

And now that HARMONi-3 does have both histologies, do you plan to wait for them both to have data to do the top line? Or can they be reported separately? Right now, the NCT before you've updated says the primary completion estimate is September '27. Now that the trial has changed, how should we think about data flow, both histologies together, et cetera?

現在 HARMONi-3 確實具有兩種組織學，您是否打算等待它們都有數據來完成頂線？或可以單獨報告嗎？目前，在您更新之前的 NCT 表示，主要完成時間預計為 27 月 27 日。既然試驗已經改變，我們該如何考慮資料流、兩種組織學等？

Yes. So, at the highest level, what I would say there, Brad, is this is a single trial. So, it's a single analysis set. So, we wouldn't necessarily look to break out timing there. Now we did say in the slides that we presented this morning that like -- and as would be expected from a stratification perspective, we would stratify by histology, but it wouldn't be from a timing perspective broken out.

是的。因此，布拉德，在最高層面上，我想說的是，這是一場試驗。因此，這是一個單一的分析集。因此，我們不一定要在那裡打破時間安排。現在，我們確實在今天早上展示的幻燈片中說過，正如從分層角度所預期的那樣，我們將按組織學進行分層，但不會從時間角度進行分層。

I would say, without going too far into the details, just given that we're intending to amend this shortly, there's a significantly broader population of non-squamous patients as well. And so, from a timing perspective, there's more availability of those patients, and there's a broader availability to enroll patients with non-squamous tumors.

我想說的是，無需過多討論細節，只要考慮到我們打算很快修改這一點，非鱗狀細胞癌患者的群體也明顯更廣泛。因此，從時間角度來看，這些患者的可用性更高，招募非鱗狀腫瘤患者的可用性也更廣泛。

Okay. And then last for me, I think as we see multiple PD-1 and L1 by VEGF bispecifics advance across multiple companies, I mean every day, there seems to be a press release. It would be great to hear your thoughts on whether other designs and constructs, be those that leverage PD-L1 or maybe broader VEGF isoform inhibition are viewed internally as close replications of Ivonescimab and its incredible profile to date or are viewed as potentially different?

好的。最後對我來說，我認為當我們看到多個 PD-1 和 L1 by VEGF 雙特異性藥物在多家公司取得進展時，我的意思是，似乎每天都有新聞稿。很高興聽到您對其他設計和構建的想法，無論是那些利用PD-L1 或更廣泛的VEGF 同工型抑制的設計和構建，是否被內部視為Ivonescimab 及其迄今為止令人難以置信的概況的密切複製，或被視為潛在的不同？

Sure. Brad so, what I would say, when we enter into the deal with Akeso, we naturally expected to see a few more assets emerge with a similar construct in general, as you mentioned, given the data that have been produced to date and our willingness to enter into a deal of that size and magnitude that we did. Of course, once the data from HARMONi-2 emerge, we expect to continue to see a rapid emergence of products looking to capitalize on the potential that Ivonescimab had created at that point. And so, most of these assets, I would point out, are very early. A majority -- a vast majority are preclinical with no in-human data.

當然。布拉德，我想說的是，當我們與康方達成交易時，我們自然期望看到更多具有類似結構的資產出現，正如您所提到的，鑑於迄今為止生成的數據和我們的意願達成我們所做的如此規模和規模的交易。當然，一旦 HARMONi-2 的數據出現，我們預計將繼續看到希望利用 Ivonescimab 當時創造的潛力的產品迅速出現。因此，我想指出的是，這些資產中的大多數都非常早期。大多數——絕大多數是臨床前的，沒有人體數據。

However, we do review the construct of each of these compounds individually. And while we're not going to comment on any individual asset, particularly, what I would say is that Ivonescimab was specifically engineered to improve antitumor activity and reduce toxicities associated with these 2 targets. And this specific engineering was not accidental. It was not serendipitous. And we're very happy with ivonescimab in its construct in particular, and that ivonescimab is our asset.

然而，我們確實單獨審查了每種化合物的構造。雖然我們不會特別評論任何單獨的資產，但我想說的是，Ivonescimab 是專門為提高抗腫瘤活性並減少與這兩個目標相關的毒性而設計的。這個特定的工程並非偶然。這並非偶然。我們對 ivonescimab 特別是其結構非常滿意，並且 ivonescimab 是我們的資產。

And we've yet to find one that we would rather have versus Ivonescimab. Two successful randomized Phase 3 clinical studies involving Ivonescimab only kind of bolster that perspective.

我們還沒有找到一種可以與 Ivonescimab 相比的藥物。兩項涉及 Ivonescimab 的成功隨機 3 期臨床研究只是支持了這一觀點。

Yigal Nochomovitz, Citi.

伊格爾·諾霍莫維茨，花旗銀行。

Hi guys. Thank you so much for taking the question. So just thinking a little bit more about the HARMONi-3 amendment, which you announced. I'm just curious, did you consider just simply starting a new study in non-squamous so you could preserve the timelines for HARMONi-3 or is the argument that because you're amending to PFS, you're going to win back time on the time to primary endpoint since you're no longer looking at OS?

嗨，大家好。非常感謝您提出這個問題。因此，請多思考一下您宣布的 HARMONi-3 修正案。我只是好奇，您是否考慮簡單地開始一項非鱗狀細胞的新研究，這樣您就可以保留 HARMONi-3 的時間表，或者是因為您正在修改 PFS，您將贏得時間由於您不再關注操作系統，因此達到主要終點的時間？

Hey, Yigal, this is Manmeet. No, we totally understand, and we validated it. But as you know, right, in order to capitalize on our existing sites, which we already have on squamous and this timeline to amend was much faster to add the non-squamous arm. And as Dave just mentioned, right, non-squamous is almost double the population, and it increases our total market size, right, and the potential. And there are long lead times.

嘿，伊格爾，這是曼米特。不，我們完全理解，並且我們驗證了這一點。但如你所知，為了利用我們現有的站點，我們已經在鱗狀上擁有這些站點，並且修改時間線要快得多，以添加非鱗狀臂。正如戴夫剛才提到的，對，非鱗狀細胞幾乎是人口的兩倍，它增加了我們的總市場規模，對，和潛力。而且交貨時間很長。

If we have to start another trial with new sites and new clinical trial agreements, the lead time is much longer. So, this would allow us to enroll patients on both arms quicker and expand our market like almost like tripling our market opportunity. Yes, we had not provided the timelines because we were still enrolling and activating sites for squamous, so we had not provided you earlier. So, we don't see this as a material change in delaying squamous, but it adds non-squamous opportunity and get non-squamous much faster and earlier into the market.

如果我們必須在新的地點和新的臨床試驗協議上開始另一項試驗，那麼交貨時間就會更長。因此，這將使我們能夠更快地招募雙臂患者並擴大我們的市場，幾乎使我們的市場機會增加兩倍。是的，我們沒有提供時間表，因為我們仍在註冊和激活鱗狀細胞部位，所以我們沒有提前提供給您。因此，我們並不認為這是延遲鱗狀細胞癌的重大變化，但它增加了非鱗狀細胞癌的機會，並使非鱗狀細胞癌更快、更早地進入市場。

Yes. If I can, Yigal, this is Allen. If I can give some physician feedback that we've been receiving, they're very excited about this change. They see the logic in this change. This is a type of patient that they see more commonly in their practices. So, it just increased sort of participation and excitement around the study.

是的。如果可以的話，伊格爾，這是艾倫。如果我可以向我們收到的一些醫生回饋，他們會對這項改變感到非常興奮。他們看到了這種變化的邏輯。這是他們在實踐中更常見的一類患者。因此，它只是增加了研究的參與度和興奮度。

Well, yes, no, I mean, clearly, it makes sense given you fill the gap in terms of the spectrum of all the non-small cell patients that are addressable. The other question I had was regarding -- we've gotten a lot of questions on HARMONi-2 hitting on OS. As you know, it's been a significant debate. I'm just wondering if you could kind of walk through the logic as far as the confidence you have that HARMONi-2 will eventually hit on OS. Obviously, people have been making comparisons, perhaps inappropriate comparisons to HARMONi-A and the strong PFS there and then the OS, which is trending well, but obviously not hitting stat sig yet.

嗯，是的，不，我的意思是，顯然，鑑於您填補了所有可尋址的非小細胞患者範圍的空白，這是有道理的。我遇到的另一個問題是——我們收到了很多關於 HARMONi-2 作業系統的問題。如你所知，這是一場重要的辯論。我只是想知道您是否可以解釋一下您對 HARMONi-2 最終會在作業系統上出現的信心程度的邏輯。顯然，人們一直在進行比較，也許與 HARMONi-A 和強大的 PFS 以及作業系統進行比較是不恰當的，作業系統趨勢良好，但顯然尚未達到 stat sig。

So just wondering if you could frame that and talk about how you see the path to confidence on hitting OS in HARMONi-2, which would obviously be a very big win and translate positively to everything you're doing over in the United States.

因此，我想知道您是否可以框架一下並談談您如何看待在HARMONi-2 中實現操作系統的信心之路，這顯然將是一個非常大的勝利，並對您在美國所做的一切產生積極的影響。

Yes. Again, I think our confidence hasn't changed. I think if you look back at data from multiple frontline non-small cell lung cancer studies, remember, the HARMONi-A study was a second-line study in patients refractory to osimertinib or other TKIs. If probably the classic study, if you look at the criticism around bevacizumab, the ECOG study that led to the approval of bevacizumab had a strong hazard ratio, I think, but it was well above 0.6, and it still hit its OS endpoint, Akeso Bev studies as well, the EMPOWER studies as well. And so, with this strong of a hazard ratio in PFS, it's unlikely that the OS won't be there, the OS benefit won't be there.

是的。再說一遍，我認為我們的信心沒有改變。我認為，如果您回顧多項第一線非小細胞肺癌研究的數據，請記住，HARMONi-A 研究是針對奧希替尼或其他 TKI 難治性患者的二線研究。如果可能是經典研究，如果你看看圍繞貝伐珠單抗的批評，我認為導致貝伐珠單抗獲得批准的ECOG 研究具有很強的風險比，但它遠高於0.6，並且仍然達到了其OS 終點，Akeso Bev 也進行了研究，EMPOWER 也進行了研究。因此，由於 PFS 的風險比如此之高，作業系統不太可能不存在，作業系統的好處也不會存在。

But I just want to remind everybody, for HARMONi-2, the primary endpoint was PFS, and this study was designed for PFS. And the question around statistical significance, that's a numeric value that people are after. And the question is how long will it take to show that given the sample size.

但我只是想提醒大家，對HARMONi-2來說，主要終點是PFS，而這項研究就是為了PFS而設計的。關於統計顯著性的問題，這是人們追求的數值。問題是，考慮到樣本量，需要多長時間才能證明這一點。

There are no further questions at this time. I would like to hand things back over to Dave Gancarz for some closing remarks.

目前沒有其他問題。我想將事情交還給戴夫·甘卡茲（Dave Gancarz）做一些結束語。

Thank you, Ian. I just want to take the time to thank everybody for attending today's earnings call. An archived version of this webcast will be available on our website, www.smmttx.com. Thank you for taking the time to join us and enjoy the rest of your day. Thank you.

謝謝你，伊恩。我只是想花時間感謝大家參加今天的財報電話會議。此網路廣播的存檔版本將在我們的網站 www.smmttx.com 上提供。感謝您抽出寶貴的時間加入我們並祝您度過愉快的一天。謝謝。