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  Title	MOUNTAINEER-03 phase III study design: first-line mFOLFOX6 + tucatinib + trastuzumab for HER2+ metastatic colorectal cancer
  ID	5416590
  External ID	7421435951
  Author	Unknown
  Published Date	Dec. 26, 2024, 6:57 a.m.
  Summary	ABSTRACT Patients diagnosed with metastatic colorectal cancer (mCRC) have a poor prognosis with survival ranging 2–3 years. The prevalence of human epidermal growth factor receptor 2 (HER2) amplifica
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  URL	https://www.tandfonline.com/doi/full/10.1080/14796694.2024.2441101
  Sentiment	Negative: 0.01398    Neutral: 0.78607    Positive: 0.19994
  Relevance	0.00389

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  Content ID	3271733
  Key	10972935-ad33-4e1a-9694-6afa9f2ac410
  Content	ABSTRACT Patients diagnosed with metastatic colorectal cancer (mCRC) have a poor prognosis with survival ranging 2–3 years. The prevalence of human epidermal growth factor receptor 2 (HER2) amplification is approximately 3–4% in mCRC and increases up to 8% in patients with KRAS NRAS BRAF wild-type (WT) CRC tumors. Tucatinib is a highly selective HER2-directed tyrosine kinase inhibitor that, in combination with trastuzumab, has demonstrated clinically meaningful activity in patients with chemotherapy-refractory, HER2-positive (HER2+), RAS WT mCRC in the MOUNTAINEER trial. The MOUNTAINEER-03 phase III trial is designed to investigate the efficacy and safety of first-line tucatinib in combination with trastuzumab and modified FOLFOX6 (mFOLFOX6) versus standard of care (mFOLFOX6 plus bevacizumab or cetuximab) in patients with untreated HER2+, RAS WT locally advanced unresectable or mCRC. MOUNTAINEER-03 will include two arms of approximately 400 patients randomized 1:1 to either treatment arm. The primary endpoint is progression-free survival per RECIST v1.1 by blinded independent central review (BICR). Key secondary endpoints are overall survival and confirmed objective response rate (according to RECIST v1.1 per BICR). Safety assessments will include surveillance and recording of adverse events, physical examination findings, vital signs, cardiac assessments, Eastern Cooperative Oncology Group performance status, concomitant medications, and laboratory tests. Clinical trial registration: NCT05253651 (ClinicalTrials.gov). Plain Language Summary Colorectal cancer is a common and leading cause of cancer deaths worldwide. Patients who have colorectal cancer that has spread to other parts of the body (metastasized) only live for 2 to 3 years after their diagnosis. Tucatinib is a medicine that has shown promising anti-tumor activity when it is given in combination with trastuzumab in patients with metastatic colorectal cancer that is of a certain type, called HER2-positive. HER2 is a protein that, when present in amounts above normal in cancer cells, can cause them to grow more and survive longer. The MOUNTAINEER-03 study is a trial in progress of patients with HER2-positive metastatic colorectal cancer. In this trial, researchers are investigating if tucatinib in combination with trastuzumab and chemotherapy increases the length of time patients live before their cancer grows or spreads (also called progression-free survival) and how long a person is alive after the start of treatment (also called overall survival) compared to standard of care treatment (chemotherapy combination). Researchers are also investigating whether this new tucatinib combination treatment makes the colorectal cancer shrink and stop spreading and if it is safe to use in patients with HER2-positive metastatic colorectal cancer. If the findings of the MOUNTAINEER-03 phase III trial are positive, the tucatinib combination treatment could be a new option for the first-line treatment of a patient population with a high unmet medical need. This paper describes the study design of the MOUNTAINEER-03 trial. 1. Introduction Colorectal cancer (CRC) is the second leading cause of cancer death worldwide, with approximately 935,000 deaths occurring in 2020 [ ]. Overall survival (OS) for patients diagnosed with metastatic CRC (mCRC) is poor, ranging from 2 to 3 years [ ]. There is an unmet need for novel therapeutic options, including targeted therapies that improve survival while maintaining quality of life. Prior to the introduction of targeted therapies for patients with mCRC, the first-line standard of care (SOC) was composed of multi-agent cytotoxic chemotherapy regimens, such as leucovorin (or levo-leucovorin), 5-fluorouracil, and oxaliplatin (FOLFOX) [ ]. The addition of an anti-vascular endothelial growth factor or anti-epidermal growth factor receptor (anti-EGFR) agent has been shown to provide a survival benefit compared with multi-agent cytotoxic chemotherapy alone [ ]. Many therapies for biomarker-selected mCRC across multiple lines of therapy are now recommended by societal guidelines, including ipilimumab plus nivolumab and pembrolizumab (DNA mismatch repair deficiency/microsatellite instability biomarker [dMMR/MSI-H]) and encorafenib plus cetuximab ( BRAF V600E mutation) [ ]. Biomarkers that are predictive of a response in mCRC continue to be a focus of new drug development. Human epidermal growth factor receptor-2 (HER2), encoded by the ERBB2 gene, belongs to the EGFR tyrosine kinase family and consists of an extracellular ligand-binding region and an intracellular signaling domain [ ]. HER2 activation mediates cell growth, differentiation, and survival, and HER2 overexpression in solid tumors can result in uncontrolled cell proliferation, inhibition of apoptosis, and metastasis through activation of multiple signaling pathways [ ]. HER2 is a validated target in multiple solid tumors, including breast and gastric cancers, with many HER2-directed therapies approved for patients with HER2+ cancers [ ]. In patients with mCRC, the prevalence of HER2 amplification is approximately 3–4% and is more frequent on the left side of the colon and in the rectum; however, among patients with KRAS NRAS BRAF wild-type (WT) CRC tumors, the prevalence of HER2 amplification increases to 5–8% [ ]. HER2-directed therapies have shown clinical activity and the potential to improve outcomes in patients with HER2+ mCRC in clinical trials ( ) [ ]. Table 1. HER2-targeted therapies in HER2+ mCRC. 2. Background and rationale Historical clinical trial data for dual treatment with a HER2-directed tyrosine kinase inhibitor (TKI) and an anti-HER2 monoclonal antibody [ ] or the combination of two HER2 monoclonal antibodies have demonstrated improved outcomes in HER2+ breast cancer compared to one HER2-directed monoclonal antibody alone [ ]. Tucatinib is a highly selective, HER2-directed TKI and is approved, in combination with trastuzumab and capecitabine, in multiple countries for the treatment of HER2+ metastatic breast cancer [ ]. In comparison to other TKIs of HER2, preclinical data has demonstrated tucatinib to be more selective for HER2, potentially minimizing many EGFR-related side effects, including severe skin rash and gastrointestinal toxicity [ ]. Recently, the benefit of dual HER2 inhibition in CRC was evaluated in the MOUNTAINEER study. Tucatinib, in combination with trastuzumab, demonstrated clinically meaningful activity in 84 patients with chemotherapy-refractory RAS WT, HER2+ (defined as immunohistochemistry [IHC] 3+ or IHC 2+/in situ hybridization [ISH]+, or HER2 amplification per next-generation sequencing [NGS] by local testing) unresectable or mCRC. The confirmed objective response rate (cORR) per blinded independent central review (BICR) was 38.1% (95% confidence interval [CI], 27.7–49.3) and the median duration of response (DOR) per BICR was 12.4 months (interquartile range, 8.3–25.5) [ ]. Combination treatment with tucatinib and trastuzumab was generally well tolerated, with a low discontinuation rate (6%) and no deaths due to adverse events (AEs) [ ]. An exploratory analysis of MOUNTAINEER observed that retrospective central assessment of HER2 status across multiple testing platforms utilizing IHC with or without ISH or NGS predicted treatment response to tucatinib plus trastuzumab. Patients with HER2+ mCRC determined by central IHC/ISH had a median DOR of 16.4 months (95% CI, 10.6–25.5) and median progression-free survival (PFS) of 10.1 months (95% CI, 4.2–15.2). cORR ranged from 41.1% to 47.7% across the central testing methods used [ ]. The clinically meaningful antitumor activity and favorable safety profile of tucatinib plus trastuzumab led to the combination being the first FDA-approved anti-HER2 regimen for the treatment of adult patients with RAS WT, HER2+ unresectable or mCRC that has progressed following treatment with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy [ ]. The current indication is an accelerated approval, and the continued approval is contingent on verifying clinical benefit in a confirmatory trial. Despite advances in the treatment of HER2+ mCRC, there remains an ongoing unmet medical need to expand the use of targeted therapies into earlier treatment lines. The objective of the MOUNTAINEER-03 study is to evaluate the efficacy and safety of tucatinib in combination with trastuzumab and modified FOLFOX6 (mFOLFOX6) compared to mFOLFOX6 given with or without either bevacizumab or cetuximab as first-line treatment in patients with HER2+, RAS WT, locally advanced unresectable or mCRC. 3. Methods MOUNTAINEER-03 (NCT05253651; date of registration: 14 February 2022) is a global, open-label, randomized, phase III, multicenter study. A study schema summarizing the study design is provided in . A map with enrolling study sites is provided in Figure 1. Study schema. Created using publicly available information at ClinicalTrials.gov (NCT05253651): https://clinicaltrials.gov/study/NCT05253651#study-plan BICR: blinded independent central review; BID: twice a day; CRC: colorectal cancer; ECOG PS: Eastern Cooperative Oncology Group Performance Status; HER2: human epidermal growth factor receptor 2; IV: intravenous; mFOLFOX6: modified leucovorin (or levoleucovorin), 5-fluorouracil, and oxaliplatin; PFS2: progression-free survival on the next line of therapy; PO: by mouth; QW: every week; Q2W: every 2 weeks; Q3W: every 3 weeks; RECIST v1.1: Response Evaluation Criteria in Solid Tumors version 1.1; WT: wild type. Figure 2. Map of study countries. Created using publicly available information at ClinicalTrials.gov (NCT05253651): https://clinicaltrials.gov/study/NCT05253651#contacts-and-locations 3.1. Eligibility criteria Eligible patients must have locally advanced unresectable or mCRC that is HER2+, RAS WT, and with evidence of radiographically measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 according to investigator assessment. HER2+ disease will be determined by tissue-based investigational HER2 IHC and ISH assays performed at a sponsor-defined central laboratory during the prescreening or screening period. HER2 overexpression/amplification will be determined using American Society of Clinical Oncology/College of American Pathologists guidelines for gastric and gastroesophageal cancer with IHC 3+ or IHC 2+/ISH+ being a positive result [ ]. Patients must have an Eastern Cooperative Oncology Group performance status (ECOG) of 0 or 1 and have adequate hematological, hepatic, renal, coagulation, and cardiac function. Patients may receive up to two doses of mFOLFOX6 in the locally advanced unresectable or metastatic setting prior to randomization. Patients may also have received prior chemotherapy for CRC in the adjuvant setting, provided the last dose of adjuvant treatment was completed more than 6 months prior to enrollment. Eligible patients may either have no evidence of brain metastases or previously treated brain metastases that are asymptomatic. Full eligibility criteria are described in Table 2. Eligibility criteria. 3.2. Study design The study consists of two arms ( ); approximately 400 patients will be randomized in a 1:1 fashion to either the tucatinib experimental arm or the SOC control arm. The experimental arm will be administered tucatinib 300 mg orally twice a day in combination with a trastuzumab 8 mg/kg loading dose intravenously, then 6 mg/kg intravenously every 3 weeks and mFOLFOX6 every 2 weeks. The SOC arm will receive one of the following treatments: mFOLFOX6 every 2 weeks, mFOLFOX6 in combination with bevacizumab every 2 weeks, or mFOLFOX6 every 2 weeks in combination with cetuximab every week. The regimen to be used in the control arm must be chosen before randomization. Antidiarrheal prophylaxis with loperamide is required for all patients on the tucatinib experimental arm for Cycle 1 (42 days) of study treatment only. Randomization will be stratified by the following factors: primary tumor location, liver metastases, and number of doses of mFOLFOX6 chemotherapy prior to randomization. Patients may continue treatment until progressive disease per RECIST v1.1 as assessed by BICR, unacceptable toxicity, withdrawal of consent, or study termination, whichever occurs first. The primary endpoint will be PFS per RECIST v1.1 by BICR. Key secondary endpoints will include OS and cORR per RECIST v1.1 according to BICR. All primary and secondary endpoints are described in 3.3. Assessments Efficacy assessments, including disease response per RECIST v1.1, will be assessed by both BICR and the investigator at protocol-specified time points. During the follow-up phase of the study, patients will be monitored for key study events such as progression, new anticancer therapies, and death, approximately every 12 weeks (±14 days). Radiological disease assessments will occur at screening, during study treatment, and at the end-of-treatment visit. During study treatment, radiological scans will be performed every 6 weeks (±7 days) for the first 72 weeks then every 12 weeks (±7 days) until the occurrence of documented progressive disease per RECIST v1.1 as assessed by BICR. Central nervous system (CNS) imaging will occur at screening, at the end of treatment, and as clinically indicated during treatment. For patients with a history of treated brain metastases at the time of study entry, CNS imaging will be repeated every 12 weeks (±7 days) until progression per BICR, death, withdrawal of consent, or study closure. Pharmacokinetic (PK) assessments will include blood samples for plasma PK assessment of trough tucatinib drug levels in all patients receiving tucatinib on Day 1 of Cycles 2 to 6 and peak levels of tucatinib on Day 1 of Cycle 3. PK assessments will also include blood samples for serum PK assessment of trough trastuzumab drug levels in all patients receiving trastuzumab on Day 1 of Cycles 2 to 6. For biomarker assessments, all patients must provide sufficient tissue specimens prior to enrollment for determination of HER2 status. RAS status can be determined by local testing; however, if local testing is unavailable or is not preferred, tissue will be submitted to a central lab prior to enrollment. Peripheral blood samples for biomarker assessments will be collected on Cycle 1 Day 1. Safety assessments will include the surveillance and recording of AEs (including serious AEs), physical examination findings, vital signs (including weight), cardiac assessments, ECOG performance status, concomitant medications, pregnancy testing, and laboratory tests. They will be performed from study Day 1 (predose) through the end of treatment visit or 30 days after last study treatment whichever is later. The following patient-reported outcome measures: the European Organization for Research and Treatment of Cancer Quality of Life 30-item core questionnaire and the European Quality of Life 5 Dimensions 5 Levels questionnaire will be administered to assess symptoms, functioning, and health-related quality of life. 3.4. Sample size determination This study is designed to detect a tucatinib treatment effect of at least a 33% reduction in the risk of progression or death. Approximately 400 patients will be randomized 1:1 to either treatment arm. After approximately 40 months, the total number of events observed is expected to be sufficient to determine a tucatinib treatment effect, assuming exponential distribution of PFS, 28 months of patient accrual, and a 5% annual dropout rate. 3.5. Statistical methods The efficacy analyses will be performed in the intent-to-treat population. Treatment differences for the primary endpoint of PFS (assessed by BICR) and the key secondary endpoint of OS will be evaluated using a stratified log-rank test. The hazard ratio will be estimated using a stratified Cox proportional hazard model, and survival probabilities over time will be estimated within each treatment group using the Kaplan–Meier method. The secondary endpoint of cORR will be summarized by treatment arm, and treatment difference will be evaluated using the Cochran-Mantel-Haenszel test. Safety will be assessed for all patients who receive at least 1 dose of study treatment. 3.6. Ethics considerations This study will be conducted in accordance with the Note for Guidance on Good Clinical Practice (International Council for Harmonization Harmonized Tripartite Guideline E6 [R2]), U.S. Food and Drug Administration Code of Federal Regulations (CFR; [21 CFR § 50, 56, 312]), the Declaration of Helsinki (Brazil 2013), the Japanese Good Clinical Practice guidelines, and all applicable regulatory requirements. In the EU/European Economic Area countries, the investigator will ensure compliance with the EU Clinical Trial Directive (2001/20/EC) or applicable European local regulations. The protocol will be approved by institutional review boards and ethics committees at each participating study site and written informed consent will be obtained from participants by investigators at each study site. 4. Conclusion CRC is a common and leading cause of cancer death worldwide. For patients diagnosed with mCRC, prognosis is poor, with survival at approximately 2–3 years. Development of efficacious and tolerable targeted treatments is needed to improve outcomes in patients with mCRC, particularly in early lines of therapy. HER2 is an actionable target with demonstrated benefit of HER2-targeted therapies in multiple solid tumors. Tucatinib, in combination with trastuzumab, has been approved in multiple countries for the treatment of adult patients with HER2+, RAS WT unresectable or mCRC, which has progressed following treatment with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy. This indication is based on data from the MOUNTAINEER study, which demonstrated the effectiveness of dual HER2 inhibition with tucatinib and trastuzumab in chemotherapy-refractory HER2+, RAS WT unresectable or mCRC. MOUNTAINEER-03 is a phase III trial designed to establish the efficacy of tucatinib in combination with trastuzumab and mFOLFOX6 versus mFOLFOX6 plus bevacizumab or cetuximab in patients with untreated HER2+, RAS WT locally advanced unresectable or mCRC, with the aim of investigating whether the combination represents a new potential first-line treatment option. Article highlights Colorectal cancer (CRC) is a common and leading cause of cancer death worldwide. For patients diagnosed with metastatic CRC (mCRC), prognosis is poor, with survival at approximately 2–3 years. The prevalence of human epidermal growth factor receptor 2 (HER2) amplification is approximately 3–4% in mCRC and increases up to 8% in patients with KRAS NRAS BRAF wild-type (WT) CRC tumors. Tucatinib is a highly selective HER2-directed tyrosine kinase inhibitor that in combination with trastuzumab has demonstrated clinically meaningful activity in patients with chemotherapy-refractory, HER2-positive (HER2+), RAS wild-type (WT) mCRC in the MOUNTAINEER trial. The MOUNTAINEER-03 phase III trial is designed to establish the efficacy of tucatinib in combination with trastuzumab and modified FOLFOX6 (mFOLFOX6) versus mFOLFOX6 plus bevacizumab or cetuximab in patients with untreated HER2+, RAS WT locally advanced unresectable or mCRC. MOUNTAINEER-03 will include two arms of approximately 400 patients who will be randomized 1:1 to either treatment arms. The primary endpoint is progression-free survival per RECIST v1.1 by blinded independent central review (BICR). Key secondary endpoints are overall survival and confirmed objective response rate per RECIST v1.1 according to BICR. The MOUNTAINEER-03 phase III trial aims to investigate whether the tucatinib combination regimen represents a new potential first-line treatment option for a patient population with a high unmet need. Herein, the protocol of the MOUNTAINEER-03 phase III trial in progress is summarized. Ethical conduct of research This study will be conducted in accordance with the Note for Guidance on Good Clinical Practice (International Council for Harmonization Harmonized Tripartite Guideline E6 [R2]), U.S. Food and Drug Administration Code of Federal Regulations (CFR; [21 CFR § 50, 56, 312]), the Declaration of Helsinki (Brazil 2013), the Japanese Good Clinical Practice guidelines, and all applicable regulatory requirements. In the EU/European Economic Area countries, the investigator will ensure compliance with the EU Clinical Trial Directive (2001/20/EC) or applicable European local regulations. The protocol will be approved by institutional review boards and ethics committees at each participating study site and written informed consent will be obtained from participants by investigators at each study site. Data sharing statement As this is a Clinical Trial Protocol, there is no data to share at this time. Upon request, and subject to review, Pfizer will provide the data that support the findings of this study. Subject to certain criteria, conditions, and exceptions, Pfizer may also provide access to the related individual de-identified participant data. See https://www.pfizer.com/science/clinical-trials/trial-data-and-results for more information. Acknowledgment The authors would like to thank the patients, their families, and all investigators involved in this study. The MOUNTAINEER-03 trial in progress has been previously presented at the Japanese Society of Medical Oncology (JSMO) Annual Meeting, March 16–18, 2023, Fukuoka, Japan. https://site2.convention.co.jp/jsmo2023/program/Program03.pdf , American Society of Clinical Oncology (ASCO) Annual Meeting, June 2 − 6, 2023, Chicago, IL. https://ascopubs.org/doi/10.1200/JCO.2023.41.16_suppl.TPS3631 , American Society of Clinical Oncology (ASCO) Gastrointestinal Cancers Symposium, January 19 − 21, 2023, San Francisco, CA. https://ascopubs.org/doi/10.1200/JCO.2023.41.4_suppl.TPS261 , and at the European Society for Medical Oncology (ESMO) Congress, September 9 − 13, 2022, Paris, France: https://www.annalsofoncology.org/article/S0923-7534(22)02427-9/fulltext Disclosure statement JS is a consultant or Advisory Role for AbbVie, Agenus, Astellas, AstraZeneca, Bayer, BeiGene, Daiichi-Sankyo, Eli Lilly, GSK, Johnson and Johnson, Jazz Pharmaceuticals, Merck, Natera, Pfizer, Roche/Genentech, Regeneron, Sanofi, Taiho, Takeda, Xilio Therapeutics; and has stocks in Triumvira Immunologics; and receives research funding or Contracted Research (Payment to Institution) from AbbVie, Amgen, AStar D3, Bayer, BeiGene, Curegenix, Daiichi-Sankyo, Eli Lilly, Erasca, GSK, Leap Therapeutics, Pfizer, Roche/Genentech, Seagen. T B-S receives research funding (to institution) from Agios, Arys, Arcus, Atreca, Boston Biomedical, Bayer, Eisai, Celgene, Lilly, Ipsen, Clovis, Seagen, Genentech, Novartis, Mirati, Merus, Abgenomics, Incyte, Pfizer, and BMS; and consulting fees (to institution) from Servier, Ipsen, Arcus, Pfizer, Seagen, Bayer, Genentech, Incyte, Eisai, Merus, Merck KGaA and Merck; and consulting fees (to self) from Stemline, AbbVie, Blueprint Medicines, Boehringer Ingelheim, Janssen, Daiichi Sankyo, Natera, TreosBio, Celularity, Caladrius Biosciences, Exact Science, Sobi, Beigene, Kanaph, AstraZeneca, Deciphera, Zai Labs, Exelixis, MJH Life Sciences, Aptitude Health, Illumina, Foundation Medicine, Sanofi, GSK, Xilio; IDMC/DSMB: The Valley Hospital, Fibrogen, Suzhou Kintor, AstraZeneca, Exelixis, Merck/Eisai, PanCan and 1Globe; Scientific Advisory Board: Imugene, Immuneering, Xilis, Replimune, Artiva and Sun Biopharma; and royalties from Uptodate; and inventions/patents for WO/2018/183488: HUMAN PD1 PEPTIDE VACCINES AND USES THEREOF – Licensed to Imugene and WO/2019/055687: METHODS AND COMPOSITIONS FOR THE TREATMENT OF CANCER CACHEXIA – Licensed to Recursion. AC receives grants or contracts from GSK and Seagen; and consulting fees from Bayer, Merck, Pfizer, Roche, AbbVie, Seagen, and GSK; and patents planned, issued or pending for Neoadjuvant PD-1 blockade in solid tumors and HAI FUDR in DPD deficient patients with mCRC to liver; and leadership or fiduciary role in other board, society, committee or advocacy group, paid or unpaid for ESMO and Fight CRC. VH receives honoraria from Merck, Amgen, Roche, Sanofi, Servier, Pfizer, Pierre-Fabre, AstraZeneca, BMS; MSD, Novartis, Boehringer Ingelheim, Celgene, SIRTEX, Seagen, GSK; and consulting fees or advisory role for Merck, Amgen, Roche, AstraZeneca, Celgene, Servier, Novartis, Pierre-Fabre, Halozyme, Merck Sharp & Dohme, Bristol Myers Squibb, GlaxoSmithKline, Janssen, Terumo, SIRTEX, OncoSil, NORDIC, Boehringer Ingelheim; and research funding (Payment to Institution) from Merck, Amgen, Roche, Celgene, Boehringer Ingelheim, Sirtex Medical, Shire; Stock: BioNTech. YN has an advisory role for Guardant Health Pte, Natera, Inc., Roche, Seagen, Premo Partners, Daiichi-Sankyo, Takeda, Exact Sciences Corporation, and Gilead Sciences; and receives a speakers' bureau from Guardant Health Pte, Merck Sharp & Dohme K.K., Eisai, Zeria, Miyarisan, Merck Biopharma, Carenet, Hisamitsu, Taiho, Daiichi-Sankyo, Chugai, and Becton, Dickinson and Company, Guardant Health Japan Corp; and research funding from Seagen, Genomedia, Guardant Health AMEA, Guardant Health, Tempus Labs, Roche Diagnostics K.K., Daiichi-Sankyo, and Chugai. KR receives grants or contracts from AbbVie, AstraZeneca, Bayer, Daiichi Sankyo, Eisai, Genentech, Guardant Health, HiberCell, Innovent, Janssen, Merck, Seagen, UCB Biosciences, and Xencor; and consulting fees from AbbVie, AstraZeneca, Bayer, Daiichi Sankyo, Eisai, Genentech, and Seagen; and support for attending meetings and/or travel from AstraZeneca, Bayer, Daiichi Sankyo, Eisai, Genentech, Jazz Pharma, Seagen, and Sanofi. SS is on the advisory board for Agenus, AstraZeneca, Bayer, Bristol Myers Squibb, CheckmAb, Daiichi-Sankyo, GlaxoSmithKline, Merck Sharp & Dohme, Merck, Novartis, Pierre-Fabre, Seagen, and T-One Therapeutics. JT is a consultant or advisory role or scientific consultancy role for Alentis, AstraZeneca, Aveo Oncology, Boehringer Ingelheim, Cardiff Oncology, CARsgen Therapeutics, Chugai, Daiichi-Sankyo, F. Hoffmann-La Roche, Genentech, hC Bioscience Inc, Ikena Oncology, Immodulon Therapeutics, Inspirna, IQVIA, Lilly, Menarini, Merck Serono, Merus, Mirati, Merck Sharp & Dohme, NeoPhore, Novartis, Ona Therapeutics, Orion Biotechnology, Peptomyc, Pfizer, Pierre Fabre, Sanofi, Scandion Oncology, Scorpion Therapeutics, Seagen, Servier, Sotio Biotech, Taiho, Takeda, and Tolremo Therapeutics; Stock Ownership: 1TRIALSP, Alentis Therapeutics, Oniria Therapeutics, Pangaea Oncology. EvC participates on advisory boards for AbbVie, Agenus, ALX, Amgen, Arcus Biosciences, Astellas, AstraZeneca, Bayer, Beigene, Bexon Clinical, BioNtech, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi, Debiopharma, Elmedix, Eisai, Galapagos, GSK, Hookipa Biotech, Incyte, Ipsen, Lilly, Merck Sharp & Dohme, Merck KGaA, Mirati, Novartis, Nordic, Pierre Fabre, Pfizer, Roche, Seagen, Servier, Simcere, Takeda, Taiho, and Terumo. TY receives honoraria for Chugai, Takeda, Merck, Bayer Yakuhin, Ono, and Merck Sharp & Dohme K.K; and consulting fees for Sumitomo Corp.; and research grants from Amgen, Bristol-Myers Squibb, Chugai Pharmaceutical, Daiichi-Sankyo, Eisai, FALCO biosystems, Genomedia, Medical & Biological Laboratories, Merus N.V., Molecular Health GmbH, MSD, Nippon Boehringer Ingelheim, Ono, Pfizer Japan, Roche Diagnostics, Sanofi, Sysmex, Taiho, and Takeda. JR is an employee at Pfizer Inc. XG is an employee at Pfizer Inc. TA is on the advisory board and receives consulting fees from AbbVie, Astellas, Aptitude Health, Bristol Myers Squibb, Gritstone Oncology, GlaxoSmithKline, Merck & Co. Inc, Nordic Oncology, Seagen, Servier, Takeda; and honoraria from Bristol Myers Squibb, GlaxoSmithKline, Merck & Co. Inc, Merck Serono, Roche, Sanofi, Seagen, and Servier; DMC: Inspirna; and support for meetings from Bristol Myers Squibb and Merck. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. Medical writing support was provided by Jessica Men, PharmD, and Anastasija Pesevska, PharmD, and editorial support was provided by Melissa Ward, BA, all of Scion (a division of Prime, London, UK), supported by Seagen Inc., which was acquired by Pfizer in Dec. 2023, in accordance with Good Publication Practice guidelines ( https://www.acpjournals.org/doi/epdf/10.7326/M22-1460 ). Medical writing support was additionally provided by Melissa Lingohr-Smith, PhD, of Oxford PharmaGenesis Inc., Newtown, PA, USA, and was funded by Pfizer Inc. Additional information Funding Study funding was provided by Seagen Inc., which was acquired by Pfizer in Dec 2023. References Sung H, Ferlay J, Siegel RL, et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin . 2021;71(3):209–249. Van Cutsem E, Kohne CH, Lang I, et al. 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