MSK Research Roundup at ESMO Congress 2022: Practice-Changing Advances in Bladder Cancer, Endometrial Cancer, Renal Cell Carcinoma, Colorectal Cancer, and Breast Cancer

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Dr. Motzer reviewing radiology images with nurse.

Medical Oncologist Robert Motzer, MD reviewing radiology images with nurse, Suzanne Gornell.

Advanced Bladder Cancer: Promising Results for Enfortumab Vedotin Plus Pembrolizumab

MSK has been spearheading the development and testing of antibody-drug conjugates — novel biopharmaceuticals that deliver precise payloads of anti-cancer agents directly to cancer cells — alone or in combination with checkpoint inhibitors, for treating advanced bladder cancer

Jonathan Rosenberg, MD, medical oncologist and Chief of the Genitourinary Oncology Service at MSK, presented promising results for cohort K of the international phase 2 trial (EV-103/KEYNOTE-869; NCT03288545). The study evaluates the safety and effectiveness of the antibody-drug conjugate enfortumab vedotin given in combination with pembrolizumab to newly diagnosed, cisplatin-ineligible patients with locally advanced or metastatic urothelial cancer.

Almost two-thirds (64.5%) of 76 patients experienced an objective response, a much better rate than is typical with standard chemotherapy such as gemcitabine and carboplatin. Tumors disappeared entirely in 10.5% of patients. The median duration of response, as confirmed by blinded independent central review, was not reached. Survival data remains immature, but researchers have noted encouraging improvements in progression-free survival (PFS) and overall survival (OS). (1)

The U.S. Food and Drug Administration granted Breakthrough Therapy Designation to enfortumab vedotin plus pembrolizumab in February 2020 for cisplatin-ineligible patients with unresectable advanced or metastatic urothelial cancer, based on results from expansion cohort A of the EV-103 trial. The combination is currently being investigated in the phase 3 trial EV-302/KEYNOTE KN-A39 (NCT04223856) versus chemotherapy alone in untreated locally advanced or metastatic urothelial cancer.

Learn more. Read ESMO Congress 2022 Abstract LBA73. Explore MSK’s clinical trials for bladder cancer. Access disclosures for Dr. Rosenberg.

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Advanced Endometrial Cancer: Lenvatinib Plus Pembrolizumab Confers Significant Survival Advantage

Earlier this year, Vicky Makker, MD, a medical oncologist at MSK, and colleagues published results for Study 309/KEYNOTE-775 (NCT03517449) in The New England Journal of Medicine. The international phase 3 trial compared the efficacy and safety of lenvatinib plus pembrolizumab with the treatment of physician’s choice (TPC), either doxorubicin or paclitaxel, in patients with endometrial cancer showing disease progression after platinum-based chemotherapy. Randomization of 897 patients was stratified by mismatch repair status: 697 patients had mismatch repair-proficient disease (pMMR), and 130 patients had mismatch repair-deficient disease (dMMR). The combination of lenvatinib plus pembrolizumab versus TPC led to significantly improved progression-free survival (PFS) and overall survival (OS) in all comers and patients with pMMR disease. (2)

At ESMO 2022, Dr. Makker reported the trial’s final survival outcomes and safety results. Median PFS was longer for lenvatinib plus pembrolizumab versus TPC in patients with pMMR advanced endometrial cancer (6.7 months versus 3.8 months) and all comers (7.3 months versus 3.8 months). Median OS was also longer with the combination therapy versus TPC in patients with pMMR disease (18.0 months versus 12.2 months) and all comers (18.7 months versus 11.9 months). Note that grade 3 or higher adverse events occurred in 90% of patients treated with lenvatinib plus pembrolizumab and in 74% of patients treated with TPC, and were managed with dose reductions. (3) Safety was consistent with the primary analysis and previous studies. (2)

Dr. Makker also co-authored an analysis of results for a subset of 104 Japanese patients in Study 309/KEYNOTE-775 that reported somewhat more favorable survival outcomes than observed in the global patient population. Median PFS was 5.6 months with lenvatinib plus pembrolizumab and 5.6 months with TPC in patients with pMMR disease, and 7.2 months versus 5.6 months for all comers, respectively. For patients with pMMR disease, median PFS was not reached with the combination treatment versus 3.7 months with TPC. Median OS was 16.7 months with lenvatinib plus pembrolizumab and 12.2 months with TPC in patients with pMMR disease, and not reached versus 8 months with TPC, respectively. The favorable outcomes and manageable safety, similar to the global study, added further support to the combination as a new standard of care for patients with advanced endometrial cancer. (4)

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Advanced Renal Cell Carcinoma: Updated Positive Outcomes for Lenvatinib Plus Pembrolizumab Versus Sunitinib

The international phase 3 CLEAR study (Study 307/Keynote-581; NCT02811861) tested the efficacy of lenvatinib plus pembrolizumab versus sunitinib in patients with advanced renal cell carcinoma. The combination therapy conferred improved progression-free survival (PFS), overall survival (OS), and objective response rate (ORR) versus sunitinib in the first-line setting, leading to its recommendation in international treatment guidelines. (5) MSK medical oncologist Robert Motzer, MD, was primary investigator of the trial, which was reported previously in The New England Journal of Medicine.

Dr. Motzer co-authored updated study results presented at ESMO Congress 2022. Median PFS was 23.3 months for 355 patients randomized to lenvatinib plus pembrolizumab, significantly longer than 9.2 months for 357 patients treated with sunitinib. The ORR was 71.0% versus 36.1%, and the duration of response was 26.0 months versus 14.7 months for the combination treatment group versus the sunitinib group, respectively. Among patients who completed two years of pembrolizumab (101 out of 355 patients), 65 had intermediate- or poor-risk disease, and only 36 had favorable-risk disease, consistent with the intent-to-treat population. The three-year OS rate was 94.5% among those who completed pembrolizumab, and 68.3% (69 patients) had treatment-related adverse events. The complete response rate was 17.2% in the lenvatinib plus pembrolizumab group versus 4.2% in the sunitinib group. (6)

Dr. Motzer et al. previously published health-related quality-of-life (HRQOL) outcomes for patients treated with lenvatinib plus pembrolizumab or everolimus versus sunitinib in the CLEAR study in The Lancet Oncology. Patients treated with the combination had similar or somewhat improved HRQOL and disease-related symptom scales from baseline, including physical functioning, fatigue, dyspnea, and constipation, and were able to remain on treatment for a more extended period than those treated with sunitinib. Further, the time to first deterioration also favored the combination therapy on several scales. The results support the use of lenvatinib plus pembrolizumab as first-line therapy for patients with advanced renal cell carcinoma. (5)

Read ESMO Congress 2022 Abstract 1449MO. Explore MSK’s clinical trials for renal cell carcinoma. Access disclosures for Dr. Motzer.

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Other Notable MSK Research News at ESMO Congress 2022:

  • Colorectal Cancer: Immune Checkpoint Inhibitors in Mismatch Repair-Deficient Solid Tumors. Andrea Cercek, MD, Section Head of Colorectal Cancer and Co-Director of the Center for Young Onset Colorectal and Gastrointestinal Cancer, provided her expert perspective on single-agent PD-1 blockade in mismatch repair deficiency (dMMR) colon and rectal tumors in a Chair interview.

    Dr. Cercek was the lead author of a study previously presented at ASCO 2022 and simultaneously published in The New England Journal of Medicine. The groundbreaking trial (NCT04165772) evaluated the anti-PD-1 monoclonal antibody dostarlimab as a first-line single-agent treatment for patients with stage 2 or 3 rectal tumors with dMMR. The novel treatment strategy resulted in complete clinical response with no evidence of tumor within at least six months of follow-up in all patients. (7) Learn more. Video: Learn about MSK’s Center for Young Onset Colorectal and Gastrointestinal Center, the first clinic in the world dedicated to the specific needs of patients under 50. Explore MSK’s clinical trials for colorectal cancer. Access disclosures for Dr. Cercek.
  • HER2-Low Breast Cancer. Shanu Modi, MD, a medical oncologist in MSK’s Breast Medicine Service, was the lead investigator of the groundbreaking DESTINY-Breast04 Trial (NCT03734029). Previously presented at ASCO 2022 and published in The New England Journal of Medicine, the phase 3 study evaluated trastuzumab deruxtecan (T-DXd) versus treatment of physician’s choice (TPC) in patients with HER2-low metastatic and hormone receptor-positive (HR+) breast cancer. For patients treated with T-DXd versus TPC, progression-free survival (PFS) was 10.1 months versus 5.4 months, and overall survival (OS) was 23.9 months versus 17.5 months. (8) At ESMO Congress 2022, Dr. Modi presented in two sessions: Extending Anti-HER2 Therapy Benefits to a Larger Population of Patients: Emerging Evidence, Implementation in Clinical Practice, and Future Directions and Exploring the Nuances of HER2-Targeted Treatment Selection for Patients With HER2-Low Breast Cancer: Expert Insights Into Implications for Practice and Team-Based Approaches to Individualizing Patient Care.

    Dr. Modi was also the senior researcher of a study presented at ESMO Congress 2022 that investigated patient-reported outcomes in the DESTINY-Breast04 trial. Patients treated with T-DXd maintained global health status/quality-of-life scores greater than patients who received TPC in all subscales while on therapy, confirming the benefit of T-DXd for patients with HER2-low metastatic breast cancer. (9)Learn more. Medical oncologist Shanu Modi, MD, discusses how patients with HER2-low metastatic breast cancer benefited from T-DXd in the DESTINY-Breast04 trial in this video and the Cancer Straight Talk from MSK podcast, episode 28. Explore MSK’s clinical trials for breast cancer. Access disclosures for Dr. Modi.
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  1. ESMO Congress 2022 Abstract LBA73 - Study EV-103 Cohort K: Antitumor activity of enfortumab vedotin monotherapy or in combination with pembrolizumab in previously untreated cisplatin-ineligible patients with locally advanced or metastatic urothelial cancer. Annals of Oncology (2022) 33 (suppl_7): S808-S869. 10.1016/annonc/annonc1089.
  2. Makker V, Colombo N, Casado Herráez A, et al. Lenvatinib plus Pembrolizumab for Advanced Endometrial Cancer. N Engl J Med. 2022;386(5):437-448.
  3. ESMO Congress 2022 Abstract 525MO. Updated efficacy and safety of lenvatinib (LEN) + pembrolizumab vs treatment of physician’s choice in patients with advanced endometrial cancer: Study 309/KEYNOTE-775. Annals of Oncology (2022) 33 (suppl_7): S235-S282. 10.1016/annonc/annonc1054.
  4. Yonemori K, Yunokawa M, Ushijima K, et al. Lenvatinib plus pembrolizumab in Japanese patients with endometrial cancer: Results from Study 309/KEYNOTE-775 [published online ahead of print, 2022 May 25]. Cancer Sci. 2022;10.1111/cas.15436.
  5. Motzer R, Porta C, Alekseev B, et al. Health-related quality-of-life outcomes in patients with advanced renal cell carcinoma treated with lenvatinib plus pembrolizumab or everolimus versus sunitinib (CLEAR): a randomised, phase 3 study. Lancet Oncol. 2022;23(6):768-780.
  6. ESMO Congress 2022 Abstract 1449MO. Updated efficacy of lenvatinib (LEN) + pembrolizumab (PEMBRO) vs sunitinib (SUN) in patients (pts) with advanced renal cell carcinoma (aRCC) in the CLEAR study. Annals of Oncology (2022) 33 (suppl_7): S660-S680. 10.1016/annonc/annonc1072.
  7. Cercek A, Lumish M, Sinopoli J, et al. PD-1 Blockade in Mismatch Repair-Deficient, Locally Advanced Rectal Cancer. N Engl J Med. 2022;386(25):2363-2376.
  8. Modi S, Jacot W, Yamashita T, et al. Trastuzumab Deruxtecan in Previously Treated HER2-Low Advanced Breast Cancer. N Engl J Med. 2022;387(1):9-20.
  9. ESMO Congress 2022 Abstract 2170. Patient-reported outcomes (PROs) from DESTINY-Breast04, a randomized phase III study of trastuzumab deruxtecan (T-DXd) vs treatment of physician’s choice (TPC) in patients (pts) with HER2-low metastatic breast cancer (MBC). Annals of Oncology (2022) 33 (suppl_7): S88-S121. 10.1016/annonc/annonc1040.