Memorial Sloan Kettering Cancer Center (MSK) experts shared the results of their cutting-edge research at the European Society of Medical Oncology (ESMO) Congress 2023, held in Madrid, Spain, October 20 to 24, 2023. Highlights included promising advances for various difficult-to-treat cancers, including gastric, breast, head and neck cancer, plus a recent molecular genetics discovery.
HER2-Positive Gastric Cancer: Pembrolizumab Added to Trastuzumab and Chemotherapy Improved Survival
Gastrointestinal oncologist Yelena Janjigian, MD, Chief of the Gastrointestinal Oncology Service at MSK, presented final progression-free survival (PFS) and interim overall survival (OS) results of the phase 3 KEYNOTE-811 trial (NCT03615326), which were published were published online in The Lancet on October 19, 2023.
The addition of pembrolizumab to trastuzumab and chemotherapy in the first-line setting improved survival in patients with metastatic gastric or gastroesophageal junction cancer overexpressing both HER2 and PD-L1 compared to placebo plus trastuzumab and chemotherapy.
Patients with advanced, unresectable gastric or gastroesophageal junction adenocarcinoma with HER2-positive tumors, who had not received prior systemic therapy, were randomized to receive pembrolizumab plus trastuzumab and physician’s choice of chemotherapy (either 5-fluorouracil plus cisplatin or capecitabine plus oxaliplatin) or placebo plus trastuzumab and chemotherapy. There were 350 patients treated in the pembrolizumab group and 346 patients in the placebo group.
Among patients with dual HER2 and PD-L1 overexpressed tumors, PFS was 10.9 months for the pembrolizumab group and 8.1 months for the placebo group (hazard ratio 0.72) at 38.5 months of follow-up. The objective response rate (ORR) was 73% versus 58%, and OS was 20 months versus 15.7 months (hazard ratio 0.81), respectively. Adverse events were similar between groups as anticipated, and no new safety issues arose.
These results led to the approval of pembrolizumab plus trastuzumab and chemotherapy as first-line therapy for HER2-positive advanced gastric or gastroesophageal junction adenocarcinoma by the European Commission in August 2023. The U.S. Food and Drug Administration (FDA) granted accelerated approval to the combination in 2021 based on ORR data from the same trial. The study continues with OS analysis ongoing.
Read ESMO Congress 2023 Abstract 1511O. Explore MSK clinical trials for gastric and gastroesophageal cancer. Access disclosures for Dr. Janjigian.
Tumors with HER2 Activating Mutations: Promising DESTINY-PanTumor01 Trial Results
Thoracic oncologist and early drug development specialist Bob Li, MD, PhD, MPH, presented the primary results of the international phase 2 DESTINY-Pan Tumor01 trial (NCT04639219).The antibody-drug conjugate trastuzumab deruxtecan (T-DXd) demonstrated clinically meaningful pan-tumor activity and durable responses in heavily pretreated patients with solid tumors harboring prespecified HER2 activating mutations.
The trial included 102 patients with a maximum of 20 per tumor type, including breast, colorectal, head and neck, gynecologic, and esophageal cancers. Overall, the ORR was 29.4%, and the median duration of response was not reached with 54.2% of responders remaining in response at 18 months of treatment. Survival results were about 60% mature, showing a median PFS of 5.4 months and a median OS of 10.9 months.
Responses were observed across HER2 expression levels, including tumors with no or low HER2 expression, suggesting that HER2 activating mutations and HER2 expression may be separate biomarkers of response to T-DXd. Safety was consistent with the drug’s existing safety profile, with no new safety signals reported.
The present study adds to the growing evidence supporting T-DXd for cancers with HER2 alterations. In August 2022, the FDA approved T-DXd for patients with non-small cell lung cancers with HER2 mutations, based on a clinical trial led by Dr. Li. The same month, the FDA approved T-DXd as the first targeted therapy for patients with advanced, unresectable HER2-low breast cancer based on a clinical trial led by MSK breast medical oncologist Shanu Modi, MD.
Advanced Breast Cancer: Imlunestrant Shows Promise in Phase 1 a/b EMBER Trial
Imlunestrant is a next-generation oral selective estrogen receptor degrader (SERD) designed to inhibit estrogen receptors continuously, including in ESR1-mutated breast cancer.
Breast oncologist and early drug development specialist Komal Jhaveri, MD, FACP, presented findings from the international phase 1a/1b EMBER trial (NCT04188548), including updated data on imlunestrant monotherapy and the first clinical evidence evaluating the drug in combination with everolimus or alpelisib in patients with estrogen receptor (ER)-positive, HER2-negative advanced breast cancer.
Clinical response and benefit rates for imlunestrant were higher in the combination approach compared with monotherapy: ORRs were 21% in the everolimus group and 58% in the alpelisib group compared with 8% in the monotherapy group. The clinical benefit rates were 62% in both combination groups and 42% in the monotherapy group. No drug-drug interaction observed between imlunestrant and everolimus or alpelisib, and no new safety signals occurred.
Median PFS was about 16 months for imlunestrant plus everolimus, 9 months for imlunestrant plus alpelisib, and 6.5 months for imlunestrant monotherapy in the second-line setting post treatment with a CDK4/6 inhibitor.
Phase 3 registration trials of imlunestrant are ongoing. The EMBER-3 study (NCT04975308) is evaluating the drug in combination with investigator’s choice of endocrine therapy (ET) and abemaciclib in patients with ER-positive, HER2-negative advanced breast cancer previously treated with ET. The EMBER-4 trial (NCT05514054) is assessing imlunestrant versus standard adjuvant ET in patients previously treated for two to five years with adjuvant ET for ER-positive, HER2-positive early breast cancer with an increased risk of recurrence.
Read ESMO Congress 2023 Abstract 383MO. Explore MSK clinical trials for breast cancer. Access disclosures for Dr. Jhaveri.
Other Notable MSK Research News from ESMO Congress 2023:
-
Advanced Head and Neck Cancer: Phase 2 TROPiCS-03 basket trial results. Sacituzumab govitecan is an antibody-drug conjugate that targets trophoblast cell surface antigens (Trop-2), which is highly expressed in some cancers, such as head and neck squamous cell carcinoma (HNSCC). In the phase 2 TROPiCS-03 trial (NCT03964727), sacituzumab govitecan demonstrated antitumor activity as monotherapy in a cohort of heavily pretreated patients with metastatic or locally recurrent HNSCC. The ORR was 16%, and the median DOR rate was 43%. The median PFS was 4.1 months. The safety profile was manageable, and no new safety signals arose. Read ESMO Congress 2023 Abstract 859MO, presented by lead author head and neck medical oncologist Loren Michel, MD. Explore MSK clinical trials for head and neck cancer. Access disclosures for Dr. Michel.
-
HER2-Expressing Solid Tumors: First-in-class immune-stimulating antibody conjugate (ISAC) well tolerated in phase 1 study. BDC-1001 consists of an antibody connected to a payload by a non-cleavable linker, designed to activate the local innate immune system and generate a durable, tumor-targeted adaptive immune response. The drug demonstrated clinical activity across all patient cohorts (n=131), with one complete response, five partial responses, and 14 patients with stable disease within 24 weeks. Tumor biopsies showed that the drug upregulated toll-like receptor, myeloid, and T cell pathways in responders, consistent with its anticipated mechanism of action. BDC-1001 is the first ISAC to advance to phase 2 trials: NCT04278144 is evaluating dose expansion of the drug as monotherapy and with nivolumab in HER2-positive colorectal, gastroesophageal, and endometrial cancers; and NCT05954143 is assessing BDC-1001 monotherapy with or without pertuzumab in HER2-positive metastatic breast cancer following prior treatment with T-DXd. Read ESMO Congress 2023 Abstract 657MO, presented by lead author thoracic oncologist and early drug development specialist Bob Li, MD, PhD, MPH. Explore MSK clinical trials for metastatic breast cancer. Access disclosures for Dr. Li.
- Intronic Variants Not Reported by Clinical Tumor Sequencing Assays May Drive Second Hit in Cancer Development. How intronic somatic mutations contribute to cancer development and progression is poorly understood. MSK researchers analyzed 33,106 tumors from 25,418 patients with 22 cancer types who underwent tumor and matched normal sequencing with MSK-IMPACT®. They assessed patterns between pathogenic and non-coding variants, and the loss of heterozygosity status of tumor suppressor genes affected by these variants. The research team found intronic variants significantly enriched in expected cancer types — such as CDH1 in invasive lobular carcinomas, APC in colorectal cancers, and RB1 in small cell lung cancer. Read ESMO Congress 2023 Abstract 2231O, presented by lead author breast oncologist Anton Safonov, MD. Learn more about MSK-IMPACT®. Access disclosures for Dr. Safonov.