Memorial Sloan Kettering Cancer Center (MSK) experts presented their latest advances in oncology research at the American Association for Cancer Research (AACR) Annual Meeting 2025, held April 25 to 30 in Chicago.
Highlights included breakthrough findings in mismatch-repair deficient (MMRd) solid tumors, KRAS G12D-mutated non-small cell lung cancer (NSCLC), ovarian and endometrial cancers with poor prognostic features, HER2-positive breast cancer, and Bacillus Calmette-Guérin (BCG)-unresponsive non-muscle invasive bladder cancer. Additionally, the MSK-IMPACT® team received the AACR Team Science Award for their pioneering contribution to advancing clinical genomic sequencing for people with cancer.
MMRd Solid Tumors: Neoadjuvant PD-1 Blockade Achieves High Rate of Organ Preservation in Select Patients
An MSK-led clinical trial (NCT04165772) found that 82% of patients with early-stage MMRd solid tumors experienced a complete clinical response after six months of treatment with the PD-1 blocker dostarlimab, eliminating the need for surgery for four out of five patients.
MSK gastrointestinal medical oncologist Andrea Cercek, MD, principal investigator of the trial and Section Head of Colorectal Cancer and founder and co-director of the Center for Young Onset Colorectal and Gastrointestinal Cancer at MSK, presented the phase 2 study findings in a plenary session. The study was published simultaneously in The New England Journal of Medicine.
At data cut-off, the analysis included 103 patients with stages 1 to 3 MMRd solid tumors eligible for curative intent surgery — 49 patients with rectal cancers and 54 with esophagogastric, colon, hepatobiliary, genitourinary, and gynecologic tumors. Patients received six months of neoadjuvant dostarlimab. Those whose tumors achieved a complete clinical response could elect non-operative management.
All 49 patients in the rectal cancer cohort achieved a complete clinical response, and none had surgery. In the non-rectal cancer cohort, 35 of 54 patients (65%) achieved a complete clinical response, and 33 (61%) elected non-operative management. Two patients, one with gastric cancer and one with urothelial cancer, elected to undergo surgery despite achieving a complete clinical response. In both instances, no cancer was found in the resection specimen.
Across 103 patients in both groups, 84 achieved a complete clinical response, and 82 did not undergo surgery. The two-year recurrence-free survival (RFS) was 92%, and the median follow-up for recurrence was 20 months. Overall, dostarlimab was well tolerated, with predominantly low-grade side effects in about 65% of patients. Notably, this treatment approach did not compromise the opportunity for curative resection during or after treatment. A total of only five patients across both cohorts developed disease recurrence.
Dr. Cercek noted that 19 of 54 patients (35%) in the non-rectal cancer cohort were incomplete responders. Comparing the genomic sequences of the pre- and remnant post-treatment tumors revealed a high likelihood of relatedness in all but two patients. In these cases, the remnant tumor was not MMRd or microsatellite instability-high and was likely a new primary tumor.
Circulating tumor DNA (ctDNA) analysis in both groups showed that 95% of 74 patients tested were positive at baseline. For those who also achieved a complete clinical response, the median time to ctDNA clearance was 1.4 months.
“These results demonstrate the feasibility of organ preservation in patients with non-rectal MMRd tumors that respond to therapy,” said Dr. Cercek. “Avoiding surgery provides a significant improvement in quality of life for a majority of these patients.”
This advance extends the success of this treatment approach in rectal tumors as demonstrated in a previous study led by Dr. Cercek and gastrointestinal medical oncologist Luis Diaz Jr., MD, Head of the Division of Solid Tumor Oncology and Grayer Family Chair at MSK. Their groundbreaking research led to the U.S. Food and Drug Administration’s designation of dostarlimab as a breakthrough therapy for patients with MMRd rectal cancers in December 2024. Read more.
Read AACR Abstract 10417.The study was supported by Swim Across America, GlaxoSmithKline, Stand Up 2 Cancer, Haystack Oncology, the Simon and Eve Colin Foundation, National Institutes of Health Exploratory/Developmental Grant R21CA252519, and the National Institutes of Health/National Cancer Institute Grant P30 CA 008748. Access disclosures for Dr. Cercek. Explore MSK clinical trials for patients with solid tumors.
MMRd Solid Tumors: Adjuvant PD-1 Blockade Clears ctDNA and Reduces Recurrence
A pilot study led by Memorial Sloan Kettering Cancer Center (MSK) has shown that adjuvant PD-1 blockade clears ctDNA in 85% of patients with MMRd solid tumors and significantly reduces the risk of cancer recurrence.
Presented by Yelena Janjigian, MD, Chief of the Gastrointestinal Medical Oncology Service at MSK, the study is the first to demonstrate the clinical utility of liquid biopsy–guided immunotherapy for patients with molecularly detectable minimal residual disease (MRD) following curative surgery. The study included patients with MMRd tumors from diverse primary sites, including colorectal, gastroesophageal, and endometrial cancers.
CtDNA, which has a half-life of approximately two hours, reflects the presence of actively dividing tumor cells. Detection of ctDNA after surgery is associated with a greater than 90% likelihood of recurrence in every solid tumor type tested. MMR deficiency, present in about 6% of all solid tumors, is a predictive biomarker for response to immune checkpoint blockade, with more than 50% of patients in the metastatic setting achieving long-term disease-free survival.
The MSK-sponsored trial (NCT03832569) screened 174 patients with 16 solid tumor types who had undergone R0 resection and completed standard adjuvant chemotherapy or chemoradiation. CtDNA analysis was conducted using MSK-ACCESS®, MSK’s next-generation sequencing-based liquid biopsy assay.
Of these 174 patients, 20 (11%) were ctDNA-positive, defined as having at least one mutation in circulating free DNA identical to the primary tumor’s mutation. Thirteen of these patients received six months of pembrolizumab. Among them, 85% (11 patients) achieved ctDNA clearance, with a median time to clearance of four months. At two years, recurrence-free survival (RFS) and overall survival (OS) rates were estimated at 64% and 92%, respectively. However, five patients recurred despite initial ctDNA clearance.
Six ctDNA-positive patients were ineligible for adjuvant immunotherapy because they showed radiographic evidence of metastatic disease. All six experienced rapid recurrence within two months of a positive ctDNA result, with a median RFS of just 0.8 months. None remained recurrence-free at two years.
In contrast, among the 152 ctDNA-negative patients who did not receive immunotherapy, only 11 (7%) experienced recurrence. Median RFS and OS were not reached in this cohort, and two-year RFS and OS rates were 94% and 99%, respectively.
“These findings exceeded our expectations, highlighting ctDNA’s potential as a biomarker to guide escalation and de-escalation of therapy in MMRd tumors,” said Dr. Janjigian. “Larger trials are needed to confirm these promising results and refine treatment strategies.”
Read AACR Abstract 10416. The study was supported by MSK’s Precision Interception and Prevention Program and Cycle for Survival. Pembrolizumab was provided by Merck. Access disclosures for Dr. Janjigian. Explore MSK clinical trials for patients with solid tumors.
KRAS G12D-Mutated NSCLC: Novel Inhibitor Shows Promising Initial Clinical Activity
The targeted therapy zoldonrasib (RMC-9805) demonstrated encouraging initial antitumor activity in a small group of patients with KRAS G12D-mutated NSCLC.
MSK thoracic medical oncologist and early drug development specialist Kathryn Arbour, MD, presented results of an ongoing, multisite, phase 1 trial evaluating escalating doses of zoldonrasib as monotherapy in patients with KRAS G12D-mutated solid tumors. Revolution Medicines is sponsoring the trial (NCT06040541).
For all 211 patients with various KRAS G12D-mutated tumor types, the oral drug was well tolerated with no dose-limiting toxicities. The maximum tolerated dose was not reached, and 1,200 mg daily was identified as the recommended dose for further study. Among 90 patients who received 1,200 mg daily, the most common treatment-related adverse events (TRAEs) occurring in at least 10% of patients were nausea (39%), diarrhea (24%), vomiting (18%), and rash (12%). Most TRAEs were grades 1 or 2, except for two patients with grade 3 events that resolved following dose interruption.
Among the subgroup of 18 patients with KRAS G12D-mutated NSCLC who received the dose of 1,200 mg daily, the objective response rate (ORR) was 61%. The median time to onset of initial responses was 1.4 months, ranging from 1.2 to 2.8 months, and the disease control rate was 89%.
“These preliminary results for patients with KRAS G12D mutated NSCLC are heartening, especially as there are no approved targeted therapies for this patient population,” said Dr. Arbour, principal investigator of the trial at MSK. “In addition to the substantial tumor shrinkage observed with monotherapy, the fact that the drug is well tolerated suggests it may perform well in combination with other chemotherapies, immunotherapies, or other targeted therapies.”
KRAS G12D mutations are found in about 4% of patients with NSCLC. Dr. Arbour noted that while most patients with KRAS-mutated NSCLC have a history of smoking, the KRAS G12D mutation is more likely to be found in patients without a smoking history. She presented a case study of a 36-year-old female with KRAS G12D-mutated NSCLC and no smoking history that demonstrated a good radiologic response.
Revolution Medicines previously reported that zoldonrasib monotherapy showed encouraging tolerability and antitumor activity in patients with KRAS G12D-mutated pancreatic cancer at the EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics in Barcelona on October 25, 2024.
MSK physician-scientists have been actively involved in identifying how KRAS mutations drive cancer growth for almost a decade. Read more. At AACR 2025, MSK physician-scientist Piro Lito, MD, PhD, presented the major symposium Developments in RAS Signaling Inhibition: Bench to Bedside.
Read AACR Abstract 10422.The study is sponsored by Revolutions Medicine. Access disclosures for Dr. Arbour. Explore MSK clinical trials for NSCLC.
Other Notable MSK Research News from AACR 2025:
- Ovarian and Endometrial Cancers with Poor Prognostic Features: Novel oral targeted therapy combination demonstrates safety and effectiveness. MSK gynecologic medical oncologist and early drug development specialist Alison Schram, MD, shared safety and efficacy results for the phase 1 MYTHIC study of lunresertib plus camonsertib in patients with ovarian and endometrial cancers with poor prognostic features (NCT04855656). Lunresertib, a first-in-class PKMYT1 inhibitor, targets tumors harboring CCNE1amp and deleterious FBXW7 and PPP2R1A mutations. Camonsertib, a novel ATR inhibitor, synergizes with lunresertib to enhance anti-tumor activity. Among 74 patients treated with the recommended phase 2 dose after schedule optimization, the most frequent grade 3 TRAE was anemia, occurring in 32% of patients. In the ovarian cancer group, the response rate was 31%, with a clinical benefit rate of 69%. In the endometrial cancer group, the response rate was 24%, with a clinical benefit rate of 49%. Paired tumor analysis confirmed target engagement in 75% and DNA damage induction in 43% of patients. Read AACR Abstract 10408. The study was sponsored by Repare Therapeutics. Access disclosures for Dr. Schram. Explore MSK’s ovarian cancer clinical trials and endometrial cancer clinical trials.
- HER2-Positive Breast Cancer: Adding trastuzumab to runimotamab demonstrated manageable safety and encouraging clinical activity. MSK breast medical oncologist Shanu Modi, MD, presented results for the phase 1 trial evaluating runimotamab, an intravenous HER2 x CD3 T-cell engaging bispecfic antibody, alone and in combination with trastuzumab in heavily-pretreated patients with HER2-positive breast cancer. Runimotamab 20/60 mg plus trastuzumab demonstrated a manageable safety profile and achieved a 30% ORR (7 of 23 patients) in phase 1b of the study (NCT03448042). Dr. Modi also noted in her plenary session that six of seven responders had a high level of HER2 expression at baseline (IHC3+). Read AACR Abstract 10428. The study was sponsored by Genentech, Inc. Access disclosures for Dr. Modi. Explore MSK breast cancer clinical trials.
- BCG-Unresponsive Non-Muscle Invasive Bladder Cancer: Novel antibody showed promising antitumor activity in a subset of patients. MSK gynecologic medical oncologist Juan Osorio, MD, presented updated results for the investigator-initiated phase 1 trial of 2141-V11 (NCT05126472), a novel anti-CD40 agonist antibody developed by physician-scientists at The Rockefeller University. This antibody contains an Fc domain engineered to enhance binding to the immune receptor FcgRIIB. The modification optimizes CD40 signaling, encouraging dendritic cells to present tumor-associated antigens to the immune system for more effective tumor destruction. The study focuses on patients with BCG-unresponsive non-muscle invasive bladder cancer. Results for the ongoing trial showed that 2141-V11 was well tolerated with no dose-limiting toxicities and achieved a complete response in 10 of 25 patients (40%). Among 21 evaluable patients at six months, eight (38%) had a complete response. Dr. Osorio noted that responses to 2141-V11 were associated with the formation of tertiary lymphoid structures and enhanced interactions between CD8+ and dendritic cells, confirming preclinical findings. Read AACR Abstract 10427. Learn more about this trial and MSK’s leadership in a new era of bladder cancer research. Access disclosures for Dr. Osorio. Explore MSK bladder cancer clinical trials.
- The MSK-IMPACT® team received the AACR Team Science Award for their groundbreaking role in advancing clinical genomic sequencing for people with cancer. MSK-IMPACT is a targeted tumor-sequencing test used to detect mutations and other critical changes in the genes of both rare and common cancers. Learn more.