Memorial Sloan Kettering Cancer Center (MSK) experts shared the results from cutting-edge advances in cancer research at the European Society of Medical Oncology (ESMO) Congress 2024, held in Barcelona, Spain, September 13 to 17, 2024.
Highlights included promising advances for KRAS G12D-mutated solid tumors, dedifferentiated liposarcoma, lung cancer, pancreatic cancer, breast cancer, ovarian cancer, and head and neck cancer.
KRAS G12D-Mutated Advanced Solid Tumors: First-in-Class Drug Shows Promising Safety and Clinical Activity
The investigational drug ASP3082, the first-in-class KRAS G12D-targeted protein degrader, has shown promising safety and preliminary efficacy in an ongoing phase 1 international dose-escalation trial (NCT05382559) among patients with previously treated KRAS G12D-mutated pancreatic ductal adenocarcinoma (PDAC), colorectal cancer (CRC), and non-small cell lung cancer (NSCLC). The results support further clinical research to determine the drug’s efficacy.
MSK gastrointestinal medical oncologist Wungki Park, MD, MS, a member of the Solid Tumor Gastrointestinal Oncology Service and the Christine Iacobuzio-Donohue Lab at the David M. Rubenstein Center for Pancreatic Cancer Research, presented the preliminary study results in a proffered paper session on behalf of the MSK clinical trial team. The MSK co-investigators were gastrointestinal medical oncologist Eileen O’Reilly, MD, thoracic medical oncologist Kathryn Arbour, MD, and gastrointestinal medical oncologist and early drug development specialist Rona Yaeger, MD.
The KRASG 12D mutation is the most common KRAS mutation, found in 40% of PDAC, 15% of CRC, and 5% of NSCLC. Unlike KRAS G12C, there is no approved therapy for KRAS G12D.
Participants in the trial received ASP3082 monotherapy intravenously once weekly over 21-day cycles. As of data cutoff, 111 participants were enrolled for all dose levels, including 74 with PDAC, 16 with CRC, and 19 with NSCLC. Among 48 participants who received biologically effective higher doses from 300mg to 600mg, 31 had PDAC, 15 had NSCLC, and 1 had CRC. All patients were pretreated with a median of two prior lines of therapy.
Response results at data cutoff were particularly promising for patients with PDAC and NSCLC who received 300 to 600 mg of ASP3082 as follows: In the PDAC group, 6 of 27 participants remained on treatment, and five participants had partial responses, with a median time to response of 2.6 months. In the NSCLC group, 8 of 13 remained on treatment, and three participants had partial responses, with a median time to response of 1.4 months. Duration of response and progression-free survival endpoints were not mature.
ASP3082 demonstrated dose-dependent degradation of KRAS G12D-mutant protein, as seen on immunohistochemistry (IHC). A manageable safety profile was observed in doses up to 600 mg. Dose-limiting toxicities were observed, but the maximum tolerable dose has not yet been reached.
Treatment-related adverse events (TRAEs) occurred in 68 of 98 patients (69.4%), including grade 3 events in five patients (5.1%), and no cases of grade 4 or 5 events. TRAEs were well-tolerated and typically limited to infusion-related reactions, rashes, and fatigue. Three patients had liver enzyme elevations that resolved soon after stopping the medication.
Read ESMO Congress 2024 Abstract 6080. The study was funded by Astellas Pharma Inc. Access disclosures for Dr. Park. Learn more about MSK clinical trials for patients with KRAS G12D-mutated solid tumors.
Sarcoma: Targeted Therapy and Immunotherapy Combination Meets Primary Endpoint in Advanced Dedifferentiated Liposarcoma
According to results from the MSK-exclusive phase 2 trial (NCT04438824), the CDK4/6 inhibitor palbociclib plus anti-PD-1 agent retifanlimab demonstrated a noteworthy response in patients with unresectable or metastatic dedifferentiated liposarcoma.
MSK sarcoma medical oncologist Evan Rosenbaum, MD, presented results from the investigator-initiated single-arm study on behalf of the research team, which included principal investigator sarcoma medical oncologist Sandra D’Angelo, MD, in a mini-oral session.
Preclinical research has shown that CDK4/6 inhibition confers many anti-cancer benefits: increased cytokine secretion, tumor-infiltrating lymphocytes, and T cell activation; stimulation of antigen processing and presentation; reduced immunosuppressive Tregs; and increased expression of a senescence-associated secretory phenotype (also known as SASP). It also synergizes well with PD-1 inhibition.
At the time of data cut-off, the trial had enrolled and treated 28 patients out of the total recruitment goal of 30. Palbociclib 125 mg was taken orally daily for 21 of 28 weeks, and retifanlimab 500 mg was administered intravenously every four weeks.
Six patients (21%) had an objective response, many of which were deep and durable responses. Hepatitis was a frequent but manageable side effect, with no grade 4 or higher hepatic events.
The research team is working on identifying biomarkers of response and resistance to this combination therapy using paired tumor biopsies and peripheral blood samples. For this work, they are collaborating with MSK colleagues in the Samuel Singer Lab, which focuses on sarcoma biology, the Andrew Koff Lab, which focuses on the roles of CDK inhibitors in cancer biology, and the Ronglai Shen Lab, for analysis of peripheral blood samples with high-parameter flow cytometry.
Results from the correlative analyses will inform future clinical trial design for this novel treatment combination in patients with dedifferentiated liposarcoma.
Read ESMO Congress 2024 Abstract 1720M0. The study was funded by Incyte Corporation and an R01 grant from the National Institutes of Health awarded to Dr. D’Angelo. Access disclosures for Dr. Rosenbaum and Dr. D’Angelo. Learn more about MSK sarcoma clinical trials.
NSCLC: Novel Brain-Penetrant ALK-Selective Inhibitor Shows Promising Results
Thoracic medical oncologist Alexander Drilon, MD, Chief of MSK’s Early Drug Development Service, presented an update of results from the international ALKOVE-1 phase 1/2 study (NCT05384626) evaluating the recommended dose, overall safety, tolerability, and preliminary antitumor activity of NVL-655 for patients with advanced solid tumors harboring an ALK fusion or activating mutation.
NVL-655 is an oral ALK-selective inhibitor designed to be active in tumors that develop resistance to first-, second-, and third-generation ALK inhibitors. It was also created to optimize central nervous system (CNS) penetrance for patients with brain metastases and to avoid side effects (such as changes in thinking, personality, and mood) due to inhibiting the tropomyosin receptor kinase (TRK) family of proteins found on nerve cells.
The safety profile for NVL-655 was favorable and consistent with avoiding TRK-related neurotoxicities. Among 133 patients with ALK+ solid tumors (131 with NSCLC and 2 with other solid tumors), 2% discontinued treatment due to a TRAE, and 15% received a dose reduction due to TRAEs.
Durable responses were observed at the recommended phase 2 dose level of 150 mg daily across patient subgroups. Objective response rates (ORRs) were as follows: 38% (15/39) for patients with ALK+ NSCLC pretreated with 1 to 5 prior ALK tyrosine kinase inhibitors (TKIs), with or without prior chemotherapy; 35% (11/31) for patients pretreated with 2 or more ALK TKIs including lorlatinib; and 57% (4/7) for lorlatinib-naïve patients pretreated with 1 or more ALK TKIs. For patients with single and compound ALK resistance mutations which can lead to disease progression, the ORR was 64% (7/11) for patients with compound ALK resistance mutations after 2 or more prior ALK TKIs including lorlatinib, and 80% (4/5) for lorlatinib-naïve patients with ALK resistance mutations after 1 or more prior ALK TKI. In all patient subgroups, the median duration of response had not yet been reached.
Notably, 84% of patients had received prior lorlatinib, and 56% had a history of CNS metastases, including cases of disease progression following treatment with lorlatinib. In this phase 1 portion of this trial, NVL-655 showed durable intracranial responses, including complete intracranial responses in patients who previously received lorlatinib, a brain-penetrant TKI.
The ongoing phase 2 portion of this trial is enrolling TKI-naïve and TKI-pretreated patients with ALK+ NSCLC or other ALK fusion or mutation containing solid tumors.
The U.S. Food and Drug Administration has granted NVL-655 breakthrough therapy designation for treating patients with locally advanced or metastatic ALK+ NSCLC who were previously treated with two or more ALK TKIs, and orphan drug designation for ALK+ NSCLC.
Read ESMO Congress 2024 Abstract 12530. The study was sponsored by Nuvalent. Access disclosures for Dr. Drilon. Learn more about MSK clinical trials for patients with NSCLC.
Other Notable MSK Research News from ESMO Congress 2024:
Metastatic Pancreatic Cancer: Phase 2 POLAR trial results
Preliminary results showed the combination of Pembrolizumab plus OLApaRib (POLAR) was safe, tolerable, and demonstrated significant clinical activity as a novel maintenance therapy in select patients with metastatic pancreatic cancer. This ongoing MSK-exclusive, investigator-initiated trial (NCT04666740) evaluates POLAR in three groups: (A) patients with a homologous recombination germline gene mutation (BRCA1/2/PALB2); (B) patients with a non-core homologous gene (HR) mutation (other gene mutations beyond cohort A); and (C) patients with no HR gene mutation who had an exceptional response to platinum-based therapy. As of data cutoff, cohort A (33 patients) had better ORR and progression-free survival (PFS) compared to cohort B (15 patients) or C (15 patients). The ORR was 35% and the disease control rate was 80% for cohort A. The follow-up is still maturing, and median was 15.7 months (95% CI: 1.4-40.7). From the data available until the cutoff date, a total of 11 patients (33%) in cohort A had a PFS greater than one year and six patients had PFS greater than two years on chemotherapy-free targeted immunotherapy (POLAR). Signals of immune activation, including genomic instability score, neoantigen, tumor infiltrating lymphocytes, and immune-related side effects were associated with clinical outcomes.
Read ESMO Congress Abstract 1504M0, presented by principal investigator gastrointestinal medical oncologist Wungki Park, MD, MS. The trial was funded by Merck. The correlative science was funded by a National Institutes of Health SPORE grant awarded to co-investigators Co-Director Eileen O’Reilly, MD, FASCO Director Christine Iacobuzio-Donahue MD, PhD and member Dana Pe’er, PhD of the David M. Rubenstein Center for Pancreatic Cancer Research. Access disclosures for Dr. Park and Dr. O’Reilly. Explore MSK clinical trials for patients with metastatic pancreatic cancer.
Breast Cancer: Developing advanced lab tests for predicting response to antibody-drug conjugates
MSK researchers and international colleagues are combining advanced technologies to develop new approaches that more precisely assess unique predictive features in breast cancer. A novel test combining multiplexed RNA-FISH-guided laser capture microdissection with RNA-sequencing (mFISHseq) demonstrated 93% accuracy compared to IHC in evaluating key biomarkers in a retrospective cohort of 1,082 breast cancer specimens. The research team leveraged this approach to develop a unique 19-feature classifier containing combinations of antibody-drug conjugate (ADC) mechanism of action markers, including antigen and payload targets, as well as markers related to endosomal processing and lysosomal degradation.
This classifier predicted responses to trastuzumab emtasine (T-DM1) better than either ERBB2 mRNA or HER2 IHC alone in the T-DM1 arm of the Neoadjuvant and Personalized Adaptive Novel Agents to Treat Breast Cancer (I-SPY2) clinical trial (NCT01042379). The results revealed clinical insights into patient selection for novel therapies such as ADCs.
Read ESMO Congress 2024 Abstract 250P, presented by MSK breast pathologist and physician-scientist Fresia Pareja, MD, PhD, on behalf of the research team. This study was conducted in collaboration with MultiplexDx and was supported by an EIC Accelerator grant awarded to MultiplexDx and an NIH/NCI P50 grant that partially funds Dr. Pareja. Access disclosures for Dr. Pareja.
Platinum-Resistant Ovarian Cancer: Updated phase 1 trial results for brenetafusp
Brenetafusp is a T cell receptor bispecific ImmTAC® molecule made by Immunocore. The drug targets preferentially expressed antigen in melanoma (PRAME), which is also expressed in more than 90% of ovarian cancers. Updated phase I trial results (NCT04262466)showed brenetafusp was well tolerated as monotherapy and in combination with gemcitabine, nab-paclitaxel, and doxorubicin in patients with advanced or recurrent ovarian cancer.
Signals of promising activity in heavily pretreated, platinum-resistant patients included a disease control rate of 58% as monotherapy and 69% in combination. The six-month overall survival (OS) rate was 73%, with data still maturing. Molecular response rates based on changes in circulating tumor DNA — 31% for monotherapy and 82% in combination — were associated with longer PFS and OS.
Results were presented in a poster presentation by MSK gynecologic medical oncologist and early drug development specialist Claire Friedman, MD. The trial was sponsored by Immunocore. Access disclosures for Dr. Friedman. Explore MSK clinical trials for ovarian cancer.
Read ESMO Congress 2024 Abstract 750P, presented in a poster presentation by MSK gynecologic medical oncologist and early drug development specialist Claire Friedman, MD. The trial was sponsored by Immunocore. Access disclosures for Dr. Friedman. Explore MSK clinical trials for ovarian cancer.
Advanced Head and Neck Cancer: Conditionally Active Biologic Shows Promising Anti-Tumor Activity
Conditionally active biologics (CABs) are drugs designed to attack cancer while reducing off-tumor toxicity and immunogenicity. Ozuriftamab vedotin (BA3021), a CAB-ROR2-ADC that conditionally and reversibly binds to the tyrosine kinase receptor ROR2 under low pH conditions, is under evaluation in an ongoing multicenter phase 2 open-label trial (NCT05271604) among heavily pre-treated patients with recurrent or metastatic squamous cell carcinoma of the head and neck.
Among 31 heavily pretreated patients evaluable for efficacy, there were 10 responders (32%; one complete response and 9 partial responses), and 14 patients had stable disease. The ORR was 32% and the disease control rate was 77%. The median duration of response has not yet been reached. Most TRAEs were low grade, with fatigue, anemia, and nausea being the most common. Six patients (19%) had grade 3 TRAEs, one patient experienced a grade 4 TRAE, and there were no grade 5 TRAEs.
Read ESMO Congress 2024 Abstract 868P, presented in a poster presentation by head and neck medical oncologist Winston Wong, MD, principal investigator of the trial at MSK. The study is funded by BioAtla, Inc. Access disclosures for Dr. Wong. Learn more about MSK clinical trials for patients with head and neck cancer.