MSK Research Roundup at ASCO 2022: Breakthrough Findings for Rectal Cancer, Breast Cancer, Leptomeningeal Metastasis, Pancreatic Cancer, and Lung Cancer

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Memorial Sloan Kettering Cancer Center (MSK) experts presented breakthrough findings in several areas of cancer research at the 2022 ASCO Annual Meeting held June 3 to 7, 2022. Highlights of practice-changing study results in rectal cancer, breast cancer, leptomeningeal metastasis, pancreatic cancer, lung cancer, and more were as follows:

Rectal Cancer: Neoadjuvant Immunotherapy Results in 100% Complete Response in MMRd Locally Advanced Rectal Cancer

Rectal cancer disappeared entirely for 14 patients to date in a phase 2 clinical trial testing the efficacy of the anti-PD-1 monoclonal antibody dostarlimab as a first-line single-agent treatment for patients with stage 2 or 3 tumors with mismatch repair deficiency (MMRd). The groundbreaking results were presented at ASCO 2022 and simultaneously published in the New England Journal of Medicine.

All 14 patients who started treatment achieved a complete clinical response with no evidence of tumor on MRI, FDG-PET, endoscopic visualization, digital rectal exam, or biopsy within at least six months of follow-up. To date, no patients have needed chemoradiation or surgery, there have been no cases of progression or recurrence during follow-up (from six to 25 months), and no serious adverse events (greater than grade 3) have been observed.

The trial (NCT04165772) led by Andrea Cercek, MD, Section Head of Colorectal Cancer and Co-Director of the Center for Young Onset Colorectal and Gastrointestinal Cancer, and Luis Alberto Diaz Jr, MD, the Grayer Family Chair and Head of the Division of Solid Tumor Oncology at MSK, also provides a framework for evaluating “immunoablative” therapy, in which immunotherapy replaces surgery, chemotherapy, and radiation.

“Surgery and radiation have permanent effects on fertility, sexual health, bowel, and bladder function. The implications for quality of life are substantial, especially in those where standard treatment would impact childbearing potential. As the incidence of rectal cancer is rising in young adults, this approach can have a major impact,” Dr. Cercek said.

“While longer follow-up is needed to assess response duration, this is practice-changing for patients with MMRd locally advanced rectal cancer,” Dr. Diaz said. “As we advance our research, we envision PD-1 blockade will be evaluated in other MMRd tumors, including not-yet-metastatic pancreatic, gastric, and prostate cancers in the neoadjuvant setting — which could open the door for a pan-tumor approach akin to MMRd in the metastatic disease.”

ASCO 2022 Abstract LBA5. The study was supported by the Simon and Eve Colin Foundation, Glaxo- SmithKline, Stand Up to Cancer, Swim Across America, and the National Cancer Institute of the National Institutes of Health (awards R21CA252519 and NCI-P30CA008748). Access author disclosures at ASCO.org and NEJM.org.

Learn more: Read how Dr. Diaz’s early work led to a shift in the treatment paradigm for patients with MMRd tumors in 2017 and the FDA’s announcement of the first pan-tumor approval of an immunotherapy for adult and pediatric patients with metastatic MMRd tumors.

Video: Learn more 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.

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Breast Cancer: Researchers Identify HER2-Low as a Targetable Subset, Redefining Treatment for More Than Half of Patients with HER2-Negative Metastatic Disease

MSK researchers and international colleagues found that trastuzumab deruxtecan (T-DXd) led to significantly improved survival compared to standard chemotherapy for patients with HER2-low metastatic breast cancer. The practice-changing results from the phase 3 international, multicenter DESTINY-Breast04 Trial (NCT03734029) were simultaneously presented by Shanu Modi, MD, a medical oncologist in MSK’s Breast Medicine Service and published in the New England Journal of Medicine.

Dr. Modi and colleagues found that for patients with HER2-low and hormone receptor-positive (HR+) breast cancer who received T-DXd versus standard chemotherapy, progression-free survival (PFS) nearly doubled (10.1 months versus 5.4 months; p < 0.001), and overall survival improved significantly (23.9 months versus 17.5 months; p = 0.003).

T-DXd is a novel antibody-drug conjugate that links the HER2 monoclonal antibody trastuzumab to deruxtecan, a topoisomerase I inhibitor that interrupts DNA replication in cancer cells. The DESTINY-04 Breast Trial included 557 patients with HER2-low metastatic breast cancer who had received one or two prior lines of chemotherapy for metastatic disease. Patients were randomized two-to-one to receive either T-DXd or their physician’s choice of standard chemotherapy.

“Approximately 60% of HER2-negative metastatic breast cancers express low levels of HER2, yet these have always been defined and treated as HER2-negative breast cancers, where treatment choice is guided by the hormone receptor status,” explained Dr. Modi. “Once there is resistance to the initial therapies, patients with HER2-low breast cancers have limited late-line targeted options and ultimately are offered palliative single agent chemotherapy. The results with T-Dxd shown today have the potential to significantly improve treatment outcomes for this large population of patients.”

ASCO 2022 Abstract LBA3. The study was supported by funding by Daiichi Sankyo and AstraZeneca. Access author disclosures at ASCO.org and NEJM.org.

Video: See MSK medical oncologist Shanu Modi, MD, discuss the results and implications of the clinical trial showing that patients with HER2-low metastatic breast cancer benefitted from trastuzumab deruxtecan.

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Leptomeningeal Metastasis: Proton Therapy Provides Effective Control

The first randomized study of radiotherapy for leptomeningeal metastasis (LM) demonstrated significantly improved outcomes with proton craniospinal irradiation (pCSI) compared to photon involved-field radiotherapy (IFRT) in patients with non-small cell lung cancer (NSCLC) or breast cancer LM. Based on significant benefits observed in the planned interim analysis, the trial was discontinued early so that pCSI could be made available to other patients as soon as possible.

LM is typically associated with short survival, and standard care with IFRT provides limited benefits. Jonathan Yang, MD, a radiation oncologist at MSK and primary investigator of the trial, and colleagues hypothesized that pCSI encompassing the central nervous system would result in superior disease control compared to IFRT.

Dr. Yang presented results from the phase 2 randomized controlled trial (NCT04343573) in which 42 patients received pCSI and 21 patients received IFRT. Radiotherapy consisted of 3 gray in 10 fractions for all patients. At the planned interim analysis, the median central nervous system progression-free survival (PFS) with pCSI was 7.5 months versus 2.0 months with IFRT (p < 0.001). There was also a significant overall survival benefit with pCSI compared to IFRT (8.2 months versus 4.9 months; p = 0.04). Grade 3 toxicities were comparable between interventions.

“It’s very exciting that we have an effective new option for a disease that is very hard to treat. The choices have traditionally been limited for leptomeningeal metastasis, but this approach gives us a much better way to control the disease,” Dr. Yang said. “We’re very lucky to be at a center of excellence where we can develop novel therapies for patients with dire needs. There are multiple treatment options in clinical trials, and there could be some really exciting things coming out in the next few years.”

Dr. Yang and MSK colleagues are studying molecular information collected during the trial to inform future selection of patients who are more likely to respond to proton therapy. They plan to validate their present findings in a larger phase 3 trial in the future, in collaboration with other institutions.

ASCO 2022 Abstract 2000. Access author disclosures at ASCO.org.

Read more about the power and precision of proton therapy for treating a range of brain tumors and Dr. Yang’s efforts to expand its use.

Video: See Dr. Yang explain how proton therapy works.

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Other Notable MSK Research News from ASCO 2022:

  • Pancreatic Cancer: Update on mRNA Vaccine Phase 1 Trial. Updated results for MSK’s investigator-initiated phase 1 trial (NCT04161755) of autogene cevumeran, a personalized mRNA neoantigen vaccine for the treatment of pancreatic ductal adenocarcinoma, continue to show the vaccine is safe, feasible to manufacture in a relevant timeframe, immunogenic to PDAC, and correlates with improved outcomes among responders. ASCO 2022 Abstract 2516, presented by Vinod Balachandran, MD, surgical oncologist and physician-scientist affiliated with the David M. Rubenstein Center for Pancreatic Cancer Research and a member of the Human Oncology and Pathogenesis Program and the Parker Institute for Cancer Immunotherapy at MSK.
  • Reducing the Financial Hardship of Cancer Treatment. MSK’s Affordability Working Group reported on a three-month pilot study of their novel EMR order set, the first patient referral system for streamlining patient referrals for financial assistance and counseling. Overall, hospital-based electronic medical record interventions helped connect patients to resources, and multilevel interventions will be required to reduce cancer-related financial hardship. ASCO 2022 Abstract 6596, presented by Bridgette Thom, PhD, senior research specialist with MSK’s Adult Survivorship Program.
  • A New Targeted Therapy for Tumors with NRG1 Fusions. Zenocutuzumab, a novel bispecific antibody targeting both HER2 and HER3, showed encouraging activity in the phase 2 eNRGy trial (NCT02912949) and favorable tolerability in a range of rare NRG1 fusion-positive tumors, including non-small cell lung cancer, pancreatic cancer, breast cancer, and colorectal cancer. The objective response rate was 34 percent, the median duration of response was 9.1 months, and most treatment-related adverse events were grade 1 or 2. ASCO 2022 Abstract 105, presented by MSK medical oncologist Alison Schram, MD.
  • No Survival Increase in Small Cell Lung Cancer for Tiragolumab Added to Standard Therapy. The phase 3 SKYSCRAPER-02 Trial (NCT04256421) found that adding tiragolumab, an anti-TIGIT experimental monoclonal antibody, to standard atezolizumab plus chemotherapy did not increase progression-free or overall survival among newly diagnosed patients with extensive-stage small cell lung cancer. ASCO 2022 Abstract LBA8507, presented by Charles Rudin, MD, PhD, Chief, Thoracic Oncology Service; Co-Director, Fiona and Stanley Druckenmiller Center for Lung Cancer Research; Sylvia Hassenfeld Chair in Lung Cancer Research at MSK.
  • Novel SERD Shows Promising Efficacy in Advanced, ER-Positive Breast Cancer. Findings from phase 1a/1b of the EMBER trial (NCT04188548) evaluating imlunestrant, a selective estrogen receptor degrader (SERD), demonstrated safety and preliminary efficacy in patients with ER-positive advanced breast and endometrial endometrioid cancers. The results suggest imlunestrant could be a promising next-generation treatment for challenging-to-treat ER-positive cancers. ASCO 2022 Abstract 1021, presented by MSK medical oncologist Komal Jhaveri, MD.
  • CAR T Cell Therapy for Relapsed or Refractory Multiple Myeloma: Update on CARTITUDE-1: The latest results for the phase 1b/2 CARTITUDE-1 trial (NCT03548207) showed that a single infusion of ciltacabtagene autoleucel (cilta-cel), a chimeric antigen receptor T (CAR T) cell therapy, led to durable responses in heavily pretreated patients with relapsed or refractory multiple myeloma. At a median follow-up of 21.7 months, rates of objective response, very good partial response, and stringent complete response were 97.9 percent, 94.9 percent, and 82.5 percent, respectively. Median progression-free survival and overall survival were not reached. Follow-up continues, with data as of two years post last patient in to be presented in the future. ASCO 2022 Abstract 8028, presented by hematologist-oncologist Saad Usmani, MD, Chief of the Myeloma Service at MSK.
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