Nivolumab Spurs Responses in non-CRC Patients With dMMR

Anita T. Shaffer @Shaffer1
Published Online: Saturday, Nov 11, 2017

Dr Nilofer S. Azad
Nilofer S. Azad, M
Nivolumab (Opdivo) demonstrated a 24% overall response rate (ORR) among patients with a range of non-colorectal cancers (CRCs) with mismatch repair deficiency (dMMR) who were identified through the NCI-MATCH trial, according to preliminary clinical trial findings reported at the 32nd SITC Annual Meeting.

The results represent the first substudy findings from NCI-MATCH, which is the largest precision medicine study ever conducted in the United States; it has involved conducting molecular testing on the tumors of 6000 patients since its inception 2 years ago, said Nilofer S. Azad, MD, in a presentation during the late-breaking abstract session at the conference on Friday. Azad, who is the principal investigator for the substudy Arm Z1D, is an assistant professor of oncology at Johns Hopkins University in Baltimore, Maryland.

The landmark clinical trial, conducted by the National Cancer Institute (NCI) and the ECOG-ACRIN Cancer Research Group, channeled patients into treatment arms based on molecular abnormalities rather than cancer types. Under the master protocol, biopsy samples were collected at more than 1000 sites for testing at a central pathology laboratory at The University of Texas MD Anderson Cancer Center. The trial is ongoing, with 18 treatment arms currently open for enrollment, according to the NCI.

“The NCI-MATCH trial is the very essence of team science,” said Azad. “The implementation and conduct of this trial has required [the collaboration of] hundreds of investigators from across the country.”

For Arm Z1D, researchers specifically were looking for patients with dMMR tumors that were not CRCs. The efficacy of the PD-1 inhibitors nivolumab and pembrolizumab (Keytruda) in dMMR metastatic CRC has been well established.

The FDA has approved both checkpoint blockade immunotherapy agents for use in patients with dMMR or microsatellite instability-high (MSI-H) metastatic CRC that has progressed after prior therapy. Pembrolizumab is also approved for unresectable or metastatic MSI-H or dMMR solid tumors that have progressed following prior treatment and when patients do not have other treatment options available.

To determine dMMR status, researchers performed immunohistochemistry (IHC) testing on formalin-fixed, paraffin-embedded tissue specimens. The samples were tested for expression of the mismatched repair proteins MLH1 and MSH2; DNA repair defects that resulted from dMMR are most commonly caused by the silencing of these 1 of these proteins, Azad said. dMMR status was defined as complete loss of nuclear expression of these proteins by tumor cells.

Of the patients who were enrolled in the study, 4901 had samples that were eligible for IHC testing for the mismatch repair proteins and results were gleaned from 4864 of those specimens. In all, 77 patients showed a loss of MLH1 or MSH2; of these, 62 were assigned to participate in Arm Z1D and 47 were eventually treated.

During her presentation, Azad reported results for 34 patients with a median age of 60 years (range, 44-85); findings involving an additional 12 patients enrolled in an expansion cohort are expected to be disclosed at a later date, while another patient was not included in the preliminary results due to an unresolved eligibility question. Sixty-eight percent of the patients were women. The participants had been heavily pretreated, with 42% having received more than 3 prior therapies. In terms of dMMR status, 71% were MLH1-negative and MSH2-positive, while 29% were MLH1-positive and MSH2-negative.

The group comprised patients with 14 histologic subtypes: 11 with endometriod endometrial adenocarcinoma; 6 with prostate cancer; 5 with uterine cancers consisting of carcinosarcoma (3 patients), leiomyosarcoma (1 patient), and uterine cancer not specified (1 patient); 3 with invasive breast cancer; and 1 each with gastroesophageal junction adenocarcinoma, small intestine adenocarcinoma, cholangiocarcinoma, gall bladder carcinoma, Hurthle cell neoplasm of the thyroid, parathyroid cancer, salivary gland cancer, bone cancer, and small cell lung cancer.

Patients received single-agent nivolumab at 3 mg/kg every 2 weeks for four 28-day cycles, followed by nivolumab at 480 mg every 4 weeks until progression. The primary endpoint for the cohort was ORR and the study was statistically powered to conclude whether an agent was promising enough to pursue in further studies.

Overall, 8 of 34 patients achieved a response for a 24% ORR (95% CI, 11%-41%); all were deemed partial responses (PRs) although there were 2 unconfirmed complete responses. “We did meet our primary endpoint,” Azad said. “…Of note, we had 5 more patients who had unconfirmed responses. Two of those patients remained on study at the time of data cutoff, so these response numbers may change as the study matures.”

The disease control rate, which consists of PRs, CRs, and stable disease, was 56%. The benefit was seen across histologies. “The duration of benefit was compelling for these patients,” Azad said. “The median time to response was 2.1 cycles and the 6-month progression-free survival was 49% [95% CI, 32%-67%].”

She said the median duration of response had not been reached at the time of data cutoff and that 11 patients overall were still undergoing treatment.

In terms of adverse events (AEs), Azad said the safety profile of nivolumab was consistent with that seen in prior studies. Treatment-related AEs consisted mostly of low-grade AEs; common all-grade AEs included fatigue (15%), anemia (10%), hypothyroidism, (6%), and anorexia (6%).
Azad N, Overman M, Gray R, et al. Nivolumab in mismatch-repair deficient (MMR-d) cancers: NCI-MATCH Trial (Molecular Analysis for Therapy Choice) Arm Z1D preliminary results.: Presented at: 32nd SITC Annual Meeting; November 9-12, 2017; National Harbor, MD. Abstract O37.

 





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