In a study (NCI-MATCH trial subprotocol, arm Z1D) reported in the Journal of Clinical Oncology, Nilofer S. Azad, MD, of Johns Hopkins Medicine Sidney Kimmel Comprehensive Cancer, and colleagues found that nivolumab was active in mismatch repair (MMR)-deficient noncolorectal cancers.1
“Nivolumab has promising activity in MMR-deficient noncolorectal cancers of a wide variety of histopathologic types.”— Nilofer S. Azad, MD, and colleagues
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As stated by the investigators: “The National Cancer Institute Molecular Analysis for Therapy Choice (NCI-MATCH) trial, the largest national precision oncology study to date (> 1,100 sites) of patients with relapsed or refractory malignancies, assigned patients to targeted therapy in parallel phase II studies based on tumor molecular alterations. The anti–programmed death receptor 1 inhibitor nivolumab previously showed activity in … MMR-deficient colon cancer. We hypothesized that nivolumab would have activity in patients with MMR-deficient, noncolorectal tumors.”
In the study, eligible patients with relapsed or refractory tumors were screened for molecular alterations. MMR deficiency was defined as complete loss of nuclear expression of MLH1 or MSH2 MMR gene products by immunohistochemistry. Of 4,902 screened patients, 2% had MMR-deficient cancer. A total of 42 evaluable patients with noncolorectal cancers were enrolled in the current protocol between August 2016 and June 2017. Patients with MMR-deficient colorectal cancer were excluded. Patients with MMR-deficient disease received nivolumab at 3 mg/kg every 2 weeks in 28-day cycles and 480 mg every 4 weeks after cycle 4.
The median age of study patients was 60 years (range = 4485 years), 28 (67%) were female, 35 (83%) were white, all had an Eastern Cooperative Oncology Group performance status of 0 (40%) or 1, and the median number of prior therapies was three.
The disease types consisted of endometrioid endometrial adenocarcinoma (n = 13); prostate adenocarcinoma (n = 5); uterine carcinosarcomas/malignant mixed Müllerian tumor (n = 4); adenocarcinoma of the esophagus/esophagogastric junction (n = 3); cholangiocarcinoma (n = 3); breast ductal carcinoma (n =3); pancreatic neuroendocrine carcinoma (n = 1); and ‘others’ consisting of mucinous small intestine adenocarcinoma, lung adenocarcinoma, parathyroid carcinoma, chordoma of the clivus of the skull, uterine leiomyosarcoma, salivary gland epithelial/myoepithelial carcinoma, small cell lung carcinoma, follicular carcinoma of the thyroid with Hürthle cell features, esophagogastric junction squamous cell carcinoma, squamous cell carcinoma of the cervix and vagina, and clear cell adenocarcinoma of the female genital tract/Müllerian origin.
The objective response on Response Evaluation Criteria in Solid Tumors, v1.1, was observed in 15 patients (36%), with a complete response in 3 (7%). An additional nine patients (21%) had stable disease. Complete responses were observed in two patients with endometrioid endometrial adenocarcinoma and one patient with cholangiocarcinoma. Partial responses were observed in three patients with endometrioid endometrial cancer, two with esophageal/esophagogastric junction cancer, two with prostate cancer, one with breast cancer, one with a Müllerian tumor, and three with “other” cancers.
Patients were treated for a median of five 28-day cycles, with a range of 1 to at least 24 cycles. At the time of analysis, nine patients (21%) were still receiving study therapy; of them, two had a complete response, five partial response, and two cases of stable disease as best response. The other patient with a complete response discontinued therapy due to adverse events in cycle 5 and remained without disease progression for 172 days before withdrawing follow-up consent. Among the 12 patients with a partial response, 3 discontinued therapy without disease progression between cycles 7 and 12; 2 were progression-free at 258 and 388 days, and the third patient was lost to follow-up after cycle 12. Among the nine patients with stable disease, one remained progression-free for 232 days after discontinuing therapy due to adverse events.
The most common additional genetic alterations in the patient population were those in TP53 (n = 16), PTEN (n = 15), PI3KCA (n = 9), and CTNNB1 (n = 7). No significant correlation was found between clinical response, disease control, or likelihood of disease progression and any particular abnormality; however, the presence of TP53 alteration vs wild-type TP53 was associated with trends toward an improved response rate (44% vs 31%) and progression-free survival (8 events in 16 patients vs 18 events in 26 patients, P = .071).
Microsatellite instability (MSI) status testing with polymerase chain reaction after completion of the study showed that 39 of 44 enrolled patients had MSI-high tumors. Partial response to nivolumab treatment was observed in one patient with MSI-low tumor and one patient with MSI-stable tumor.
In the entire group, the median progression-free survival was 6.3 months, with estimated 12- and 18-month rates of 46.2% and 31.4%, respectively. The median overall survival was 17.3 months.
The most common grade 1 to 3 treatment-related adverse events were fatigue (40%), anemia (33%), rash (17%), and hypoalbuminemia (17%). The most common grade 3 adverse event was anemia (7%); two patients (5%) each had dehydration, fatigue, maculopapular rash, and skin infection. Grade 4 adverse events occurred in three patients, consisting of sepsis in two and pneumonitis in one. Study treatment was discontinued due to adverse events in 10 patients (24%).
The investigators concluded: “A variety of refractory cancers (2% of those screened) had MMR deficiency as defined in NCI-MATCH. Nivolumab has promising activity in MMR-deficient noncolorectal cancers of a wide variety of histopathologic types.
DISCLOSURE: The study was supported by National Cancer Institute grants. For full disclosures of study authors, visit ascopubs.org.
1. Azad NS, Gray RJ, Overman MJ, et al: Nivolumab is effective in mismatch repair–deficient noncolorectal cancers: results from arm Z1D—A subprotocol of the NCI-MATCH (EAY131) study. J Clin Oncol 38:214-222, 2020.
Mismatch repair (MMR)-deficiency and consequently high DNA microsatellite instability (MSI-H) are associated with high tumor mutational burden. A high mutational load increases the potential number of neoantigens that can be presented by the tumor cell and recognized by host lymphocytes. Detection...