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TMB-High Status Does Not Predict Opdivo-Yervoy Response in Pan-Tumor Analysis

NEW YORK –  High tumor mutational burden (TMB) was not associated with improved outcomes in solid tumor patients treated with the combination of Bristol Myers Squibb's nivolumab (Opdivo) and ipilimumab (Yervoy) in a Phase II basket trial, researchers reported in a paper published Thursday in Cancer Cell.

Although researchers conducted the retrospective biomarker analysis on a small cohort of 83 patients with available tumor tissue out of 120 enrolled in the basket trial, the results are noteworthy in that they add to a growing body of data that TMB-high status at a cutoff of 10 mutations per megabase may not be a useful tumor-agnostic biomarker for predicting response to checkpoint inhibitors. 

The US Food and Drug Administration's decision last year to grant accelerated approval to the PD-1 inhibitor pembrolizumab (Merck's Keytruda) for a refractory, tumor-agnostic patient population who have TMB of at least 10 mutations per megabase. That approval was one of the reasons why study authors, including Oliver Klein of the Olivia Newton-John Cancer Research Institute in Melbourne, Australia, decided to investigate whether the same biomarker using the same cutoff would predict which patients with solid tumors would benefit from the combination of the CTLA-4 inhibitor ipilimumab and the PD-1 inhibitor nivolumab.

Although the Keynote-158 trial, which led to pembrolizumab's tissue-agnostic approval, demonstrated an increased response rate in patients with TMB-high tumors, "no correlative TMB analyses have been reported for a pan-tumor cohort treated with combination immunotherapy," wrote Klein and colleagues.

The 120 patients enrolled in the Phase II nivolumab-ipilimumab trial all had advanced solid cancers, and the majority of them had received prior systemic treatment. The objective response rate with the combination of checkpoint inhibitors was 33 percent, and the clinical benefit rate, defined as the percentage of patients who achieved complete remission, partial remission, or stable disease at 12 weeks following therapy, was 67 percent.

Within the TMB-evaluable group, the median TMB score was 4.17 mutations per megabase, and 13 patients — comprising 15 percent of the cohort — had TMB-high tumors harboring at least 10 mutations per megabase. Of note, the nivolumab-ipilimumab trial used Thermo Fisher Scientific's Oncomine tumor mutation load assay rather than Foundation Medicine's FoundationOne CDx next-generation sequencing assay used in the Keynote-158 pembrolizumab trial. That said, the Thermo Fisher test "has shown comparable results in validation studies to those from the Foundation Medicine assay," Klein and colleagues wrote.

Patients in the nivolumab-ipilimumab study with TMB-high tumors had a variety of rare tumor types, including uterine cancer, cholangiocarcinoma, and adrenocortical carcinoma, among others. In these TMB-high patients, the response rate with the checkpoint inhibitor combo was 46 percent. In the TMB-low group, this response rate was 31 percent.

However, the TMB-high group included a couple of patients with microsatellite instability-high (MSI-high) status — a biomarker that is also characterized by an increased burden of tumor mutations and is already known to be associated with response to immunotherapy — so the researchers performed their analysis again taking this into account. "Given that sensitivity of MSI-high cancers to checkpoint inhibitor therapy is only partially due to the high TMB of these tumors, we excluded the two patients with MSI-high tumors," wrote the researchers. In this analysis, the response rate among the remaining TMB-high patients was 36 percent — not a significant improvement over the 31 percent response rate seen in the TMB-low group.

Because the cancer types included in the analysis were rare and diverse, the researchers also looked into whether the median TMB measurement varied much depending on the location and type of tumor. They found that median TMB was similar across cohorts of upper gastrointestinal, neuroendrocrine, and gynecological cancers, with a median of 3.33, 3.36, and 4.84 mutations per megabase, respectively. Within each of these respective cohorts, the median TMB for responders did not differ significantly from the median TMB for non-responders.

Ultimately, Klein and colleagues wrote, even though the response rate of 33 percent and the clinical benefit rate of 67 percent observed in the trial of nivolumab-ipilimumab were "higher than previously reported with anti-PD-1 monotherapy," TMB-high status "didn't appear to be a clinically useful predictor for response [in this trial] using nivolumab-ipilimumab combination immunotherapy."

While cross-trial comparisons are imperfect — and the study at hand considered fewer patients than did Keynote-158 — the researchers highlighted that there was significant overlap in the enrolled tumor types in Keynote-158 and the nivolumab-ipilimumab trial. In fact, 70 percent of patients in the combination trial had tumor types that were likewise enrolled in Keynote-158. The proportion of patients — 15 percent — with TMB-high tumors in the combo trial, moreover, was similar to the proportion of patients with TMB-high tumors in the Keynote-158 trial, which was 13 percent.

Based on these observations, Klein and colleagues concluded that their research suggests "the predictive value of the TMB-high biomarker in the context of monotherapy might not be extrapolated when combination therapies are employed."  To confirm these findings, the researchers called for analyses in additional datasets going forward.