Nivo/Ipi Induces Promising Response in Advanced tTMB- and bTMB-High Solid Tumors

In the phase 2 CheckMate-848 study (NCT03668119). The combination of nivolumab (Opdivo) and ipilimumab (Yervoy) elicited encouraging and durable responses with acceptable safety in patients with advanced or metastatic tumor mutational burden (TMB)–high solid tumors that were refractory to standard therapies, meeting the study’s primary end point.¹

Data, which were presented during the AACR Annual Meeting 2022, indicated that the doublet (n = 148) produced an objective response rate (ORR) of 35.3% (95% CI, 24.1%-47.8%) in the cohort of patients determined to have tissue TMB–high (tTMB-H) disease (n = 68), which was higher than the ORR of 22.5% (95% CI, 13.9%-33.2%) achieved by the cohort of patients with blood TMB–high (bTMB-H) disease (n = 80).

Among those who received nivolumab alone (n = 81), the immunotherapy elicited an ORR of 27.8% (95% CI, 14.2%-45.2%) in the tTMB-H cohort (n = 36) and 15.6% (95% CI, 6.5%-29.5%) in the bTMB-H cohort (n = 45).

“Nivolumab plus ipilimumab demonstrated clinical efficacy with a manageable safety profile in patients with advanced or metastatic tTMB-H and/or bTMB-H solid tumors that were refractory to standard therapies, with increased efficacy observed in patients with tTMB-H tumors,” lead study author Michael Schenker, MD, PhD, of Sf Nectarie Oncology Center and University of Medicine and Pharmacy, Craiova, Romania, said in a presentation on the data.

Because TMB is known to correlate with neoantigen load, tumors that are TMB-H are expected to be more immunogenic and responsive to treatment with immunotherapy, according to Schenker. Data have also indicated that TMB is a key predictive biomarker for immunotherapy spanning a range of solid tumor types. It is known that TMB can be determined from both the tissue and the blood.

In the prospective CheckMate-848 trial, investigators set out to examine whether nivolumab with or without ipilimumab would improve responses in patients with advanced or metastatic solid tumors that have high tTMB and/or high bTMB. Notably, the trial was not powered to compare the doublet with the monotherapy.

During the meeting, Schenker shared data from an interim analysis of the tTMB-H cohort and findings from final analyses of the bTMB-H cohort.

Patients with immunotherapy-naïve solid tumors that were refractory to standard therapies or who did not have standard treatment options available to them were enrolled. Patients needed to have tTMB and/or bTMB of at least 10 mutations/megabase (mut/Mb). Those with melanoma, non–small cell lung cancer, and renal cell carcinoma were excluded.

Participants were prospectively randomized in a 2:1 fashion to receive either nivolumab at 240 mg every 2 weeks plus ipilimumab at 1 mg/kg every 6 weeks for up to 24 months or nivolumab at 480 mg every 4 weeks for up to 24 months. Key stratification factors included line of therapy, tTMB of at least 16 mut/Mb, and bTMB of at least 16 mut/Mb.

The primary end points were ORR in patients with tTMB-H tumors and ORR in those with bTMB-H tumors. Key secondary end points comprised duration of response (DOR), investigator-assessed ORR, time to response, clinical benefit rate, progression-free survival (PFS), overall survival (OS), and safety.

To determine TMB in tissue specimens that were collected from participants, investigators leveraged the FoundationOne CDx-based Clinical Trial Assay. To identify TMB in the blood specimens that were collected, they used the Foundation Medicine bTMB Clinical Trial Assay.

Participants were prospectively classified as being tTMB-H or bTMB-H utilizing a cutoff of 10 mut/Mb or higher, according to Schenker. Patients were also stratified using a cutoff of at least 16 mut/Mb to ensure an even distribution of patients with relatively low TMB and relatively high TMB, as well as to allow for further analyses based on TMB stratification.

A total of 1954 patients were prescreened. Of these patients, 1141 had available tTMB data, 1573 had available bTMB data, and 1017 had both bTMB and tTMB data available. A total of 319 patients were screened and 212 patients underwent randomization on the trial. Of the 212 patients, 201 were refractory to standard therapies; 135 of these patients were determined to be tTMB-H and 147 patients were determined to be bTMB-H.

A total of 170 patients comprised the primary analysis population; 104 of these patients had tTMB-H tumors and 125 had bTMB-H tumors. Thirty-eight percent (n = 65) of the 170 patients were found to have both tTMB-H and bTMB-H tumors, Schenker said.

The trial population included over 40 different tumor types, which included biliary cancer (n = 7), carcinoma of unknown primary (n = 7), neuroendocrine cancer (n = 5), anal cancer (n = 5), sarcoma (n = 5), small bowel cancer (n = 4), squamous cell carcinoma (n = 3), glioblastoma (n = 3), adrenal cancer (n = 3), basal cell carcinoma (n = 3), vulvar cancer (n = 3), thymus cancer (n = 2), and penile cancer (n = 2), among others.

“The patient characteristics of age, sex, and geographic region were comparable and well distributed across tTMB-H and bTMB-H cohorts and across the treatment arms,” Schenker noted. “Additionally, the number of previous standard treatments was comparable across groups; this was the second stratification factor after TMB status.”

The median DOR was not yet evaluable in any of the cohorts examined on the trial. A DOR of 9 months or longer was observed in 91% (95% CI, 68%-98%) of those with tTMB-H disease who received the doublet (n = 68) and 88% (95% CI, 61%-97%) of those in the bTMB-H cohort who received the combination (n = 80).

Moreover, 78% (95% CI, 37%-94%) of patients who had tTMB-H tumors and received nivolumab monotherapy (n = 36) and 86% (95% CI, 33%-98%) of those with bTMB-H tumors who received nivolumab alone (n = 45) experienced a DOR of at least 9 months.

“Regarding the subgroup analysis of ORR in the tTMB-H cohort, the most important observation is that responses were independent of bTMB-H status,” Schenker explained. “The responses were observed in those with microsatellite instability–high (MSI-H), microsatellite stable, PD-L1–positive, and PD-L1–negative subgroups. In the bTMB-H cohort, responses were improved with tTMB-H status. MSI-H prevalence was too small to reach any kind of conclusions.”

Similar depths of response were observed in those with tTMB-H tumors, regardless of bTMB status, Schenker added. In those with bTMB-H tumors who received the doublet, depth of response seemed to be driven by tTMB-H status, and similar findings were noted in those who received nivolumab alone.

Additionally, although the study was not designed to directly compare PFS in the tTMB-H and bTMB-H cohorts, a trend toward a prolonged median PFS was observed in those with tTMB-H tumors vs those with bTMB-H tumors who received nivolumab plus ipilimumab.

Within the doublet arm, the median PFS was 4.1 months (95% CI, 2.8-11.3) in the tTMB-H cohort vs a median of 2.8 months (95% CI, 2.3-3.0) in the bTMB-H cohort. In the nivolumab-monotherapy arm, the median PFS was 2.9 months (95% CI, 2.6-5.7) in the tTMB-H cohort and 2.8 months (95% CI, 2.6-3.2) in the bTMB-H cohort.

A similar trend was observed with regard to OS, according to Schenker. In the nivolumab/ipilimumab cohort, the median OS was 14.5 months (95% CI, 7.7–not evaluable [NE]) in the tTMB-H cohort and 8.5 months (95% CI, 5.8-10.5) in the bTMB-H cohort. In the nivolumab-alone cohort, the median OS was 11.7 months (95% CI, 5.3-NE) in the tTMB-H cohort and 11.3 months (95% CI, 5.3-19.0) in the bTMB-H cohort.

Regarding safety, nivolumab plus ipilimumab was found to have a manageable toxicity profile; these profiles were consistent with what has previously been observed with the doublet and with nivolumab monotherapy. The most frequently experienced treatment-related adverse effects of any grade with the doublet included pruritus, diarrhea, and fatigue.

One patient who was included in both the tTMB-H and bTMB-H cohorts experienced a fatal toxicity associated with a study drug, which was hyperglycemia.

_Reference

_{Schenker M, Burotto M, Richardet M, et al. CheckMate 848: a randomized, open-label, phase 2 study of nivolumab in combination with ipilimumab or nivolumab monotherapy in patients with advanced or metastatic solid tumors of high tumor mutational burden. Presented at: 2022 AACR Annual Meeting; April 8-13, 2022; New Orleans, LA. Abstract CT022.}