NEW YORK – The combination of Bristol Myers Squibb's anti-PD-1 inhibitor nivolumab (Opdivo) and its anti-CTLA-4 therapy ipilimumab (Yervoy) demonstrated modest activity in metastatic, castration-resistant prostate cancer (mCRPC) patients, according to recently published preliminary data from the CheckMate-650 trial.
However, exploratory biomarker analysis in the same study suggested that patients with higher tumor mutational burden may potentially derive greater benefit from the regimen than those with lower TMB levels and should be investigated further.
The results, published Thursday in the journal Cancer Cell, are the first to assess the anti-tumor activity of the nivolumab-ipilimumab combination in mCRPC, a cancer that has not historically benefitted from single-agent checkpoint inhibitors.
CheckMate-650, led by team of researchers from multiple institutions including MD Anderson Cancer Center, included two cohorts. One cohort included asymptomatic or minimally symptomatic patients who progressed after at least one second-generation hormone therapy and had not received chemotherapy for their metastatic disease. And a second cohort involved mCRPC patients who had progression on cytotoxic chemo.
In the first cohort of 45 chemo-naïve patients, the median overall response rate was 25 percent and median overall survival was 19 months on the combination regimen. In the second cohort of 45 chemo-treated patients, the overall response rate and median overall survival was 10 percent and 15 months, respectively. Two patients in each cohort achieved complete responses.
Though the results suggest mCRPC patients are likely to derive modest benefit from the nivolumab-ipilimumab regimen compared to the activity seen in other tumor types, the authors led by Padmanee Sharma of the MD Anderson Cancer Center noted in their paper that the benefit seen with the combination still appeared to be an improvement over checkpoint inhibitor monotherapy reported in other studies. Previous trials had reported overall response rates in the range of 0 percent to 5 percent with anti-PD-1 monotherapy in the post-chemotherapy mCRPC setting.
Sharma and colleagues conducted the CheckMate-650 study after initial research demonstrated that ipilimumab could increase tumor-infiltrating T cells in the prostate tumor microenvironment and upregulate the PD-1/PD-L1 inhibitory pathway, in turn leading to a rationale for combining ipilimumab and nivolumab.
"The lack of benefit in unselected mCRPC is likely due to the immunologically 'cold' nature of the tumor, with relatively few tumor-infiltrating T cells in most men," wrote Sharma and colleagues, calling the results in the post-chemotherapy population "encouraging compared with historical data."
As for the chemotherapy-naïve patient population, the authors pointed out that although cross-trial comparisons are imperfect, patients in studies of hormone therapies, such as abiraterone and enzalutamide, have had median overall survival of around 35 months, which is above the 19 months seen with the checkpoint inhibitor combination in CheckMate-650.
That said, the authors noted that there have not been large randomized studies reporting overall survival with consecutive second-line treatment with either hormone therapy (such as abiraterone followed by enzalutamide, or vice versa), while in the CheckMate-650 trial, roughly half of the patients enrolled in both arms had received previous treatment with one of the hormone therapies. Ultimately, the researchers wrote, "the observed activity of nivolumab plus ipilimumab in both the pre- and the post-chemotherapy setting raises the question of where this therapy may potentially fit in the treatment paradigm of mCRPC."
In an attempt to home in on groups that might derive greater benefit from nivolumab-ipilimumab, researchers conducted whole-exome sequencing on patients' tumor samples and used their whole-blood DNA as a control. They identified several factors that correlated with improved clinical outcomes with the combination, such as higher TMB and, to a lesser extent, patients' homologous recombination deficiency or DNA damage repair mutation status. Higher PD-L1 expression according to immunohistochemistry also correlated with improved outcomes, though to a lesser extent than TMB.
Because prostate cancer is known to have a much lower somatic mutation frequency than other cancers, TMB was not calculated in terms of mutations per megabase but in terms of the total number of somatic mutations per patient. In the study, the median TMB across both cohorts was 74.5 mutations per patient. In patients with TMB above that cutoff, the objective response rate was 50 percent, versus 5 percent for those with TMB below that cutoff.
Additionally, the exploratory analysis showed preliminary evidence of a possible relationship between increased inflammation gene signature scores and objective response, although the researchers noted that this finding — as well as the other biomarker findings they listed — should be interpreted with caution due to the study's small sample size. Not all of the patients enrolled in the study had available biomarker data, the researchers pointed out, writing, "Our biomarker data, along with other published data in this area, remain exploratory and will require further investigations with larger numbers of patients to determine significance and/or clinical relevance."
Going forward, the authors urged future analyses on other emerging biomarkers, such as microsatellite instability-high disease and CDK12 alterations.
Notably, about half the patients in both cohorts of CheckMate-650 experienced grade 3 and 4 treatment-related adverse events, and 31 patients in total discontinued treatment due to adverse events. Four treatment-related deaths occurred as well, leading the researchers to conclude that an amended protocol with adjusted dosing would be necessary to improve the combination's safety profile in future studies.
Accordingly, based on these preliminary data, the CheckMate-650 trial has been expanded to include more than 400 patients treated with amended dosing schedules, with the goal of identifying strategies to improve the efficacy of the nivolumab-ipilimumab combination in mCRPC and minimize its toxicities.