Nivolumab/Ipilimumab Combo Induces Improved Responses in Chemo-Naïve mCRPC

Padmanee Sharma, MD, PhD

The combination of nivolumab (Opdivo) and ipilimumab (Yervoy) demonstrated improved responses in a cohort of chemotherapy-naïve patients with metastatic castration-resistant prostate cancer (mCRPC) compared with a cohort of chemotherapy-exposed patients, according to findings from a preliminary analysis of the phase 2 CheckMate-650 trial.¹

Per investigator assessment, the overall response rate (ORR) with the combination was 25% among chemotherapy-naïve patients and 10% among chemotherapy-exposed patients.

Additionally, the median radiographic progression-free survival, which served as a co-primary end point with ORR, was 5.5 months (95% CI, 3.5-7.1) versus 3.8 months (95% CI, 2.1-5.1), respectively.

“Historically, prostate cancer has been very resistant to checkpoint inhibitors because it is immunologically cold with few tumor-infiltrating T cells,” principal investigator Padmanee Sharma, MD, PhD, a professor of genitourinary oncology at The University of Texas MD Anderson Cancer Center, said in a press release.² “These results suggest that a combination approach to increase T-cell infiltration and then block inhibitory pathways may be a useful strategy for treating these patients.”

The study, which was recently published in Cancer Cell, enrolled 45 patients in each cohort. All patients had to have a diagnosis of mCRPC and be receiving ongoing androgen deprivation therapy confirmed by a testosterone level of less than or equal to 50 ng/dL. All patients had to have an ECOG performance status of 0 to 1.

Patients who were enrolled in the chemotherapy-naïve cohort were asymptomatic or minimally symptomatic. These patients had to have progressed after 1 or more second-generation hormonal therapies and could not have received chemotherapy in the mCRPC setting.

Conversely, patients in the chemotherapy-exposed cohort had to have progressed after cytotoxic chemotherapy in the mCRPC setting.

All patients received 1 mg/kg of intravenous (IV) nivolumab combined with 3 mg/kg of intravenous ipilimumab every 3 weeks for up to 4 doses, followed by 480 mg of IV nivolumab every 4 weeks. Treatment was continued until progression or unacceptable toxicity, and treatment beyond progression was permitted.

In cohort 1 of pre-chemotherapy patients, the median patient age was 69 compared with 65 in cohort 2 of post-chemotherapy patients. Moreover, 66.7% and 53.3% of patients enrolled were 65 years or older, respectively. In cohort 1, 73.3% of patients were White, 13.3% were African American, and 13.3% were other races. In cohort 2, 82.2% of patients were White, 6.7% were African American, and 11.1% were other.

Regarding disease characteristics, 57.8% of patients in cohort 1 had an ECOG performance score of 0 versus 55.6% in cohort 2. The remainder of patients in both cohorts had ECOG scores of 1.

At diagnosis, 35.6% of patients in cohort 1 had a Gleason score of 7 or less, 60% had a score of greater than 7, and 4.4% were not reported. In cohort 2, 42.2% of patients had a score of 7 or less, 51.1% had a score of greater than 7, and 6.7% were not reported. The median time since diagnosis was 7.1 years in the chemotherapy-naïve cohort versus 7.5 years in the chemotherapy-exposed cohort. Also, at baseline, 62.2% of patients in cohort 1 had nonmetastatic disease, 33.3% had metastatic disease, and 4.4% had unknown spread compared with 48.9%, 44.4%, and 6.7% in cohort 2, respectively.

Twenty percent of patients in cohort 1 did not have baseline bone lesions compared with 6.7% of patients in cohort 2. Moreover, 13.3% of patients in cohort 1 and 2.2% of patients in cohort 2 had less than 4 baseline bone lesions, and 66.7% and 91.1% of patients, respectively, had 4 or more baseline bone lesions. In both cohorts, 24.4% of patients had any visceral metastases at baseline. In cohorts 1 and 2, respectively, sites of visceral metastases included the lung (22.2% vs 20%), adrenal gland (2.2% vs 6.7%) and peritoneum (2.2% vs 0%).

At baseline, 71.1% of chemotherapy-naïve patients had measurable disease versus 66.7% of chemotherapy-exposed patients. At baseline, 60% of patients in cohort 1 had less than 1% PD-L1 expression at baseline, 17.8% had 1% or greater PD-L1 expression, and 22.2% had non-quantifiable expression compared with 44.4%, 17.8%, and 37.8% of patients in cohort 2, respectively.

Over half of patients in cohort 1 (64.4%) reported an average daily worst pain intensity of less than 4 compared with 46.7% in cohort 2. Additionally, 15.6% and 46.7% reported an intensity of 4 or more, respectively.

Patients in cohort 1 had a median prostate-specific antigen (PSA) of 59.5 ng/mL compared with 158.9 ng/mL in cohort 2.

In cohort 1, 97.8% of patients received prior systemic therapy in any setting including the neoadjuvant setting (17.8%), adjuvant setting (28.9%), and metastatic setting (95.6%). Within the metastatic setting, 44.4% of patients received 1 prior line of therapy, 31.1% received 2, and 20% received 3 or more. Conversely, 100% of patients in cohort 2 received prior systemic therapy in any setting. No patients received neoadjuvant therapy, but 31.1% received adjuvant treatment, and 95.6% of patients received treatment in the metastatic setting. Within the metastatic setting, 17.8% of patients received 1 prior line of therapy, 13.3% received 2, and 64.4% received 3 or more.

The most common prior systemic therapies patients received included abiraterone acetate (Zytiga), enzalutamide (Xtandi), bicalutamide, leuprolide, docetaxel, cabazitaxel (Jevtana),

prednisone, sipuleucel-T (Provenge), carboplatin, degarelix (Firmagon), and investigational antineoplastic.

As of the data cut-off in November 2018 , the median overall survival was 19.0 months in cohort 1 (95% CI, 11.5–not estimable [NE]) compared with 15.2 months in cohort 2 (95% CI, 84–NE). Notably, 2 patients in each cohort achieved a complete response.

Additionally, confirmed PSA responses occurred in 17.6% of PSA-evaluable patients in cohort 1 (n = 34) and 10% of those in cohort 2 (n = 40). The combination also elicited a disease control rate of 46.9% and 13.3%, respectively.

Exploratory analyses pointed to tumor mutational burden, homologous recombination deficiency status, and mismatch repair deficiency status as potential biomarkers of response in this patient population.

Regarding safety, all-grade treatment-related adverse effects (TRAEs) occurred in 93.3% of chemotherapy-naïve patients and 95.6% of chemotherapy-exposed patients. Grade 3/4 TRAEs occurred in 42.2% of patients in cohort 1 and 53.3% of those in cohort 2. The most common grade 3/4 TRAEs included diarrhea, pneumonitis, and increased lipase in cohort 1, and diarrhea and colitis in cohort 2. Fifteen patients in cohort 1 discontinued treatment due to TRAEs compared with 16 patients in cohort 2.

In cohort 1, 62.2% of patients experienced an immune-mediated AE requiring immunosuppressive/immunomodulatory medications. Among these patients, 40% required high-dose corticosteroids in the form of at least 40 mg of prednisone per day or the equivalent. Sixty percent of patients in cohort 2 required immunosuppressive/immunomodulatory medications for immune-mediated AEs, 42.2% of which required high-dose corticosteroids.

Four patients died during treatment. These fatalities were due to sudden death and grade 4 myocarditis, both in cohort 1, and grade 4 septic shock and grade 4 interstitial lung disease, both in cohort 2.

“The CheckMate-650 study represents a first-step in trying to define an appropriate dose and schedule of combination immune checkpoint therapy with nivolumab plus ipilimumab in pre- and post-chemotherapy cohorts of patients with mCRPC,” concluded Sharma in a statement to OncLive. “The responses were encouraging, but dose and schedule modifications will be necessary to minimize toxicities. This may improve time on therapy with subsequent responses.”

Investigators are planning to expand the chemotherapy-exposed cohort to 405 patients with mCRPC. These patients will be randomized to 4 different treatment arms, one of which will be the combination of nivolumab and ipilimumab.

References:

Sharma P, Pachynski RK, Narayan V, et al. Nivolumab plus ipilimumab for metastatic castration-resistant prostate cancer: preliminary analysis of patients in the CheckMate 650 trial. Cancer Cell. 2020; 38:1-11. doi:10.1016/j.ccell.2020.08.007

Combination immunotherapy benefits subset of patients with advanced prostate cancer. News Release. MD Anderson. September 10, 2020. Accessed September 16, 2020. https://bit.ly/3kjXMcc.