Nivolumab Plus Talazoparib Does Not Induce Responses in Heavily Pretreated Melanoma

James Isaacs, MD

Treatment with nivolumab (Opdivo) in combination with talazoparib (Talzenna) did not lead to RECIST-based tumor responses in patients with unresectable or metastatic melanoma who have mutations in the BRCA or BRCA-ness genes, according to data from a phase 2 study (NCT04187833) presented at the 2024 AACR Annual Meeting.

All 7 patients with relapsed/refractory, heavily pretreated melanoma, who were enrolled in the study experienced disease progression within 6 months of treatment initiation, as assessed by RECIST criteria. The median duration of treatment was 12 weeks (range, 6-36).

“RECIST-based tumor responses were not seen with the combination [of] talazoparib and nivolumab,” James Isaacs, MD, a medical oncologist in the Department of Hematology and Medical Oncology at the Cleveland Clinic, in Ohio, and study authors, wrote in a poster of the data.

Patients with melanoma who are refractory to PD-1 agents need effective treatment options, and few agents currently target biologically selected subgroups. In the Cleveland Clinic Gross Family Melanoma Registry, almost half (47%) of germline mutations have been observed in proteins that regulate DNA repair, and PARP inhibitors possess the potential to provide benefit to those whose tumors harbor mutations linked with DNA damage repair, such as BRCA mutations. Preclinical data suggest that PARP inhibition can result in STING activation, supporting the exploration of these agents combined with immunotherapy.

The phase 2 study enrolled patients with primary or recurrent metastatic or unresectable melanoma who have progressed on prior checkpoint inhibitors and who had germline or somatic mutations in HRD genes. Patients needed to have an ECOG performance status ranging from 0 to 2, normal organ and bone marrow function, and measurable disease by RECIST v1.1 criteria.²

Study participants were given 480 mg of intravenous nivolumab every 4 weeks plus oral talazoparib 1 mg daily. The primary end point of the study was overall response rate (ORR).

“[This] cohort included melanoma with features traditionally associated with low response rates to treatment: uveal melanoma, blue nevus melanoma, BAP1 mutations, low tumor mutational burden, and primary progression on ipilimumab/nivolumab [treatment],” the study authors wrote.

Of the 7 patients evaluated in the trial, 3 had cutaneous melanoma, 2 had uveal melanoma, and 2 had cutaneous/blue nevus melanoma. The first patient with cutaneous melanoma had a germline mutation in the ATM gene, BRAF wild-type status, had previously received nivolumab, and had progressed after adjuvant treatment with the anti­–PD-1 therapy. The second patient with cutaneous melanoma had a somatic mutation in the ATR gene, BRAF V600E–mutated disease, previously received ipilimumab (Yervoy) plus nivolumab and had primary progression. The third patient with cutaneous melanoma had a somatic double mutation in the ARID2 gene, BRAF wild-type disease, had previously received ipilimumab plus nivolumab, and had secondary resistance.

One patient with uveal melanoma had germline BRCA2 and BAP1 mutations, BRAF wild-type disease, previously received ipilimumab plus nivolumab, and experienced primary progression. The second patient with uveal melanoma had a somatic BAP1 mutation, BRAF wild-type disease, previously received pembrolizumab (Keytruda), and experienced primary progression. One patient with cutaneous/blue nevus melanoma had a somatic BAP1 mutation, BRAF wild-type disease, previously received ipilimumab plus nivolumab, and experienced primary progression. The second patient with cutaneous/blue nevus melanoma had germline BAP1 mutations, BRAF wild-type disease, previously received ipilimumab plus nivolumab, and experienced primary progression.

The safety profile of the regimen was consistent with what has been observed with PARP inhibitors combined with immune checkpoint inhibition. In general, the most common adverse effects (AEs) were fatigue (grade 1, n = 5; grade 2, n = 1; grade 3, n = 0), edema limbs (n = 1; n = 0; n = 0), weight loss, (n = 1; n = 1; n = 0), and anorexia (n = 1; n = 1; n = 0). The most common gastrointestinal (GI) AEs included abdominal pain (n = 1; n = 1; n = 0), increased alanine aminotransferase (n = 1; n = 0; n = 0), increased aspartate aminotransferase (n = 0; n = 0; n = 1), increased bilirubin (n = 0; n = 0; n = 1), constipation (n = 1; n = 0; n = 0), diarrhea (n = 1; n = 0; n = 0), nausea (n = 1; n = 1; n = 0), dyspepsia (n = 1; n = 0; n = 0), and other GI disorders (n = 1; n = 0; n = 0).

The most common hematologic AEs included anemia (grade 1, n = 2; grade 2, n = 3; grade 3, n = 1), arthritis (n = 1; n = 0; n = 0), decreased lymphocyte count (n = 2; n = 0; n = 0), decreased white blood count (n = 2; n = 0; n = 0), and decreased platelet count (n = 1; n = 0; n = 0). Lastly, the most common musculoskeletal AEs included increased creatinine phosphokinase (n = 0; n = 0; n = 1), arthritis (n = 1; n = 0; n = 0), and maculopapular rash (n = 1; n = 0; n = 0).

Study limitations included small sample size and the heavily pretreated patient population limits drawing concrete conclusions with regard to the efficacy of PARP inhibitors in melanoma, according to the authors.

Additional studies are needed to confirm these findings, and possible alternative selection strategies may include evaluating for genomic evidence of homologous recombination repair deficiency or targeting specific mutations, the study authors concluded.

Reference

Isaacs J, Sussman TA, Kennedy LB, et al. Phase II trial of nivolumab in combination with talazoparib in patients with unresectable or metastatic melanoma and mutations in BRCA or BRCA-ness. Presented at: 2024 AACR Annual Meeting; April 5-10, 2024; San Diego, CA. Abstract CT261.