Maintenance With Niraparib and Ipilimumab Demonstrates PFS Benefit in Pancreatic Cancer

Niraparib (Zejula) plus ipilimumab (Yervoy) maintenance therapy elicited encouraging progression-free survival (PFS) results in patients with advanced pancreatic cancer who achieved a stable response to platinum-based chemotherapy, according to findings from a phase 1b/2 trial (NCT03404960).

At a median follow-up of 23.0 months (interquartile range [IQR], 15.0-31.5) for all eligible patients and 16.5 months (IQR, 10.1-23.0) for the 28 surviving patients at data cutoff, the 6-month PFS rate was 59.6% (95% CI, 44.3%-74.9%; P = .045) in the niraparib plus ipilimumab group and 20.6% (95% CI, 8.3%-32.9%; P = .0002) in the niraparib plus nivolumab (Opdivo) group. The activity in each treatment group was assessed against a clinically meaningful 6-month PFS rate of 44%, which served as the null hypothesis.

Because the upper bound of the 95% CI for 6-month PFS in the nivolumab group did not include the 44% null hypothesis rate, niraparib plus nivolumab was deemed inferior. Because the lower bound of the 95% CI in the ipilimumab group exceeded the 44% null hypothesis rate, niraparib plus ipilimumab was deemed superior and met the study’s primary objective.

“The results of this phase 1b/2 study suggest activity of the PARP inhibitor niraparib plus ipilimumab as maintenance therapy for patients with advanced pancreatic cancer who stopped chemotherapy after at least 4 months of stability on platinum-containing chemotherapy,” lead study author, Kim A. Reiss Binder, MD, an assistant professor of medicine in the Department of Medicine at the Hospital of the University of Pennsylvania, and colleagues, wrote. “The study results suggest that niraparib plus nivolumab was not active in the same clinical setting.”

Preclinical models have shown PARP inhibition combined with immune checkpoint blockade leads to antitumor activity characterized by DNA damage repair deficiencies. Moreover, some preclinical studies have demonstrated CTLA-4 inhibitors are more effective than PD-1 inhibitors in combination with PARP inhibitors.

This open-label, investigator-initiated, randomized study evaluated the safety and antitumor activity of PARP inhibitor maintenance with niraparib plus immune checkpoint blockade with nivolumab, a PD-1 inhibitor, or ipilimumab, a CTLA-4 inhibitor, in patients with platinum-sensitive, advanced pancreatic cancer.

To be eligible, patients needed to be older than 18 years of age and have histologically or cytologically confirmed locally advanced or metastatic pancreatic cancer. Patients with a known DNA damage repair pathway variant were allowed to enroll, though this was not a requirement. Patients also needed to have received at least 16 weeks of palliative platinum-based chemotherapy and show no evidence of platinum resistance, defined as new lesions, growing tumors, or a steadily rising tumor marker during or within 8 weeks of stopping platinum therapy.

The permitted duration of platinum therapy was unlimited. Patients were still allowed to enroll if they had at least stable disease during platinum-based chemotherapy but had active progression on a non-platinum–based regimen such as FOLFIRI or fluorouracil plus leucovorin. Additionally, patients needed to have adequate organ function, an ECOG performance status of 0 or 1, and a life expectancy of at least 12 weeks.

Patients with neuroendocrine variants of pancreatic cancer were excluded, as were patients who had previous treatment with PARP inhibitors or immune checkpoint inhibitors. Key comorbidities that contributed to exclusion were active autoimmune disease or an active condition requiring systemic steroids or other immunosuppressive agents within 14 days of study drug initiation; uncontrolled malabsorption; a history of interstitial lung disease; and an active infection requiring intravenous (IV) antibiotics, antifungals, or antivirals within 14 days of trial enrollment.

From February 7, 2018, to October 5, 2021, 91 patients were randomly assigned to niraparib plus nivolumab (51%; n = 46) or niraparib plus ipilimumab (49%; n = 45). Of these patients, 84 were evaluable for PFS (niraparib plus nivolumab = 44; niraparib plus ipilimumab = 40). A total of 8% (n = 7) of patients were excluded from the efficacy analysis because of rapid clinical decline (n = 2); niraparib-related adverse effects ([AEs] n = 2); neuroendocrine primary cancer as identified by internal pathology assessment (n = 2); and non-malignant small bowel obstruction (n = 1).

Across both groups, most patients had measurable and metastatic disease at the time of enrollment, with the most common metastatic disease sites being the liver, lung, and peritoneum. Additionally, most patients had responding or stable disease at enrollment, although several were progressing or having mixed responses to current non-platinum–based treatment.

Regarding mutation status, 96% (n = 81) of patients in the efficacy analysis had available germline testing results, and 51% (n = 43) had received clinical somatic next-generation sequencing. Most patients who had somatic sequencing also had a pathogenic KRAS variant. Of the nivolumab group, 16% (n = 7) had a germline or somatic pathogenic variant in BRCA1 (n = 1), BRCA2 (n = 5), or PALB2 (n = 1). Of the ipilimumab group, 18% (n = 7) had a variant in BRCA1 (n = 5), BRCA2 (n = 1), or PALB2 (n = 1). A total of 5 and 3 additional patients in the nivolumab and ipilimumab groups respectively had non-core DNA damage repair gene mutations.

Additionally, of the 32 patients in the nivolumab group and 30 patients in the ipilimumab group without a known DNA damage repair variant, 56% (n = 18) and 50% (n = 15), respectively, had a personal or family history of at least 1 BRCA1 or BRCA2–related cancer.

Patients received oral niraparib at 200 mg per day with either IV nivolumab at 240 mg every 2 weeks (later changed to 480 mg IV every 4 weeks per manufacturer update) or IV ipilimumab at 3 mg/kg every 4 weeks for 4 doses. Dose reductions were not allowed for nivolumab or ipilimumab. Patients were treated until progression or unacceptable toxicity.

Superiority of a treatment regimen would be declared if the 6-month PFS rate was at least 60%, and inferiority of a treatment regimen would be declared if the 6-month PFS rate was 27% or lower. The coprimary end points of this trial were safety and 6-month PFS, defined as the proportion of patients who were alive and progression-free 6 months after beginning treatment.

The efficacy population included all patients who received at least 1 dose of study treatment and had at least 1 post-treatment response assessment according to RECIST v1.1 criteria. The safety population included all patients who received at least 1 dose of study treatment.

Key secondary end points were objective response rate (ORR), defined as the proportion of patients with confirmed complete response (CR) or partial response (PR) per RECIST; overall survival (OS), defined as the time from the start of the study treatment until last follow-up or death from any cause; duration of response (DOR), defined as the time from first CR or PR by RECIST to disease progression or death from any cause; identification of allele-specific loss of heterozygosity and DNA damage repair variants in patients who achieved a stable response on platinum-based therapy; the correlation of DNA damage repair defects with response to niraparib plus nivolumab or ipilimumab; and the correlation of immune activation before and during treatment with response to niraparib plus nivolumab or ipilimumab.

At a data cutoff of January 25, 2022, all 91 patients had received at least 1 dose of the study drug and were therefore evaluable for toxicity. Three patients were still receiving niraparib plus nivolumab and 8 patients were still receiving niraparib plus ipilimumab. Additionally, 87% (n = 73) of all patients had disease progression.

The median number of cycles of niraparib plus nivolumab was 3 (IQR, 2-8), and the median number of cycles of niraparib plus ipilimumab was 8 (IQR, 3-18).

The median OS was 13.2 months (95% CI, 8.1-16.7) in the nivolumab group and 17.3 months (95% CI, 12.8-21.9) in the ipilimumab group. The ORR of the 39 patients with measurable disease was 7.7% (n = 3; 95% CI, 1.5%-19.5%) in the nivolumab group and 15.4% (n = 6; 95% CI, 5.9%-30.5%) in the ipilimumab group. The median DOR was not calculated because of the small number of responses.

After progressing on the trial regimens, 15 patients in the nivolumab group and 14 patients in the ipilimumab group received platinum-based therapy, of which 40% (n = 6) and 57% (n = 8) of the nivolumab and ipilimumab groups respectively had at least stable disease in response to this treatment.

A planned subgroup analysis evaluated patient outcomes based on the presence or absence of a DNA damage repair variant, a family history of BRCA1 or BRCA2–related cancers, or the presence or absence of BRCA1 and BRCA2. Among patients without DNA damage repair mutations who had a known family history of BRCA1 or BRCA2–related cancers, the median PFS was 1.8 months (95% CI, 1.7-2.0) in the nivolumab group (n = 18) and 6.2 months (95% CI, 1.5-10.8) in the ipilimumab group (n = 15). In this population, the median OS was 15.4 months (95% CI, 11.8-18.9) and 18.7 months (95% CI, 0.0-38.3) in the nivolumab and ipilimumab groups, respectively.

Among patients in this population with BRCA1, BRC2, or PALB2 variants, the median PFS was 3.7 months (95% CI, 1.1-6.3) in the nivolumab group (n = 7) and 10.4 months (95% CI, 1.5-19.2) in the ipilimumab group. In this population, the median OS was 12.2 months (95% CI, not estimable [NE]) in the nivolumab group and 38.0 months (95% CI, NE) in the ipilimumab group.

An unplanned, post-hoc intention-to-treat (ITT) analysis of the ipilimumab group scored 2 of the 5 patients in this group, who were previously unevaluable and had symptomatic deterioration without imaging confirmation of progression, as having had PFS events. Additionally, the investigators censored 3 patients for PFS, with incidental imaging showing no progression in 1 patient, and AEs that caused withdrawal without progression in 2 patients.

The ITT 6-month PFS estimate in the post-hoc ipilimumab group was 56.8% (95% CI, 41.7%-71.9%) vs 59.6% (95% CI, 44.3%-74.9%) in the per-protocol analysis. The post-hoc median PFS was 1.9 months (95% CI, 1.4-2.3) in the nivolumab group and 8.1 months (95% CI, 5.5-10.6) in the ipilimumab group.

Regarding safety, the phase 1b assessment defined dose-limiting toxicities as those that occurred within the first 3 weeks of study therapy. Dose-limiting toxicities included: non-hematological AEs of at least grade 3 that were possibly related to treatment (excluding nausea, vomiting, and hypertension that had not been optimally treated); grade 4 neutropenia lasting over 7 days; febrile neutropenia; and platelet count of less than 10,000 platelets per μL.

A total of 88% (n = 376) of the 427 treatment-related AEs (TRAEs) were grade 1 or 2, including 92% (n = 173) of the 189 seen in the nivolumab group and 85% (n = 203) of the 238 seen in the ipilimumab group. Overall, the most common TRAEs in the nivolumab group were thrombocytopenia (30%; n = 14), arthralgia (26%; n = 12), nausea (24%; n = 11), and fatigue (24%; n = 11). The most common TRAEs in the ipilimumab group were thrombocytopenia (44%; n = 20), anemia (42%; n = 19), fatigue (42%; n = 19), nausea (40%; n = 18), aspartate aminotransferase increase (36%; n = 16), rash (33%; n = 15), and alanine aminotransferase increase (30%; n = 13).

In total, 22% (n = 10) of the niraparib plus nivolumab group and 50% (n = 23) of patients in the ipilimumab group had TRAEs of at least grade 3. The most common grade 3 or higher TRAEs in the nivolumab group were hypertension (8%; n = 4), anemia (4%; n = 2), and thrombocytopenia (4%; n = 2). The most common grade 3 or higher TRAEs in the ipilimumab group were fatigue (14%; n = 6), anemia (11%; n = 5), and hypertension (9%; n = 4).

Serious TRAEs occurred in 11% (n = 5) of the nivolumab group and 24% (n = 11) of the ipilimumab group. In the ipilimumab group, 13% (n = 6) of patients experienced grade 3 immune-mediated AEs, including rash (n = 3), pneuomonitis (n = 2), and colitis (n = 1). The only immune-mediated AE in the nivolumab group was colitis (n = 1). No grade 4 or 5 immune-mediated AEs occurred.

In the nivolumab group, 11% (n = 5) of patients discontinued nivolumab because of AEs but continued taking niraparib. In the ipilimumab group, 24% (n = 11) of patients discontinued ipilimumab but continued taking niraparib. Additionally, 5 patients discontinued niraparib because of thrombocytopenia (n = 2), anemia (n = 2), and fatigue (n = 1). No patient discontinued both investigational drugs because of AEs.

At the data cutoff, 55 patients had died, 31 in the nivolumab group and 24 in the ipilimumab group. At the time of data analysis, 73% (n = 32) and 60% (n = 24) of the PFS-evaluable nivolumab and ipilimumab populations, respectively, had died. No treatment-related deaths occurred.

“A benefit of niraparib plus ipilimumab maintenance therapy in patients with advanced pancreatic cancer was recorded in this trial, and this benefit extended to patients without known DNA damage repair variants, suggesting that the efficacy could be independent of DNA damage repair deficiency, or equally likely, that such deficiencies were not detected using clinical-grade testing,” the study authors concluded. “Future studies to explore maintenance niraparib plus ipilimumab compared with PARP inhibitor monotherapy and to maintenance cytotoxic chemotherapy should be pursued.”

Reference

Reiss KA, Mick R, Teitelbaum U, et al. Niraparib plus nivolumab or niraparib plus ipilimumab in patients with platinum-sensitive advanced pancreatic cancer: a randomized, phase 1b/2 trial. Lancet Oncol. 2022;23(8):1009-1020. doi: 10.1016/S1470-2045(22)00369-2