Veliparib and nivolumab in combination with platinum doublet chemotherapy in patients with metastatic or advanced non-small cell lung cancer: A phase 1 dose escalation study

Abstract

Both combinations of the PARP inhibitor veliparib plus platinum doublet chemotherapy (CT), and the programmed death receptor-1 (PD-1) inhibitor nivolumab plus CT have demonstrated encouraging efficacy for treatment of non-small cell lung cancer (NSCLC). This phase 1 dose-escalation study (NCT02944396) evaluated the quadruple combination of veliparib with nivolumab and doublet CT in patients with unresectable advanced/ metastatic NSCLC. Materials and methods: Patients were enrolled into five dosing cohorts: patients received veliparib 120 mg twice daily (BID) combined with nivolumab 360 mg, carboplatin AUC 6 mg/mL•min, and paclitaxel 200 mg/m 2 (C/ PAC) or veliparib 80/120/200/240 mg BID in combination with nivolumab 360 mg, carboplatin AUC 6 mg/ mL•min, and pemetrexed 500 mg/m 2 (C/PEM). Primary objective was to identify the recommended phase 2 dose (RP2D) of veliparib + nivolumab + CT. Safety, tolerability, and efficacy of this combination were also assessed. Results: Twenty-five patients were enrolled: 6 patients received veliparib 120 mg BID + nivolumab + C/PAC and 19 received veliparib (80-240 mg BID) + nivolumab + C/PEM. No dose-limiting toxicities were reported, and the RP2Ds were veliparib 120 mg BID + nivolumab + C/PAC, and veliparib 240 mg BID + nivolumab + C/PEM. The most common any-grade adverse events (AEs) were fatigue (56%), nausea (52%), and anemia (48%). Grade 3/4 AEs included anemia (32%) and neutropenia (24%), and the most frequent serious AE was malignant neoplasm progression (12%). Veliparib exhibited approximately dose proportional kinetics in the dose range Abbreviations: AUC 0-x , area under the plasma concentration-time curve from time 0 to x hour post dose concentration; AUC t , area under the plasma concentrationtime curve from time 0 to the last measurable concentration; AUC ∞ , area under the plasma concentration-time curve from time 0 to time infinity; AE, adverse event; AUC, target area under the concentration time curve;

The potential of PARP inhibitors in targeted cancer therapy and immunotherapy

“…The overall response rate (ORR) reached 27% for cohort with pemetrexed and 17% for paclitaxel. This trial also confirmed the anticipated safety signals with no additional toxicity upon adding veliparib to these regimens ( Clarke et al, 2021 ).…”

“…The overall response rate (ORR) reached 27% for cohort with pemetrexed and 17% for paclitaxel. This trial also confirmed the anticipated safety signals with no additional toxicity upon adding veliparib to these regimens (Clarke et al, 2021). PD-L1 is known target for most of the ICIs in use as monotherapies, therefore the impact of PD-L1 expression differences between individuals on the trials involving ICIs and PARPi was probed in an interventional JASPER phase II study [NCT03308942] 2 tested the combination of niraparib and pembrolizumab or dostarlimab on a group of chemotherapy-naïve patients with locally advanced or metastatic NSCLC with no prior PD-(L1) chemotherapy.…”

Effect of the PARP inhibitor veliparib on germ cell tumor cell lines

“…The combination of veliparib plus carboplatin and etoposide demonstrated improved PFS as first-line treatment in patients with extensive-stage small cell lung cancer ( 59 ). Promising antitumor activity was also observed in patients with metastatic or advanced non-small cell lung cancer receiving quadruple therapy with veliparib, nivolumab, carboplatin and paclitaxel ( 60 ). Moreover, combination therapy with veliparib plus carboplatin and gemcitabine demonstrated promising PFS and response rates in ovarian cancer patients with germline BRCA mutations ( 30 ).…”

Targeted Combination of Poly(ADP-ribose) Polymerase Inhibitors and Immune Checkpoint Inhibitors Lacking Evidence of Benefit: Focus in Ovarian Cancer

“…A total of 25 patients enrolled; 6 patients received veliparib + nivolumab + carboplatin/paclitaxel and 19 received veliparib (dose-escalated) + nivolumab + carboplatin/pemetrexed. All 25 patients (100%) who received treatment experienced at least one TRAE, of which 18 patients (72%) experienced at least one Grade 3–4 TRAEs leading to 6 patients (24%) discontinuing treatment [ 147 ]. Five patient (20%) deaths, 4 due to disease progression and 1 for unknown causes, occurred within 100 days of receiving the last treatment dose, but none were reported to be treatment-related [ 147 ].…”