Frontline maintenance rucaparib and nivolumab in extensive stage small-cell lung cancer

As the overall survival benefit by the addition of immune checkpoint inhibitors (ICIs) to frontline treatment of extensive stage small-cell lung cancer (ES SCLC) is only modest, improved treatment strategies are needed. Chauhan et al. hypothesised that the addition of poly (ADP-ribose) polymerase inhibitors in platinum-sensitive ES SCLC could improve the anti-tumour efficacy of ICIs and demonstrated clinical benefit in 10 out of 19 patients.

Immune checkpoint inhibitors (ICIs) are part of the standard of care frontline management of extensive stage small cell lung cancer (ES SCLC). However, the overall survival (OS) benefit by addition of ICIs to frontline treatment of ES SCLC is modest and further improvements in treatment strategies are needed. The addition of poly (ADP-ribose) polymerase (PARP) inhibitors in platinum-sensitive ES SCLC patients could improve antitumour efficacy of ICI. Preclinical evidence already suggested that increased DNA damage by a PARP inhibitor (PARPi) could potentially yield a greater mutational burden and expand neo-antigens. Furthermore, the addition of a PARPi to immune checkpoint blockade could complement the clinical benefit of immune checkpoint inhibition. Finally, PARPi upregulated PD-L expression in pre-clinical cancer models.

Study Design

Patients with histologically or cytologically confirmed stage IV ES SCLC who achieved either a partial response (PR) or complete response (CR) per RECIST 1.1 post frontline platinum based chemotherapy received nivolumab 480 mg IV every 4 weeks, and rucaparib, 600 mg PO twice a day. Treatment was continued until radiologic disease progression, for up to 24 months of treatment or until unacceptable toxicity occurs. Patients were enrolled in this phase II study within six weeks of last chemotherapy, had an ECOG performance status of maximum 2 and adequate bone marrow, hepatic and renal function. The interim analysis presented at the 2021 World Conference on Lung Cancer included 20 patients with a median age of 62 years, predominantly male (68%). Five patients are currently still on active treatment, receiving both rucaparib and nivolumab.

Results

The median progression-free survival (mPFS) is 2.67 months (95%CI: 1.87-5.57) from time of enrolment on frontline maintenance therapy (post platinum doublet). The mPFS is 7.27 months (95%CI: 4.73-9.33) from the time of diagnosis on frontline therapy. All patients received at least 4 cycles of platinum doublet with at least a partial response (PR) by RECIST1.1 at enrolment. Nineteen patients were evaluable for objective response assessment at the time of interim analysis. Clinical benefit was observed in 10 patients (2 patients with partial response and 8 patients with stable disease). At the time of analysis, the longest responder  was receiving more than 20 months of maintenance trial therapy. No grade 5 toxicities were reported in this study but one patient withdrew due to Grade 4 alanine aminotransferase (ALT) elevation. However, liver function normalised with steroids and the patient had sustained durable response for several months after stopping the treatment. Exploratory correlative studies and biomarkers are now ongoing to evaluate, in a preliminary manner, immune-related response markers; (I) the percentage of CD4 T cells and CD8 T cells expressing PD-1 and Ki-67, (II) the percentage of polyfunctional effector CD4 T cells and CD8 T cells producing IFNγ and TNFα, (III) the percentage of effector CD4 T cells and CD8 T cells expressing CD38, HLADR, CD28, ICOS, CD27, and low Bcl2 level.

Conclusion

Median PFS of frontline maintenance rucaparib and nivolumab post platinum doublet treatment is 2.67 months, with 25% of patients still on active treatment at present. The median PFS on frontline therapy from time of diagnosis was 7.27 months. At the time of the interim analysis, the combination seems to be well tolerated. Selecting patients based on platinum sensitivity thus is a promising approach for subsequent PARP inhibition/immune checkpoint maintenance in ES SCLC.

Reference

Chauhan A. Phase II study of frontline maintenance Rucaparib + Nivolumab in ES SCLC: Interim Analysis. Presented at the 2021 World Conference on Lung Cancer; Abstract OA07.03.