Olaparib maintenance versus placebo monotherapy in patients with advanced non-small cell lung cancer (PIN): A multicentre, randomised, controlled, phase 2 trial

Dean A Fennell, Catharine Porter, Jason Lester, Sarah Danson, Fiona Blackhall, Marianne Nicolson, Lisette Nixon, Georgina Gardner, Ann White, Gareth Griffiths, Angela Casbard, Dean A Fennell, Catharine Porter, Jason Lester, Sarah Danson, Fiona Blackhall, Marianne Nicolson, Lisette Nixon, Georgina Gardner, Ann White, Gareth Griffiths, Angela Casbard

Abstract

Background: Impaired double strand DNA repair by homologous repair deficiency (HRD) leads to sensitivity to poly ADP ribose polymerase (PARP) inhibition. Poly-ADP ribose polymerase (PARP) inhibitors target HRD to induce synthetic lethality and are used routinely in the treatment of BRCA1 mutated ovarian cancer in the platinum-sensitive maintenance setting. A subset of non-small cell lung cancers (NSCLCs) harbour impaired DNA double strand break repair. We therefore hypothesised that patients with metastatic non-small cell lung cancer exhibiting partial responses to platinum doublet-based chemotherapy, might enrich for impaired HRD, rendering these tumours more sensitive to inhibition of PARP inhibition by olaparib.

Methods: The Olaparib Maintenance versus Placebo Monotherapy in Patients with Advanced Non-Small Cell Lung Cancer trial (PIN) was a multicentre double-blind placebo controlled randomised phase II screening trial. This study was conducted at 23 investigative hospital sites in the UK. Patients had advanced (stage IIIB/IV) squamous (Sq) or non-squamous (NSq) NSCLC, and had to be chemo-naive, European Cooperative Oncology Group (ECOG) performance status 0-1. Prior immunotherapy with a PD1 or PDL1 inhibitor was allowed. Patients could be registered for PIN prior to (stage 1), or after (stage 2) initiation of induction chemotherapy. If any tumour shrinkage was observed (any shrinkage of RECIST target lesions), following a minimum of 3 cycles of platinum doublet chemotherapy, patients were randomised 1:1 using a centralised online system, to either olaparib (300 mg twice daily by mouth in 21-day cycles) or placebo, which was continued until disease progression, or unacceptable toxicity. Intention to treat (ITT) analyses of the primary endpoint included all randomised participants. Per protocol (PP) safety analysis included all participants who received at least one dose of study drug. Primary endpoint was progression-free survival (PFS), with a one-sided p-value of 0.2 to demonstrate statistical significance. Hazard ratios (HR) for PFS were both unadjusted and adjusted for the randomisation balancing factors (smoking status and histology). The trial was registered with ClinicalTrials.gov (NCT01788332) and EudraCT (2012-003383-51).

Findings: A total of 940 patients were assessed for stage 1 eligibility of whom 263 were registered between Feb 24, 2014 and Nov 7, 2017. 194 patients were excluded prior to stage 2 (no tumour shrinkage or unevaluable) and 70 were randomised; 32 (46%) to Olaparib and 38 (54%) to placebo. 4% (3/70) of patients randomised had a CR and 96% (67/70) had a PR (or other evidence of tumour response/mixed stable) during induction therapy. A total of 36 patients were registered in stage 2 only, i.e., post induction therapy. Intention to treat (ITT) unadjusted analysis showed a PFS hazard ratio (HR) of 0.83 (one-sided 80% CI upper limit 1.03, one-sided unadjusted log rank test p-value=0.23). ITT Cox-adjusted model showed a HR 0.73 (one-sided 80% CI upper limit 0.91, one sided p-value 0.11). Adverse events were reported in 31/32 subjects (97%) in the olaparib arm and 38/38 (100%) in the placebo group. The most commonly reported adverse events in the olaparib group were fatigue (20/31; 65%), nausea (17/31; 55%), anaemia (15/31; 48%) and dyspnea (13/31; 42%). In the placebo group the most common adverse events were fatigue (25/38; 66%), coughing (22/38; 58%), dyspnea (15/38; 39%) and nausea (11/38; 29%). There were no treatment-related deaths.

Interpretation: PFS was longer in the olaparib arm, but this did not reach statistical significance. When the PFS HR was adjusted for smoking status and histology, a significant difference at the one-sided 0.2 level was observed, suggesting that tumour control may be achieved for chemosensitive NSCLC treated with PARP monotherapy. We speculate that this signal may be driven by a molecular subgroup harbouring HRD.

Funding: This study was funded between AstraZeneca CRUK, National Cancer Research Institute, and Cancer Research UK Feasibility Study Committee.

Keywords: HRD; Maintenance; NSCLC; Olaparib; PARP; Placebo; Randomised.

Conflict of interest statement

AC reports grants from Cancer Research UK, during the conduct of the study. FB reports grants and personal fees from Astra Zeneca, outside the submitted work. GGr reports grants from AstraZeneca, personal fees from AstraZeneca, outside the submitted work. DAF reports grants from Astex Therapeutics, personal fees from Aldeyra, grants from Boehringer Ingelheim, non-financial support from Clovis, non-financial support from Eli Lilly, from BMS, personal fees from Inventiva, personal fees from Paredox, personal fees and non-financial support from Roche, grants from MSD, grants from Bayer, during the conduct of the study. JL reports personal fees from Astra Zeneca, personal fees from Boehringer Ingelheim, personal fees from Roche, outside the submitted work. MN reports payments for Pfizer Lung Cancer Advocacy board work; membership of the BMS lung cancer screening committee; and participation on a data safety monitoring board for Roche. All other authors declare no competing interests.

© 2022 The Authors.

Figures

Figure 1
Figure 1
PIN trial - Consort diagram.
Figure 2
Figure 2
Progression-free and overall survival by trial arm. A. Progression Free Survival (ITT unadjusted). HR 0.83 (one-sided 80% CI upper limit 1.03, one-sided p value 0.23). B. Overall survival (ITT population), HR 0.68 (95% CI 0.37–1.26, two-sided p-value 0.22).

References

    1. Farmer H, McCabe N, Lord CJ, et al. Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy. Nature. 2005;434(7035):917–921.
    1. Coleman RL, Oza AM, Lorusso D, et al. Rucaparib maintenance treatment for recurrent ovarian carcinoma after response to platinum therapy (ARIEL3): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2017;390(10106):1949–1961.
    1. Robson M, Im SA, Senkus E, et al. Olaparib for metastatic breast cancer in patients with a germline BRCA mutation. N Engl J Med. 2017;377(6):523–533.
    1. Pujade-Lauraine E, Ledermann JA, Selle F, et al. Olaparib tablets as maintenance therapy in patients with platinum-sensitive, relapsed ovarian cancer and a BRCA1/2 mutation (SOLO2/ENGOT-Ov21): a double-blind, randomised, placebo-controlled, phase 3 trial. Lancet Oncol. 2017;18(9):1274–1284.
    1. Litton JK, Rugo HS, Ettl J, et al. Talazoparib in patients with advanced breast cancer and a germline BRCA mutation. N Engl J Med. 2018;379(8):753–763.
    1. Mateo J, Carreira S, Sandhu S, et al. DNA-repair defects and olaparib in metastatic prostate cancer. N Engl J Med. 2015;373(18):1697–1708.
    1. Golan T, Hammel P, Reni M, et al. Maintenance olaparib for germline BRCA-mutated metastatic pancreatic cancer. N Engl J Med. 2019;381(4):317–327.
    1. McCabe N, Turner NC, Lord CJ, et al. Deficiency in the repair of DNA damage by homologous recombination and sensitivity to poly(ADP-ribose) polymerase inhibition. Cancer Res. 2006;66(16):8109–8115.
    1. Riaz N, Blecua P, Lim RS, et al. Pan-cancer analysis of bi-allelic alterations in homologous recombination DNA repair genes. Nat Commun. 2017;8(1):857.
    1. Shim JH, Kim HS, Cha H, et al. HLA-corrected tumor mutation burden and homologous recombination deficiency for the prediction of response to PD-(L)1 blockade in advanced non-small-cell lung cancer patients. Ann Oncol. 2020;31(7):902–911.
    1. Kadouri L, Rottenberg Y, Zick A, et al. Homologous recombination in lung cancer, germline and somatic mutations, clinical and phenotype characterization. Lung Cancer. 2019;137:48–51.
    1. Ji W, Weng X, Xu D, Cai S, Lou H, Ding L. Non-small cell lung cancer cells with deficiencies in homologous recombination genes are sensitive to PARP inhibitors. Biochem Biophys Res Commun. 2020;522(1):121–126.
    1. Birkelbach M, Ferraiolo N, Gheorghiu L, et al. Detection of impaired homologous recombination repair in NSCLC cells and tissues. J Thorac Oncol. 2013;8(3):279–286.
    1. Mirza MR, Monk BJ, Herrstedt J, et al. Niraparib maintenance therapy in platinum-sensitive, recurrent ovarian cancer. N Engl J Med. 2016;375(22):2154–2164.
    1. Ledermann J, Harter P, Gourley C, et al. Olaparib maintenance therapy in platinum-sensitive relapsed ovarian cancer. N Engl J Med. 2012;366(15):1382–1392.
    1. Ramalingam SS, Blais N, Mazieres J, et al. Randomized, placebo-controlled, phase II study of veliparib in combination with carboplatin and paclitaxel for advanced/metastatic non-small cell lung cancer. Clin Cancer Res. 2017;23(8):1937–1944.
    1. Gelmon KA, Tischkowitz M, Mackay H, et al. Olaparib in patients with recurrent high-grade serous or poorly differentiated ovarian carcinoma or triple-negative breast cancer: a phase 2, multicentre, open-label, non-randomised study. Lancet Oncol. 2011;12(9):852–861.
    1. Audeh MW, Carmichael J, Penson RT, et al. Oral poly(ADP-ribose) polymerase inhibitor olaparib in patients with BRCA1 or BRCA2 mutations and recurrent ovarian cancer: a proof-of-concept trial. Lancet. 2010;376(9737):245–251.
    1. Gonzalez-Martin A, Pothuri B, Vergote I, et al. Niraparib in patients with newly diagnosed advanced ovarian cancer. N Engl J Med. 2019;381(25):2391–2402.
    1. Moore K, Colombo N, Scambia G, et al. Maintenance olaparib in patients with newly diagnosed advanced ovarian cancer. N Engl J Med. 2018;379(26):2495–2505.
    1. Paz-Ares L, de Marinis F, Dediu M, et al. Maintenance therapy with pemetrexed plus best supportive care versus placebo plus best supportive care after induction therapy with pemetrexed plus cisplatin for advanced non-squamous non-small-cell lung cancer (PARAMOUNT): a double-blind, phase 3, randomised controlled trial. Lancet Oncol. 2012;13(3):247–255.
    1. Marquard AM, Eklund AC, Joshi T, et al. Pan-cancer analysis of genomic scar signatures associated with homologous recombination deficiency suggests novel indications for existing cancer drugs. Biomark Res. 2015;3:9.
    1. Campbell JD, Alexandrov A, Kim J, et al. Distinct patterns of somatic genome alterations in lung adenocarcinomas and squamous cell carcinomas. Nat Genet. 2016;48(6):607–616.
    1. Paz-Ares L, Luft A, Vicente D, et al. Pembrolizumab plus chemotherapy for squamous non-small-cell lung cancer. N Engl J Med. 2018;379(21):2040–2051.
    1. Gandhi L, Rodriguez-Abreu D, Gadgeel S, et al. Pembrolizumab plus chemotherapy in metastatic non-small-cell lung cancer. N Engl J Med. 2018;378(22):2078–2092.
    1. Socinski MA, Jotte RM, Cappuzzo F, et al. Atezolizumab for first-line treatment of metastatic nonsquamous NSCLC. N Engl J Med. 2018;378(24):2288–2301.
    1. Shen J, Zhao W, Ju Z, et al. PARPi triggers the STING-dependent immune response and enhances the therapeutic efficacy of immune checkpoint blockade independent of BRCAness. Cancer Res. 2019;79(2):311–319.
    1. Ding L, Kim HJ, Wang Q, et al. PARP inhibition elicits STING-dependent antitumor immunity in Brca1-deficient ovarian cancer. Cell Rep. 2018;25(11):2972–2980.e5.
    1. Ramalingam SS, Thara E, Awad MM, et al. JASPER: phase 2 trial of first-line niraparib plus pembrolizumab in patients with advanced non-small cell lung cancer. Cancer. 2022;128(1):65–74. doi: 10.1002/cncr.33885. Epub 2021 Sep 3.
    1. Passiglia F, Bironzo P, Righi L, et al. A prospective phase II single-arm study of niraparib plus dostarlimab in patients with advanced non-small-cell lung cancer and/or malignant pleural mesothelioma, positive for PD-L1 expression and germline or somatic mutations in the DNA repair genes: rationale and study design. Clin Lung Cancer. 2021;22(1):e63–e66.

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