Spigel, David R. MD
Sarah Cannon Research Institute, Nashville, Tennessee.
Disclosure: The author has served as a consultant for Lilly, Genentech, sanofi-aventis, and AstraZeneca.
Address for correspondence: David R. Spigel, MD, Lung Cancer Research Program, Sarah Cannon Research Institute, 250 25th Avenue North, Suite 110 Nashville, TN 37203. E-mail: email@example.com
Poly (adenosine diphosphate–ribose) polymerase (PARP) is an important regulator of DNA repair and the target of several agents in development across tumor types. Geoff Shapiro provided a comprehensive review of PARP biology and the strong rationale for cancer drug development.
DNA repair can occur through several pathways including base-excision repair, nuclear-excision repair, mismatch repair, homologous repair (HR), nonhomologous end-joining, and single-strand annealing.1 PARP plays an important role in repairing single-strand breaks through the base-excision repair mechanism. PARP inhibitors prevent single-strand break repair leading to double-stranded breaks (DSB) and γH2AX foci formation.2 DSB repair occurs preferentially through the HR pathway.3 This pathway is disrupted in several conditions, including ataxia telangiectasia mutated (ATM) deficiency (mutations present in 10%–15% of non–small-cell lung cancer [NSCLC]), phosphatase and tensin homolog (PTEN) deficiency, Fanconi deficiency, and BRCA1/2 deficiency. DSB that are not repaired efficiently lead to cell death. BRCA deficient cells are highly sensitive to single-agent PARP inhibition. Low BRCA1 expression (mRNA) has been associated with improved survival in patients with stage II–IIIA NSCLC treated with preoperative cisplatin and gemcitabine.4 PARP inhibitors also sensitize cells to the effects of chemotherapy.
PARP INHIBITORS IN CLINICAL DEVELOPMENT IN NSCLC
Several inhibitors in clinical development in lung cancer were reviewed.
Veliparib (ABT-888; Abbott, Abbott Park, IL) is a potent inhibitor of PARP with good oral bioavailability and the ability to cross the blood–brain barrier. Veliparib potentiates platinum agents and temozolomide, as well as radiation.5 Veliparib is currently in phase II testing in a multicenter first-line randomized trial in unselected patients with NSCLC (N = 120). Patients receive carboplatin/paclitaxel with and without veliparib. The trial’s primary endpoint is progression-free survival (PFS). Dr. Shapiro presented a schema for a Cancer Therapy Evaluation Program (CTEP)-sponsored phase I dose-escalation trial (CTEP 8484) combining veliparib (administered orally daily) with a cyclin-dependent kinase inhibitor (SCH727965, days 8 and 22) in patients with BRCA proficient cancers.
David Gandara discussed the potential role of PARP inhibitors in combination with chemoradiotherapy for locally advanced NSCLC. Chemoradiation can prevent HR of DSB induced by PARP inhibitors.6 Dr. Gandara presented preclinical data showing how veliparib potentiates the antitumor effects of platinum and radiation. Data were also presented, which demonstrated how squamous tumors express higher levels of PARP1, ERCC1, and BRCA 1/2 compared with adenocarcinomas. Finally, a schema for a phase I Southwest Oncology Group (SWOG) trial (NCI 8811) was presented looking at the combination of carboplatin, paclitaxel, veliparib, and radiation in patients with stage III NSCLC. The goal then would be to proceed with a randomized placebo-controlled phase II trial in 104 patients, where enrollment is stratified by histology (squamous versus nonsquamous), performance status, and prior weight loss.
Olaparib (AZD 2281; AstraZeneca, London, England) is an oral PARP inhibitor, which has shown potent antitumor activity in patients with BRCA-mutated breast cancer7 and in ovarian cancer with or without BRCA1 or 2 mutations.8 A pivotal phase II dose-escalation trial demonstrated activity in patients with refractory and BRCA-mutated ovarian, breast, and prostate cancer. Reversible dose-limiting toxicity included mood changes, fatigue, somnolence, and thrombocytopenia. A phase II study of olaparib in ovarian cancer demonstrated responses in 41% and 24% in patients with and without BRCA1/2 mutations, respectively. Recently, olaparib was studied in a randomized phase II trial in patients with platinum-sensitive advanced ovarian cancer, who achieved a partial or complete response to chemotherapy. Patients (N = 265) were randomized to switch-maintenance therapy with olaparib 400 mg orally twice daily or to placebo. Olaparib improved PFS (median, 8.4 versus 4.8 months, hazard ratio (HR), 0.35; 95% confidence interval (CI), 0.25–0.49; p < 0.001). Toxicity included nausea, fatigue, vomiting, and anemia. Giuseppe Giaccone presented results from a phase I study at the National Cancer Institute where olaparib was combined with cisplatin and gemcitabine in patients with refractory solid tumors. This trial was designed to study the safety of this combination and find the maximum tolerated dose (MTD) of olaparib. This trial also examined chemotherapy’s effects, with or without olaparib, on PAR levels in biopsy and peripheral blood specimens, pre and post-treatment. Twenty-three patients were enrolled, eight (35%) of whom had NSCLC.
Myelosuppression was the primary toxicity and prevented the use of standard doses of chemotherapy with olaparib. The MTD of the combination with olaparib dosed on days 1 through 4 is olaparib 100 mg orally daily days 1 to 4, cisplatin 50 mg/m2 intravenously on day 3, and gemcitabine 400 mg/m2 intravenously on days 3 and 10. The MTD of the combination with olaparib dosed on day 1 is olaparib 100 mg twice daily on day 1, cisplatin 60 mg/m2 on day 1, and gemcitabine 500 mg/m2 on days 1 and 8. Olaparib exposure was modestly increased by concomitant gemcitabine, and PAR levels dropped with olaparib administration in tumor specimens. Levels also declined in peripheral blood mononuclear cells, but recovered in some patients by the start of the next cycle. Finally, Dr. Giaccone reviewed a multicenter, randomized, phase Ib/IIb study still in progress evaluating olaparib and gefitinib versus gefitinib alone in patients with EGFR-mutated NSCLC being conducted by the Spanish Lung Group.
LY2603618 (IC-83; Lilly Indianapolis, IN) was presented within the PARP session, but is not a PARP inhibitor. Rather, this is an inhibitor of the cell-cycle checkpoint kinase 1 (chk1), an adenosine triphosphate (ATP)-dependent serine-threonine kinase. Chk1 is activated by DSB and is overexpressed in a number of cancers. Chk1 inhibition prevents DNA repair and may potentiate chemotherapy. LY2603618 has been safely combined with gemcitabine in patients with refractory cancers, and was combined with pemetrexed in a recently completed trial. Patients with newly diagnosed stage IV nonsquamous NSCLC are currently being recruited for a single-arm phase II trial of LY2603618, cisplatin, and pemetrexed, with the primary aim of assessing PFS.
Iniparib (BSI-201; sanofi-aventis, Paris, France) was another agent presented in this session with an antitumor effect that seems to be other than PARP inhibition. This agent was initially described as a PARP inhibitor and was associated with remarkable survival benefits, with no excess toxicity when combined with carboplatin and gemcitabine in women with metastatic triple-negative breast cancer in a randomized phase II study.9 However, the improvement in overall survival could not be replicated in a phase III study, and iniparib’s mechanism of action was re-explored. Recent data suggested that iniparib may have several antitumor effects including inhibition of DNA repair; however, its level of PARP inhibition is considered modest. Iniparib has been studied in patients with newly diagnosed stage IV NSCLC in a randomized phase II study presented recently at the 14th World Congress on Lung Cancer in Amsterdam.10 One hundred and nineteen patients were randomized to cisplatin and gemcitabine, with or without iniparib. The primary endpoint was to assess the objective response rate. Investigators found no advantage for the iniparib cohort in terms of response; however, the PFS (5.7 versus 4.3 months, HR 0.69) and overall survival (11.2 versus 8.5 months, HR 0.75) favored iniparib, although not statistically significant. Iniparib is currently in phase III testing in patients with advanced squamous lung cancer. Patients are randomized to carboplatin and gemcitabine, with or without iniparib. The study’s primary endpoint is to assess overall survival.
PARP inhibitors are in active development as single agents and in combination with chemotherapy across tumor types, including lung cancer. Trials in unselected patients were designed with the hypothesis that PARP inhibition benefits all patients. A recent positive trial in BRCA-mutated and wild-type ovarian cancer with maintenance olaparib supports this design. However, future development of these agents should also include studies focused in patients with tumors already at risk for compromised DNA repair. Trials should be designed with PARP inhibitors in patients with BRCA1 and 2 methylated, Excision Repair Cross-Complementing 1 aberrant, PTEN-deficient, or ATM-deficient lung cancers. These could be single-agent trials, or combination studies with chemotherapy and/or radiation. Agents such as veliparib, which cross the blood–brain barrier, may also play a role in reducing central nervous system progression.
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