PARP Inhibition Combined with Immune Checkpoint Blockade in SCLC: Oasis in an Immune Desert or Mirage?
2019; Elsevier BV; Volume: 14; Issue: 8 Linguagem: Inglês
10.1016/j.jtho.2019.05.004
ISSN1556-1380
Autores Tópico(s)Cancer therapeutics and mechanisms
ResumoDespite dramatic responses to frontline therapy, patients with extensive-stage (ES) SCLC are often plagued by rapid and refractory relapses.1Byers L.A. Rudin C.M. Small cell lung cancer: where do we go from here?.Cancer. 2015; 121: 664-672Crossref PubMed Scopus (365) Google Scholar The phase 3 IMpower133 trial demonstrated that addition of atezolizumab (an anti–programmed death ligand 1 [PD-L1] agent) to carboplatin and etoposide results in significant improvement in median overall survival (OS) (12.3 months versus 10.3 months for carboplatin and etoposide versus placebo [hazard ratio = 0.7, p = 0.007]).2Horn L. Mansfield A.S. Szczęsna A. et al.First-line atezolizumab plus chemotherapy in extensive-stage small-cell lung cancer.N Engl J Med. 2018; 379: 2220-2229Crossref PubMed Scopus (1569) Google Scholar On the basis of these data, the U.S. Food and Drug Administration (FDA) approved atezolizumab in combination with carboplatin and etoposide for the frontline treatment of ES SCLC in March 2019. Unfortunately, the survival benefit in an unselected patient population is modest, and thus, although this regimen has gained initial traction as a new standard of care in some regions, efforts to enhance responses are needed. The approval of atezolizumab follows the FDA approving nivolumab (an anti–programmed death 1 agent) and granting expedited review for pembrolizumab (an anti–programmed death 1 agent) for relapsed SCLC in the third-line setting. Although there is no doubt that some patients receive durable benefit from immune checkpoint blockade (ICB)—beyond what is typical with chemotherapy for relapsed disease—these patients remain the exception. In Checkmate-032, which led to the approval of nivolumab, overall response rates (ORRs) were just 11.9% after two prior lines of therapy.3Ready N. Farago A.F. de Braud F. et al.Third-line nivolumab monotherapy in recurrent SCLC: Checkmate 032.J Thorac Oncol. 2019; 14: 237-244Abstract Full Text Full Text PDF PubMed Scopus (202) Google Scholar, 4Antonia S.J. Lopez-Martin J.A. Bendell J. et al.Nivolumab alone and nivolumab plus ipilimumab in recurrent small-cell lung cancer (CheckMate 032): a multicentre, open-label, phase 1/2 trial.Lancet Oncol. 2016; 17: 883-895Abstract Full Text Full Text PDF PubMed Scopus (915) Google Scholar A second trial (Checkmate-331) found no difference in OS between nivolumab and standard of care chemotherapy (topotecan or amrubicin), although investigators did observe a significant improvement in OS (HR = 0.71, 95% confidence interval: 0.54–0.94) in patients with platinum-resistant SCLC.5Reck M. Vicent D. Ciuleanu T. et al.Efficacy and safety of nivolumab monotherapy versus chemotherapy in recurrent small cell lung cancer: results from CheckMate 331.Ann Oncol. 2018; 29: x39-x43Google Scholar More promising outcomes have been observed with single-agent pembrolizumab in previously treated, PD-L1–positive SCLC in KEYNOTE-158: an ORR of 35.7% and median OS of 14.6 months in PD-L1–positive SCLC compared with 6.0% and 7.7 months in PD-L1–negative SCLC).6Chung H.C. Lopez-Martin J.A. Kao S.C.H. et al.Phase 2 study of pembrolizumab in advanced small-cell lung cancer: KEYNOTE-158 [abstract].J Clin Oncol. 2018; 36: 8506Crossref Google Scholar Collectively, these data underscore the need to optimize patient selection and explore novel combinatorial strategies to maximize benefit from ICB in SCLC. Recent preclinical studies suggest that DNA damage response (DDR) inhibition may sensitize to ICB. For example, in tumors including breast cancer and NSCLC, treatment with poly (ADP-ribose) polymerase 1 inhibitors (PARPIs) increased expression of PD-L1.7Jiao S. Xia W. Yamaguchi H. et al.PARP inhibitor upregulated PD-L1 expression and enhances cancer-associated immunosuppression.Clin Cancer Res. 2017; 23: 3711-3720Crossref PubMed Scopus (538) Google Scholar, 8Sato H. Niimi A. Yasuhara T. et al.DNA double-strand break repair pathway regulates PD-L1 expression in cancer cells.Nat Commun. 2017; 8: 1751Crossref PubMed Scopus (363) Google Scholar Mechanistically, DNA damage caused by PARPIs increases cytosolic DNA, which activates the cyclic GMP-AMP synthase (CGAS)/stimulator of interferon genes (STING) innate immune pathway, ultimately yielding T-cell recruitment and PD-L1 expression.9Ding L. Kim H.J. Wang Q. et al.PARP inhibition elicits STING-dependent antitumor immunity in Brca1-deficient ovarian cancer.Cell Rep. 2018; 25: 2972-2980Abstract Full Text Full Text PDF PubMed Scopus (268) Google Scholar, 10Parkes E.E. Walker S.M. Taggart L.E. et al.Activation of STING-dependent innate immune signaling by S-phase-specific DNA damage in breast cancer.J Natl Cancer Inst. 2016; 109: djw199Crossref PubMed Scopus (265) Google Scholar, 11Chabanon R.M. Muirhead G. Krastev D.B. et al.PARP inhibition enhances tumor cell-intrinsic immunity in ERCC1-deficient non-small cell lung cancer.J Clin Invest. 2019; 129: 1211-1228Crossref PubMed Scopus (162) Google Scholar Similar observations were recently reported for SCLC by our group, wherein either olaparib (a PARPI) or prexasertib (a checkpoint kinase 1 inhibitor) with an anti–PD-L1 agent led to increased PD-L1 expression and cytotoxic T-cell infiltration, decreased T-cell exhaustion, and dramatic tumor regression in mouse models that were otherwise resistant to treatment with a single-agent DDR inhibitor (DDRI) and an anti–PD-L1 agent.12Sen T. Rodriguez B.L. Chen L. et al.Targeting DNA damage response promotes antitumor immunity through STING-mediated T-cell activation in small cell lung cancer.Cancer Discov. 2019; 9: 646-661Crossref PubMed Scopus (392) Google Scholar Clinically, there is also growing support for the connection between impaired DDR and improved ICB response. In 2017, pembrolizumab was approved by the FDA for patients whose tumors have evidence of high microsatellite instability, independent of cancer type, on the basis of frequent responses in this population.13Le Dt Uram J.N. Wang H. et al.PD-1 blockade in tumors with mismatch-repair deficiency.N Engl J Med. 2015; 372: 2509-2530Crossref PubMed Scopus (6169) Google Scholar, 14Le D.T. Durham J.N. Smith K.N. et al.Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade.Science. 2017; 357: 409-413Crossref PubMed Scopus (3822) Google Scholar In addition, data from the MEDIOLA trial, which investigated olaparib together with durvalumab (an anti–PD-L1 agent) in relapsed cancers, suggested that this combination is well tolerated and may enhance ICB in some tumors. For example, patients with platinum-sensitive germline breast cancer gene–mutated relapsed ovarian cancer experienced an ORR of 63%.15Drew Y. de Jonge M. Hong S.H. et al.An open-label, phase II basket study of olaparib and durvalumab (MEDIOLA): results in germline BRCA-mutated (gBRCAm) platinum-sensitive relapsed (PSR) ovarian cancer (OC).Gynecol Oncol. 2018; 149: 246-247Google Scholar An earlier trial found an ORR of only 38% for olaparib alone, albeit in a population that included platinum-refractory disease, and required at least three prior lines of therapy, whereas the median in MEDIOLA was two prior lines.16Kaufman B. Shapira-Frommer R. Schmultzler R.K. et al.Olaparib monotherapy in patients with advanced cancer and a germline BRCA1/2 mutation.J Clin Oncol. 2015; 33: 244-250Crossref PubMed Scopus (1283) Google Scholar Similarly high response rates were observed in patients with germline breast cancer gene–mutated, erb-b2 receptor tyrosine kinase 2–negative metastatic breast cancer.17Domcheck S.M. Postel-Vinay S. Im S.-A. et al.An open-label, phase II basket study of olaparib and durvalumab (MEDIOLA): updated results in patients with germline mutated metastatic breast cancer [abstract].Cancer Res. 2019; 79 (PD5–04)Google Scholar Although limited biomarker data are available from this trial, one instance of paired biopsy specimens obtained before and after olaparib run-in showed significant increase in PD-L1 expression and tumor-infiltrating lymphocytes in a patient whose cancer responded to the combination. In contrast, a cohort with relapsed ES SCLC in MEDIOLA did not experience the same benefits as the DDR-deficient cohorts.18Krebs M. Ross K. Kim S. et al.An open-label, multitumor phase II basket study of olaparib and durvalumab (MEDIOLA): results in patients with relapsed SCLC [abstract].J Thorac Oncol. 2017; 12: S2044-S2045Google Scholar However, almost half of these patients progressed during the 4-week run-in and thus were never treated with durvalumab. Among 38 patients with relapsed ES SCLC, only four of 38 (11%) had confirmed Response Evaluation Criteria in Solid Tumors responses, and each of these occurred before the initiation of durvalumab. Eleven of 38 patients experienced disease control at 12 weeks (the primary end point), which fell below the prespecified futility cutoff. Despite these findings, the OS in this patient population was better than expected, providing a rationale for further investigation of the combination without the prolonged olaparib run-in. In their single-arm, phase II study of olaparib and durvalumab in 19 patients with relapsed SCLC, Thomas et al. eliminated the olaparib run-in, instead initiating both agents at day 1 of cycle 1.19Thomas A. Vilimas R. Trindade C. et al.Durvalumab in combination with olaparib in patients with relapsed: results from a phase II study.J Thorac Oncol. 2019; 14: 1447-1457Abstract Full Text Full Text PDF PubMed Scopus (97) Google Scholar Unfortunately, as in the MEDIOLA SCLC cohort, the investigators again observed a disappointing ORR, with confirmed partial or complete responses in only two of 19 evaluable patients (10.5%). However, clinical benefit—rather than response rates—may be a more meaningful measure for ICB trials in SCLC. There are glimpses of this discrepancy between ORR and clinical benefit in these results, including that four of 19 patients (21.1%) had extended clinical benefit (≥8 months) and one other patient had early CNS-only progression, but after treatment of brain metastases, had 6 months of systemic response before disease progression. The investigators were also able to collect key correlative data that provide insights toward maximizing the benefit of DDRIs and ICB in SCLC. Mandatory pretreatment biopsies provided the opportunity to assess the tumor immune phenotype. The authors found that both patients with inflamed phenotypes (i.e., CD8-positive T-cells in direct contact with tumor) had confirmed responses. Despite the small number of inflamed tumors, these findings are consistent with observations in other tumors that preexisting inflamed microenvironments independently predict response to ICB.20Ott P.A. Bang Y.J. Piha-Paul S.A. et al.T-cell-inflamed gene-expression profile, programed death ligand 1 expression, and tumor mutational burden predict efficacy in patients treated with pembrolizumab across 20 cancers: KEYNOTE-028.J Clin Oncol. 2019; 37: 318-327Crossref PubMed Scopus (438) Google Scholar Further exploration of the frequency and biology of this phenotype is warranted. Eight patients on this study had PD-L1–positive staining within tumor cells. Among these eight patients were all four patients with any evidence of more than a 30% tumor reduction (including both confirmed complete and partial responses) and one of the two nonresponders with extended clinical benefit (the other did not undergo PD-L1 testing). Paired pretreatment and posttreatment (at 2–4 weeks after initiation of therapy) biopsy specimens collected from nine patients provided a glimpse into the capacity for PARPIs to alter PD-L1 expression and lymphocyte infiltration in SCLC. In three of four cases in which pretreatment PD-L1 expression was observed and a paired posttreatment biopsy specimen was available, substantial increases in number and intensity of PD-L1–positive cells were observed after treatment, including both confirmed responses. Among the five cases in which pretreatment biopsy specimens were negative for PD-L1 expression, the investigators found that tumor cells expressed PD-L1 in three of five posttreatment biopsy specimens. However, in these latter cases, the emergence of PD-L1 expression was not associated with increased T-cell infiltration into the tumor. Several tumor intrinsic features from this trial warrant further consideration and investigation as well. The patient with confirmed complete response had a mutation in BRCA1, DNA repair associated gene (BRCA1), which is a known predictive biomarker for PARPIs. Although this finding suggests a broader consideration of DDR deficiency as a predictive biomarker for this combination, such mutations are rare in SCLC (BRCA1 and BRCA2, DNA repair associated [BRCA2] mutations are observed in approximately 0.9% and 1.8% of cases, respectively).21George J. Lim J.S. Jang S.J. et al.Comprehensive genomic profiles of small cell lung cancer.Nature. 2015; 524: 47-53Crossref PubMed Scopus (1231) Google Scholar However, the other confirmed responder, an EGFR-mutated adenocarcinoma with SCLC transformation is an SCLC subtype that, although still accounting for a minority of cases, represents a growing population with an unmet need for therapeutic options. The response in an SCLC-transformed, EGFR-mutated adenocarcinoma is therefore notable, especially as these cancers have been reported to be resistant to ICB.22Nicolas Marcoux Gettinger S.N. O’Kane G. et al.EGFR-mutant adenocarcinoms that transform to small-cell lung cancer and other neuroendocrine carcinomas: clinical outcomes.J Clin Oncol. 2019; 37: 278-285Google Scholar Although the prior published analysis of this subtype is too small to speculate about whether olaparib may have reversed intrinsic ICB resistance in this case, two additional patients with SCLC from this trial with prolonged stable disease (≥ 8 months) had previously progressed while taking ICB (after 4 and 6 months, respectively). Notably, 60% of patients on this trial had platinum-resistant/refractory disease. Because platinum and PARPI resistance are highly correlated, this raises the question as to whether initiating this combination before the development of platinum resistance (e.g., in the maintenance setting) may enhance its activity. Nevertheless, both confirmed responses were in platinum-refractory patients. Similar to in other cancers in which ICB and DDRIs have been successful, patient selection and predictive biomarkers will be critical to their success in SCLC. Although BRCA1 and BRCA2 mutations are rare in SCLC, expression of schlafen family member 11 protein (SLFN11) has repeatedly been identified as a viable biomarker for PARPI sensitivity in SCLC and warrants investigation as a potential biomarker for PARPI-ICB combinations.23Lok B.H. Gardner E.E. Schneeberger V.E. et al.PARP inhibitor activity correlates with SLFN11 expression and demonstrates synergy with temozolomide in small cell lung cancer.Clin Cancer Res. 2017; 23: 523-535Crossref PubMed Scopus (210) Google Scholar, 24Stewart C.A. Tong P. Cardnell R.J. et al.Dynamic variations in epithelial-to-mesenchymal transition (EMT), ATM, and SLFN11 govern response to PARP inhibitors and cisplatin in small cell lung cancer.Oncotarget. 2017; 8: 28575-28587Crossref PubMed Scopus (123) Google Scholar, 25Murai J. Feng Y. Yu G.K. et al.Resistance to PARP inhibitors by SLFN11 inactivation can be overcome by ATR inhibition.Oncotarget. 2016; 7: 76534-76550Crossref PubMed Scopus (187) Google Scholar, 26Pietanza M.C. Wagar S.N. Krug L.M. et al.Randomized, double-blind, phase II study of temozolomide in combination with either veliparib or placebo in patients with relapsed-sensitive or refractory small-cell lung cancer.J Clin Oncol. 2018; 36: 2386-2394Crossref PubMed Scopus (205) Google Scholar Putative biomarkers for ICB, including tumor mutation burden, PD-L1 expression, and inflamed immune phenotypes, also require prospective evaluation in SCLC.20Ott P.A. Bang Y.J. Piha-Paul S.A. et al.T-cell-inflamed gene-expression profile, programed death ligand 1 expression, and tumor mutational burden predict efficacy in patients treated with pembrolizumab across 20 cancers: KEYNOTE-028.J Clin Oncol. 2019; 37: 318-327Crossref PubMed Scopus (438) Google Scholar One or more of the recently described transcriptionally defined subtypes of SCLC may include tumors that are well suited for ICB and/or DDRI treatment, providing another potential avenue for patient selection.27Gay C.M. Diao L. Stewart C.A. et al.Inter- and intra-tumoral variations in ASCL1, NEUROD1, and POU2F3 transcriptional programs underlie three distinct molecular subtypes of small cell lung cancers [abstract].in: American Association for Cancer Research. AACR 2019 Proceedings: Abstracts 2749–5314. Coe Truman International, Chicago IL2019: 3772Google Scholar, 28Rudin C.M. Poirier J.T. Byers L.A. et al.Molecular subtypes of small cell lung cancer: a synthesis of human and mouse model data.Nat Rev Cancer. 2019; 19: 289-297Crossref PubMed Scopus (421) Google Scholar A DDRI plus ICB remains a tantalizing combination, even in SCLC. Although infrequent, the responses observed were deep, durable, and accompanied by provocative correlative data. Integrating the aforementioned SCLC subtypes with immune phenotypes (desert, excluded, and inflamed), predictive biomarkers, and, eventually, immunotherapy responses, will be paramount and emphasizes the necessity to include longitudinal sample (tumor, blood, etc.) acquisition in future trials to assess these features dynamically. Finally, as relapsed SCLC is highly refractory to many therapies, investigators should consider implementing DDRI and ICB combinations earlier, such as in the maintenance setting, to minimize the evolution of resistance mechanisms that may limit responses to either agent class. Durvalumab in Combination with Olaparib in Patients with Relapsed SCLC: Results from a Phase II StudyJournal of Thoracic OncologyVol. 14Issue 8PreviewDespite high tumor mutationburden, immune checkpoint blockade has limited efficacy in SCLC. We hypothesized that poly (ADP-ribose) polymerase inhibition could render SCLC more susceptible to immune checkpoint blockade. Full-Text PDF Open Archive
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