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Identifying markers of immune response in ovarian cancer: does PD-L1 expression meet the mark?

2019; Elsevier BV; Volume: 30; Issue: 7 Linguagem: Inglês

10.1093/annonc/mdz166

1569-8041

Stéphanie Gaillard, Robert L. Coleman,

Ovarian cancer diagnosis and treatment

Epithelial ovarian cancer is the leading cause of death among gynecologic malignancies. Worldwide, ∼239 000 new cases and 152 000 deaths are attributable to this disease annually [1.Ferlay J. Soerjomataram I. Dikshit R. et al.Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012.Int J Cancer. 2015; 136: E359-E386Crossref PubMed Scopus (21251) Google Scholar]. Platinum-based chemotherapy following surgery has been the standard of care for decades, although relapse rates are high (∼70% in the first 3 years post diagnosis) [2.Ledermann J.A. Raja F.A. Fotopoulou C. et al.Newly diagnosed and relapsed epithelial ovarian carcinoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up.Ann Oncol. 2013; 24: vi24-vi32Abstract Full Text Full Text PDF PubMed Scopus (564) Google Scholar] and the 5-year survival rate for women diagnosed at advance stage (stage III or IV) is <25%. Even in patients who initially benefit from chemotherapy, recurrence is associated with a poor prognosis because of the eventual development of chemotherapy resistance. After multiple lines of therapy, chemotherapy is associated with low response rates (10%–15%) and short progression-free intervals (3–4 months) [3.Herzog T.J. Monk B.J. Bringing new medicines to women with epithelial ovarian cancer: what is the unmet medical need?.Gynecol Oncol Res Pract. 2017; 4: 13Crossref PubMed Google Scholar]. Thus, there has been great emphasis on developing therapies with improved response rates and duration of response. Immune checkpoint inhibitors, especially PD-1/PD-L1 inhibitors, have emerged as an exceptionally effective therapeutic strategy for certain cancers, such as melanoma and classical Hodgkin lymphoma. Treatment efficacy depends on two key principles: (i) tumor accessibility to effector immune cells and (ii) dominance of the PD-1/PD-L1 pathway as the mechanism suppressing antitumor immunity [4.Gaillard S.L. Secord A.A. Monk B. The role of immune checkpoint inhibition in the treatment of ovarian cancer.Gynecol Oncol Res Pract. 2016; 3: 11Crossref PubMed Google Scholar]. In support of the first requirement, a majority of ovarian cancers exhibit T-cell infiltration, which has been associated with significantly improved survival [5.Hwang W.-T. Adams S.F. Tahirovic E. et al.Prognostic significance of tumor-infiltrating T cells in ovarian cancer: a meta-analysis.Gynecol Oncol. 2012; 124: 192-198Abstract Full Text Full Text PDF PubMed Scopus (431) Google Scholar]. Markers of the second principle are less well defined, though expression of PD-L1, both on tumor cells and tumor-associated immune cells, is suggested as a predictive biomarker and is present in the majority of ovarian tumors. Attempts at categorizing ovarian cancers by their tumor-infiltrating lymphocyte (TIL) pattern, gene expression, and specifically PD-L1 expression, suggest that most high-grade serous epithelial ovarian cancers are immunoreactive [6.Webb J.R. Milne K. Kroeger D.R. et al.PD-L1 expression is associated with tumor-infiltrating T cells and favorable prognosis in high-grade serous ovarian cancer.Gynecol Oncol. 2016; 141: 293-302Abstract Full Text Full Text PDF PubMed Scopus (223) Google Scholar, 7.Tothill R.W. Tinker A.V. George J. et al.Novel molecular subtypes of serous and endometrioid ovarian cancer linked to clinical outcome.Clin Cancer Res. 2008; 14: 5198-5208Crossref PubMed Scopus (1024) Google Scholar] and that they could be expected to respond to checkpoint inhibition. Following the early success in other cancers, multiple studies were launched evaluating these drugs in the treatment of recurrent ovarian cancer. Despite the prognostic significance of T-cell infiltration in ovarian cancer, checkpoint inhibitor therapy has yielded lower than expected antitumor effects. Several studies of PD-1/PD-L1 pathway inhibitors in ovarian cancer reported typical response rates of <15%, markedly lower than response rates observed in other diseases. However, when responses occur in ovarian cancer, they are frequently durable (Table 1) [8.Disis M.L. Taylor M.H. Kelly K. et al.Efficacy and safety of avelumab for patients with recurrent or refractory ovarian cancer: phase 1b results from the JAVELIN solid tumor trial.JAMA Oncol. 2019; 5: 393-401Crossref PubMed Scopus (217) Google Scholar, 9.Hamanishi J. Mandai M. Ikeda T. et al.Safety and antitumor activity of anti-PD-1 antibody, nivolumab, in patients with platinum-resistant ovarian cancer.JCO. 2015; 33: 4015-4022Crossref PubMed Scopus (771) Google Scholar, 10.Varga A. Piha-Paul S. Ott P.A. et al.Antitumor activity and safety of pembrolizumab in patients (pts) with PD-L1 positive advanced ovarian cancer: interim results from a phase Ib study.J Clin Oncol. 2015; 33 (Abstr 5510)Google Scholar, 11.Infante JR, Braiteh F, Emens LA et al. Safety, clinical activity and biomarkers of atezolizumab (atezo) in advanced ovarian cancer (OC). In ESMO, Copenhagen, Denmark, October 2016.Google Scholar]. Evaluation of PD-L1 expression in these studies did not correlate with improved response rates.Table 1Studies of single-agent PD-1/PD-L1 pathway inhibitors in ovarian cancer with reported resultsPD-1/PD-L1 inhibitorNKey characteristicsORRMedian DORaIf n 3 monthsBy prior therapybIncluding frontline therapy.By prior therapy:Matulonis [12.Matulonis U.A. Shapira-Frommer R. Santin A.D. et al.Antitumor activity and safety of pembrolizumab in patients with advanced recurrent ovarian cancer: results from the phase 2 KEYNOTE-100 study.Ann Oncol. 2019; 30: 1080-1087Abstract Full Text Full Text PDF PubMed Scopus (301) Google Scholar]2 cohorts by no. prior therapiesbIncluding frontline therapy.1–37.4%1–3 8.2 monthsA: 1–3 prior (N=285)4–69.9%4–6 NRB: 4–6 prior (N=91)By CPS: 11 monthsHamanishi [9.Hamanishi J. Mandai M. Ikeda T. et al.Safety and antitumor activity of anti-PD-1 antibody, nivolumab, in patients with platinum-resistant ovarian cancer.JCO. 2015; 33: 4015-4022Crossref PubMed Scopus (771) Google Scholar]≥4 prior therapies: 55%By PD-L1 expression (response versus non-response):PD-L1 high: 2 versus 14PD-L1 low: 1 versus 3Atezolizumab9cResponse-evaluable patients.Recurrent≥2 prior therapies: 92%22%8.1 and 16+ monthsInfante [11.Infante JR, Braiteh F, Emens LA et al. Safety, clinical activity and biomarkers of atezolizumab (atezo) in advanced ovarian cancer (OC). In ESMO, Copenhagen, Denmark, October 2016.Google Scholar]Pembrolizumab (KEYNOTE-28)26Recurrent, tumor PD-L1 positivedPD-L1 positive defined as ≥1% of cells in tumor nests or PD-L1+ bands in stroma.≥4 prior therapies: 80%11.5%>6 monthsVarga [10.Varga A. Piha-Paul S. Ott P.A. et al.Antitumor activity and safety of pembrolizumab in patients (pts) with PD-L1 positive advanced ovarian cancer: interim results from a phase Ib study.J Clin Oncol. 2015; 33 (Abstr 5510)Google Scholar]CPS, combined positive score; DOR, duration of response; N, number of ovarian cancer patients treated; ORR, objective response rate; TFI, treatment free interval.a If n < 3, then the actual values are reported.b Including frontline therapy.c Response-evaluable patients.d PD-L1 positive defined as ≥1% of cells in tumor nests or PD-L1+ bands in stroma. Open table in a new tab CPS, combined positive score; DOR, duration of response; N, number of ovarian cancer patients treated; ORR, objective response rate; TFI, treatment free interval. In this issue of Annalsof Oncology, Matulonis et al. [12.Matulonis U.A. Shapira-Frommer R. Santin A.D. et al.Antitumor activity and safety of pembrolizumab in patients with advanced recurrent ovarian cancer: results from the phase 2 KEYNOTE-100 study.Ann Oncol. 2019; 30: 1080-1087Abstract Full Text Full Text PDF PubMed Scopus (301) Google Scholar] present the results of KEYNOTE-100, a large phase II study evaluating the efficacy of the PD-1 inhibitor pembrolizumab for the treatment of recurrent ovarian cancer. A primary end point of this study was to evaluate response rate by RECIST as well as by PD-L1 expression measured as a combined positive score (CPS) of tumor and immune PD-L1 staining by first defining and then validating PD-L1 expression cut points. Response rate in the entire study population was 8.0%, with no difference based on number of prior therapies [7.4% in cohort A (1–3 priors) and 9.9% in cohort B (4–6 priors)]. Response duration was 8.2 months. No new safety concerns were identified. Acknowledging the limitations of cross-study comparisons, these results are remarkably similar to previous reports. While a higher CPS score correlated with improved response (Table 1), the ORR remained <20% even in the highest CPS group. Neither patient, tumor, nor prior treatment characteristics influenced ORR. Ideally, a predictive efficacy biomarker should either enrich for a population more likely to respond or identify non-responders so exposure to an ineffective drug can be avoided. Compared with PD-L1 staining in prior studies, use of CPS score incrementally enriches for treatment response in this study, but still misses some responders. The limitations to PD-L1 testing have been well described [13.Topalian S.L. Taube J.M. Anders R.A. et al.Mechanism-driven biomarkers to guide immune checkpoint blockade in cancer therapy.Nat Rev Cancer. 2016; 16: 275-287Crossref PubMed Scopus (1627) Google Scholar] and utility of testing varies across tumor types. In endometrial cancer, microsatellite instability (MSI) and/or mismatch repair (MMR) deficiency is a much better biomarker for response than PD-L1 status. However, rates of MSI/MMR in ovarian cancer are very low. No MSI-H cases were identified in KEYNOTE-100 and thus do not account for the responses observed. It has been hypothesized that BRCA mutations may be a marker given their association with increased TILs and a high tumor mutational burden (TMB); however, so far, BRCA status has not been associated with response in this or prior studies [8.Disis M.L. Taylor M.H. Kelly K. et al.Efficacy and safety of avelumab for patients with recurrent or refractory ovarian cancer: phase 1b results from the JAVELIN solid tumor trial.JAMA Oncol. 2019; 5: 393-401Crossref PubMed Scopus (217) Google Scholar, 14.Ledermann J. Shapira-Frommer R. Santin A.D. et al.Association of PD-L1 expression and gene expression profiling with clinical response to pembrolizumab in patients with advanced recurrent ovarian cancer: results from the phase 2 KEYNOTE-100 study.ESMO 2018 Congress. 2018Abstract Full Text Full Text PDF Scopus (4) Google Scholar]. Indeed, TMB is generally low in ovarian cancer, a disease much more associated with copy number alterations. At this point, no clear biomarker for PD-1/PD-L1 therapy in ovarian cancer has emerged. Fundamentally, there is still little understanding of the ovarian cancer immune microenvironment and how it may be pharmacologically manipulated. The low response rates with PD-1/PD-L1 inhibitors suggest that this is not the dominant pathway regulating suppression of antitumor immunity, even in those with higher CPS. Whether other immune checkpoints or factors are impairing the cycle of immunity is unclear. Improvement in response rate with combinatorial checkpoint blockade (i.e. CTLA-4 and PD-1) suggests there may be validity to this approach. Chemotherapy can increase neoantigenicity, which in combination with PD-1/PD-L1 inhibitors is hypothesized to increase clinical benefit. The recently reported Javelin Ovarian 200 study [15.Pujade-Lauraine E. Fujiwara K. Ledermann J. et al.Avelumab alone or in combination with pegylated liposomal doxorubicin vs pegylated liposomal doxorubicin alone in platinum-resistant or refractory epithelial ovarian cancer: primary and biomarker analysis of the phase 3 JAVELIN Ovarian 200 trial.SGO 50th Annual Meeting on Women's Cancer. 2019Google Scholar], showed no advantage with combination liposomal doxorubicin and avelumab treatment compared with liposomal doxorubicin alone in an unselected population. In the subset of PD-L1-positive staining tumors (defined by both tumor and immune cell expression), combination therapy resulted in an improved hazard ratio compared with liposomal doxorucibin alone. However, the median PFS with combination therapy for patients with PD-L1-positive and PD-L1-negative tumors was not different; thus, it is unclear whether PD-L1 staining enriched for a population more likely to benefit. Combinations with chemotherapy are being widely studied, although a planned interim analysis of the Phase III Javelin Ovarian 100 study led to termination of the trial due to lack of superiority over chemotherapy alone [16.Merck KGaA, Darmstadt, Germany, and Pfizer Provide Update on JAVELIN Ovarian 100 Trial of Avelumab in Previously Untreated Advanced Ovarian Cancer, 21 December 2018. https://www.emdgroup.com/en/news/javelin-ovarian-100-21-12-2018.html (22 May 2019, date last accessed).Google Scholar] and resulted in early discontinuation of the Phase III JAVELIN Ovarian PARP 100 study [17.Merck KGaA, Darmstadt, Germany, and Pfizer Announce Discontinuation of Phase III JAVELIN Ovarian PARP 100 Trial in Previously Untreated Advanced Ovarian Cancer, 19 March 2019. https://www.pfizer.com/news/press-release/press-release-detail/merck_kgaa_darmstadt_germany_and_pfizer_announce_discontinuation_of_phase_iii_javelin_ovarian_parp_100_trial_in_previously_untreated_advanced_ovarian_cancer (22 May 2019, date last accessed).Google Scholar]. Alternative immunotherapy approaches currently in clinical trial include PD-1/PD-L1 inhibitor combinations with PARP inhibitors, targeting of MDSC/macrophages, adoptive immune transfer technologies, and inhibition of other immunosignaling pathways (e.g. GAS6/AXL). Despite response rates no better than late-line chemotherapy in this disease, there is still promise for PD-1/PD-L1 inhibitors in ovarian cancer. The potential for long duration of response, generally lower rates of high-grade toxicity and lower treatment discontinuation rates when compared with chemotherapy bolster continued development for ovarian cancer. However, due caution is needed as certain serious toxicities of immuno-oncologics are irreversible and increasing reports of hyperprogression suggest potential detrimental effects in unselected populations [18.Kato S. Goodman A. Walavalkar V. et al.Hyperprogressors after immunotherapy: analysis of genomic alterations associated with accelerated growth rate.Clin Cancer Res. 2017; 23: 4242-4250Crossref PubMed Scopus (574) Google Scholar]. Thus, it is imperative that research focuses on optimizing predictive biomarkers for anti-PD-1/PD-L1 therapy and elucidate the key mechanisms regulating immune suppression in these tumors. None declared.