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Exceptional Response to Pembrolizumab in a Metastatic, Chemotherapy/Radiation-Resistant Ovarian Cancer Patient Harboring a PD-L1-Genetic Rearrangement.

ABSTRACT: Purpose: Ovarian carcinoma no longer responsive to surgery and chemotherapy remains an incurable disease. Alternative therapeutic options remain desperately needed.Patients and Methods: We describe a heavily pretreated patient with ovarian cancer with recurrent disease experiencing a remarkable clinical response to treatment with the anti-PD1 immune checkpoint inhibitor pembrolizumab. The clinical, pathological, and genomic characteristics of this exceptional ovarian cancer responder were carefully investigated using immunohistochemistry (IHC), quantitative multiplex fluorescence methods (i.e., automated quantitative analysis, AQUA) and whole-exome sequencing (WES) techniques.Results: The patient harbored a recurrent/metastatic radiation and chemotherapy-resistant high-grade ovarian carcinoma with clear cell features. While progressing on any standard treatment modality, she demonstrated a remarkable complete response to the anti-PD1 immune checkpoint inhibitor pembrolizumab. WES results were notable for the presence a relative low number of mutations (tumor mutation load/Mb = 4.31, total mutations = 164) and a peculiar structural variant disrupting the 3' region of the PD-L1 gene causing aberrant PD-L1 surface expression as confirmed by IHC and AQUA technology. Heavy infiltration of the PD-L1-mutated and PD-L1-overexpressing tumor with T-cell lymphocytes (i.e., CD4+/CD8+ TIL), CD68+ macrophages, and CD20+ B cells was detected in the surgical specimen strongly suggesting immune evasion as a key mechanism of tumor growth and survival. Patient's complete clinical responses remain unchanged at the time of the writing of this report with no significant side effects reported to date.Conclusions: Anti-PD1 inhibitors may represent a novel treatment option for recurrent/metastatic human tumors refractory to salvage treatment harboring PD-L1 gene structural variations causing aberrant PD-L1 expression. Clin Cancer Res; 24(14); 3282-91. ©2018 AACRSee related commentary by Lheureux, p. 3233.

SUBMITTER: Bellone S

PROVIDER: S-EPMC6050068 | biostudies-literature | 2018 Jul

REPOSITORIES: biostudies-literature

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Exceptional Response to Pembrolizumab in a Metastatic, Chemotherapy/Radiation-Resistant Ovarian Cancer Patient Harboring a PD-L1-Genetic Rearrangement.

Bellone Stefania S Buza Natalia N Choi Jungmin J Zammataro Luca L Gay Laurie L Elvin Julia J Rimm David L DL Liu Yuting Y Ratner Elena S ES Schwartz Peter E PE Santin Alessandro D AD

Clinical cancer research : an official journal of the American Association for Cancer Research 20180119 14

<b>Purpose:</b> Ovarian carcinoma no longer responsive to surgery and chemotherapy remains an incurable disease. Alternative therapeutic options remain desperately needed.<b>Patients and Methods:</b> We describe a heavily pretreated patient with ovarian cancer with recurrent disease experiencing a remarkable clinical response to treatment with the anti-PD1 immune checkpoint inhibitor pembrolizumab. The clinical, pathological, and genomic characteristics of this exceptional ovarian cancer respond ...[more]

PMID: 29351920

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Project description:Objective To compare the cost-effectiveness of the combination of pembrolizumab and chemotherapy (Pembro+Chemo) versus pembrolizumab monotherapy (Pembro) as the first-line treatment for metastatic non-squamous and squamous non-small-cell lung cancer (NSCLC) with PD-L1expression ≥50%, respectively, from a US health care perspective. Material and Methods A comprehensive Makrov model were designed to compare the health costs and outcomes associated with first-line Pembro+Chemo and first-line Pembro over a 20-years time horizon. Health states consisted of three main states: progression-free survival (PFS), progressive disease (PD) and death, among which the PFS health state was divided into two substates: PFS while receiving first-line therapy and PFS with discontinued first-line therapy. Two scenario analyses were performed to explore satisfactory long-term survival modeling. Results In base case analysis, for non-squamous NSCLC patients, Pembro+Chemo was associated with a significantly longer life expectancy [3.24 vs 2.16 quality-adjusted life-years (QALYs)] and a substantially greater healthcare cost ($341,237 vs $159,055) compared with Pembro, resulting in an ICER of $169,335/QALY; for squamous NSCLC patients, Pembro+Chemo was associated with a slightly extended life expectancy of 0.22 QALYs and a marginal incremental cost of $3,449 compared with Pembro, resulting in an ICER of $15,613/QALY. Our results were particularly sensitive to parameters that determine QALYs. The first scenario analysis yielded lower ICERs than our base case results. The second scenario analysis founded Pembro+Chemo was dominated by Pembro. Conclusion For metastatic non-squamous NSCLC patients with PD-L1 expression ≥50%, first-line Pembro+Chemo was not cost-effective when compared with first-line Pembro. In contrast, for the squamous NSCLC patient population, our results supported the first-line Pembro+Chemo as a cost-effective treatment. Although there are multiple approaches that are used for extrapolating long-term survival, the optimal method has yet to be determined.

Project description:To evaluate the cost-utility of pembrolizumab versus chemotherapy as the first-line setting for metastatic non-small cell lung cancer (NSCLC) from the US health care system perspective, a Markov model was developed to compare the lifetime cost and effectiveness of pembrolizumab versus chemotherapy for untreated metastatic NSCLC, based on the clinical data derived from phase III randomized controlled trial (KEYNOTE-042; ClinicalTrials.gov; NCT02220894). Weibull distribution was fitted to simulate the parametric survival functions. Drug costs were collected from official websites, and utility values were obtained from published literature. Total costs, quality-adjusted life years (QALYs), and incremental cost-effectiveness ratios (ICERs) were computed as primary output indicators. The impact of different PD-L1 expression levels on ICER was also evaluated. One-way and probabilistic sensitivity analyses were performed to assess the model uncertainty. Compared with chemotherapy, patients treated with pembrolizumab provided an additional 1.13, 1.01, and 0.59 QALYs in patients with PD-L1 expression levels of ?50%, ?20%, and ?1%, with corresponding incremental cost of 53,784, 47,479, and 39,827, respectively. The resultant ICERs of pembrolizumab versus chemotherapy were 47,596, 47,184, and 68,061/QALY, in three expression levels of PD-L1, respectively, all of which did not exceed the WTP threshold of 180,000/QALY. Probability sensitivity analysis outcome supported that pembrolizumab exhibited evident advantage over chemotherapy to be cost-effective. One-way sensitivity analysis found that ICERs were most sensitive to utility value of pembrolizumab in progression survival state. All the adjustment of parameters did not qualitatively change the result. For treatment-naive, metastatic NSCLC patients with PD-L1+, pembrolizumab was estimated to be cost-effective compared with chemotherapy for all PD-L1 expression levels at a WTP threshold of 180,000/QALY in the context of the US health care system.

Project description:On September 22, 2017, the U.S. Food and Drug Administration (FDA) granted accelerated approval for pembrolizumab (Keytruda, Merck & Co., Inc., Whitehouse Station, NJ) for the treatment of patients with recurrent, locally advanced or metastatic, gastric or gastroesophageal junction (GEJ) adenocarcinoma with disease progression on or after two or more systemic therapies, including fluoropyrimidine- and platinum-containing chemotherapy and, if appropriate, HER2/neu-targeted therapy, and whose tumors express programmed death-ligand 1 (PD-L1), as determined by an FDA-approved test. Approval was based on demonstration of durable overall response rate (ORR) in a multicenter, open-label, multicohort trial (KEYNOTE-059/Cohort 1) that enrolled 259 patients with locally advanced or metastatic gastric or GEJ adenocarcinoma. Among the 55% (n = 143) of patients whose tumors expressed PD-L1 based on a combined positive score ?1 and either were microsatellite stable or had undetermined microsatellite instability or mismatch repair status, the confirmed ORR as determined by blinded independent central review was 13.3% (95% CI, 8.2-20.0); 1.4% had complete responses. Response durations ranged from 2.8+ to 19.4+ months; 11 patients (58%) had response durations of 6 months or longer, and 5 patients (26%) had response durations of 12 months or longer. The most common (?20%) adverse reactions of pembrolizumab observed in KEYNOTE-059/Cohort 1 were fatigue, decreased appetite, nausea, and constipation. The most frequent (?2%) serious adverse drug reactions were pleural effusion, pneumonia, dyspnea, pulmonary embolism, and pneumonitis. Pembrolizumab was approved concurrently with the PD-L1 immunohistochemistry 22C3 pharmDx test (Dako, Agilent, Santa Clara, CA) for selection of patients with gastric cancer for treatment with pembrolizumab based on PD-L1 tumor expression. IMPLICATIONS FOR PRACTICE: This report presents key information on the basis for Food and Drug Administration approval of pembrolizumab for the treatment of patients with locally advanced or metastatic gastric or GEJ adenocarcinoma whose tumors express PD-L1. The report discusses the basis for limiting the indication to patients with PD-L1-expressing tumors and the basis for recommending that PD-L1 status be assessed using a fresh tumor specimen if PD-L1 expression is not detected in an archival gastric or GEJ cancer specimen.

Dataset Information

Exceptional Response to Pembrolizumab in a Metastatic, Chemotherapy/Radiation-Resistant Ovarian Cancer Patient Harboring a PD-L1-Genetic Rearrangement.

Publications

Exceptional Response to Pembrolizumab in a Metastatic, Chemotherapy/Radiation-Resistant Ovarian Cancer Patient Harboring a PD-L1-Genetic Rearrangement.

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