Pembrolizumab with low-dose carboplatin for recurrent platinum-resistant ovarian, fallopian tube, and primary peritoneal cancer: survival and immune correlates

Abstract

Background: Anti-programmed death 1 (PD1)/programmed cell death ligand 1 (PD-L1) therapies have shown modest activity as monotherapy in recurrent ovarian cancer. Platinum chemotherapies induce T-cell proliferation and enhance tumor recognition. We assessed activity and safety of pembrolizumab with carboplatin in recurrent platinum-resistant ovarian cancer.

Patients and methods: This phase I/II, single-arm clinical trial studied concurrent carboplatin and pembrolizumab in recurrent platinum-resistant ovarian, fallopian tube, and primary peritoneal cancer. Primary platinum refractory patients were excluded. Patients were treated after progression on subsequent non-platinum systemic therapy after becoming platinum resistant or refractory. Pembrolizumab 200 mg was given on day 1 and carboplatin area under the curve 2 on days 8 and 15 of a 3-week cycle until progression. Imaging was assessed by blinded independent review. PD-L1 expression was assessed by immunohistochemistry. Flow cytometry on peripheral blood mononuclear cells was performed for CD3, CD4, CD8, PD1, CTLA4 and Ki67.

Results: The most common treatment-related adverse events were lymphopenia (18%) and anemia (9%) with most being grade 1 or 2 (93%). Of 29 patients treated, 23 patients were evaluable for best objective response: 10.3% (95% CI 2.2 to 27.4) had partial response (PR), 51.7% (95% CI 32.5 to 70.6) had stable disease (SD). 56.5% of patients had decreases in target lesions from baseline. All PD-L1-positive patients achieved PR (3/7, 42.8%) or SD (4/7, 57.2%). Median progression-free survival was 4.63 months (95% CI 4.3 to 4.96). Median OS was 11.3 months (95% CI 6.094 to 16.506). Peripheral CD8+PD1+Ki67+ T cells expanded after 3 (p=0.0015) and 5 (p=0.0023) cycles. CTLA4+PD1+CD8+ T cells decreased through the course of treatment up to the 12th cycle (p=0.004). When stratified by ratio of peripheral CD8+PD1+Ki67+ T cells to tumor burden at baseline, patients with a ratio ≥0.0375 who had a significantly longer median OS of 18.37 months compared with those with a ratio <0.0375 who had a median OS of 8.72 months (p=0.0099). No survival advantage was seen with stratification by tumor burden alone (p=0.24) or by CD8+PD1+Ki67+ T cells alone (p=0.53).

Conclusions: Pembrolizumab with carboplatin was well-tolerated and active in recurrent platinum-resistant ovarian cancer. A ratio of peripheral T-cell exhaustion to radiographic tumor burden may identify patients more likely to benefit from this chemoimmunotherapy.

Trial registration number: NCT03029598.

Keywords: CD8-positive t-lymphocytes; combination; drug therapy; female; genital neoplasms; immunotherapy.

Conflict of interest statement

Competing interests: JL received research funding through his institution from Merck, Forty-Seven, Sanofi-Aventis US, Harpoon Therapeutics, Sumitomo Dainippon Pharma Oncology, and Precigen. AC has a consulting or advisory role with Halozyme, Seattle Genetics, Merrimack, and AbbVie. AC received research funding from XBiotech, Newlink Genetics, Taiho Pharmaceutical, Immunomedics, Onconova Therapeutics, Lilly, Gilead Sciences, Genentech, Seattle Genetics, AbGenomics International, Halozyme, Novocure, MedImmune, and Amgen. KMcG has a consulting or advisory role with Ambry Genetics. KMcG has stock ownership of AbbVie. MLD received research funding from Pfizer, Bavarian Nordisk, Precigen, and EMD Serono. MLD has stock ownership of Epithany. BG has an immediate family member employed by Lilly.

© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

Figures

Figure 1

(A) Waterfall plot. Best percentage change in tumor size from baseline by RECIST V.1.1. (B) Spider plot. Percentage change in tumor size over time from baseline by RECIST V.1.1.

Figure 2

Progression-free survival (PFS) and overall survival (OS). Symbols at censored patients. (A) PFS median (95% CI)=4.633 (4.301 to 4.966), 6-month PFS rate=44.14%. (B) OS median (95% CI)=11.3 (6.094 to 16.506) months.

Figure 3

(A) Change in Ki67+PD1+CD8+ T cells throughout treatment, p=0.0004. Cycle 1 vs cycle 4 p=0.0015, cycle 1 vs cycle 6 p=0.0023. Dots at mean, error bars SD. (B) Change in CTLA-4+PD1+CD8+ T cells throughout treatment, p=0.0004. Dots at mean, error bars SD. Tukey’s multiple comparisons test showed the following significant comparisons: cycle 1 vs cycle 4 p=0.0034; cycle 1 vs cycle 6 p=0.0010; cycle 1 vs cycle 12 p=0.0336. (C) Change in CD8+CD4+ T cells throughout treatment. No significant difference was observed in the total peripheral CD8+ population after 3 cycles (p=0.81) and 5 cycles (p=0.21). Dots at mean, error bars SD.

Figure 4

Kaplan-Meier plot of baseline Ki67/tumor burden (TB) ratio stratified by less than and greater than the median ratio (0.0375);

Figure 5

(A) Overall response rate (ORR) comparison. (B) Progression-free survival (PFS) comparison with other monotherapies for platinum-resistant ovarian cancer: KEYNOTE (pembrolizumab), JAVELIN (avelumab), nivolumab, and AURELIA Chemo (paclitaxel, pegylated liposomal doxorubicin, topotecan).