Circulating immune biomarkers as predictors of the response to pembrolizumab and weekly low dose carboplatin and paclitaxel in NSCLC and poor PS: An interim analysis
- Authors:
- Published online on: November 19, 2018 https://doi.org/10.3892/ol.2018.9724
- Pages: 1349-1356
Abstract
Introduction
Most patients with advanced non-small cell lung cancer (NSCLC) are candidates for systemic therapy. Platinum-based doublet chemotherapy has been the cornerstone of first line treatment regimens with response rates of ~30% (1). Immunotherapy with antibodies that target the programmed cell death protein 1 pathway (PD-1/PD-L1) are now approved in both the first- and second-line settings (2–4). Response rates of ~20% have been observed; many of the responses have been durable. Cytotoxic chemotherapy can enhance immune responses through several mechanisms and have been effectively combined with immunotherapeutics. Several platinum-based combination chemotherapy regimens have been tested with the anti-PD-1 antibody, nivolumab, in patients with NSCLC (5). The combination of another anti-PD-1 antibody, pembrolizumab, with carboplatin and pemetrexed has recently been approved for the first-line treatment of metastatic non-squamous NSCLC. The approval was based on data from the KEYNOTE-021 trial in which the response rate with the combination was 55% compared to 29% in patients treated with chemotherapy alone (6).
One of the strongest predictors of response and survival in patients with advanced NSCLC is performance status (PS) (7). Although platinum-based combination chemotherapy has been shown to be beneficial for patients with a good PS, 0 or 1, there is still debate regarding its efficacy for patients with a poor PS, 2 or worse (8). PS 2 patients account for up to 30% of patients with advanced NSCLC. In addition to poor responses and survival outcomes, many of the treatment options can cause substantial toxicity in this subset of patients which is why no regimen is accepted as the standard-of-care (9,10). Accrual to most NSCLC clinical trials, including the PD-1-inhibitor-chemotherapy trials, has been limited to patients with PS 0 or 1. The frequent administration of low doses of chemotherapy, referred to as metronomic chemotherapy, has been tested in patients with NSCLC with poor PS (11–16). Although these approaches have been shown to be active and well tolerated, patients with advanced NSCLC and poor PS represent a large unmet need for new treatment options.
Cancer patients with poor PS have been characterized by decreases in T cell function and increases in myeloid suppressor cells (MDSC) and T regulatory (Treg) cells, cells that suppress antitumor immunity (17). Platinum and taxane compounds have been shown to stimulate cytolytic T lymphocytes and to inhibit MDSC and Treg cells (18,19). There is evidence that weekly low-dose carboplatin and paclitaxel produces superior antitumor immune responses, including T cell activation and MDSC and Treg cell inhibition, when compared with maximally tolerated dosing (20). We report the interim analysis of an ongoing study which examines the feasibility of using weekly low-dose carboplatin and paclitaxel with pembrolizumab in patients with advanced NSCLC and poor PS.
Patients and methods
Patients
Patients were enrolled to this clinical trial, which was reviewed and approved by the Wake Forest Health Sciences Institutional Review Board (Winston-Salem, NC, USA). All patients provided written informed consent before undergoing any study-related procedures or testing. Eligibility criteria included histologically confirmed NSCLC that was recurrent (progression after surgery or radiation or chemo-radiation treatment for loco-regional disease) or metastatic; ECOG PS of 2 or 3; age >18; and at least one measurable lesion as defined by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 (21). Key exclusion criteria included more than two previous lines of systemic treatment; active, untreated central nervous system metastases requiring steroids; previous exposure to PD-1/PD-L1 inhibitors; history of pneumonitis; infection with HIV or hepatitis B/C; pregnancy; a requirement for immunosuppression or chronic steroids; and active infection on antibiotics, antifungals, or antivirals.
Study design and treatment
Patients were randomized to pembrolizumab alone or pembrolizumab combined with weekly carboplatin and paclitaxel. The dosing for pembrolizumab was the same in both arms, 200 mg intravenously over 30 min every 3 weeks. Carboplatin and paclitaxel were administered every 7 days at an AUC 1 (Calvert formula) intravenously over 1 h and 25 mg/m2 intravenously over 1 h, respectively. Standard-of-care dosing adjustments were used. Treatment continued until unacceptable toxicity or disease progression. Three weeks of treatment were considered to be one cycle. This study is registered with NCI (NCT02581943).
Study assessments
Baseline assessments included a complete medical history, physical exam, electrocardiogram, complete blood count (CBC), comprehensive metabolic panel (CMP), and a CT scan of the chest and abdomen. A physical exam was performed every three weeks in all patients. Weekly CBC and CMP were obtained prior to each chemotherapy infusion for patients receiving the combination of low-dose chemotherapy and pembrolizumab and every three weeks for patients receiving pembrolizumab alone. Thyroid function studies were obtained every six weeks. Adverse events were characterized and graded using Common Terminology Criteria for Adverse Events version 4.0. The causal relationship (related or not related) between treatment and adverse events was determined by the investigator. Tumor response was assessed by CT scan at 7 weeks of initiation of therapy and every 12 weeks thereafter. In case of clinical suspicion of tumor progression, CT scans were obtained at a shorter interval. Complete response (CR) partial response (PR) and stable disease (SD) and progressive disease (PD) were evaluated and assigned according to RECIST version 1.1. Patients who manifested a CR, PR, or SD were considered to have achieved disease control. All imaging assessments were reviewed by at least one investigator and one radiologist. Blood, for immune laboratory correlates was collected into heparin from each patient before the first dosing and at weeks 4 and 7, after the completion of cycles 1 and 2, respectively.
Flow cytometry
An aliquot of whole peripheral blood was evaluated by multicolor flow cytometry using a FACSCalibur flow cytometer (BD Biosciences, Mountain View, CA, USA). Immune cell populations were identified using phycoerythrin-labeled FoxP3 and HLA-DR, fluorescein-isothiocynate-labeled cluster of differentation (CD)4, CD14, and inducible costimulator (ICOS); and allophycocyanin-labeled CD8. All labeled antibodies were purchased from BD Biosciences with the exception of FoxP3, which was purchased from eBiosciences (San Diego, CA, USA). The percentage of populations of interest was determined using gate statistics. The absolute number of MDSCs was calculated as follows: (total white blood cell count (cells/µl) × percent MDSCs). Treg cell frequencies were calculated by normalization to total CD4 T cell numbers.
miRs
Total RNA was isolated from plasma using the miRNeasy Mini kit (Qiagen Inc., Valencia, CA, USA) according to the manufacturer's instructions. Reverse transcription reactions were performed using a TaqMan MicroRNA Reverse Transcription kit (Applied Biosystems; Thermo Fisher Scientific, Inc., Waltham, MA, USA) according to the manufacturer's instructions. Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) was performed using the reverse transcription reaction product, TaqMan MicroRNA Assay kit, and TaqMan Universal PCR Master Mix (Applied Biosystems; Thermo Fisher Scientific, Inc.) according to the manufacturer's instructions. TaqMan MicroRNA Assay kits for human miRs were used. Reactions were loaded onto a 96-well plate and run in duplicate on an ABI 7500 Fast Real-Time PCR System (Applied Biosystems; Thermo Fisher Scientific, Inc.). The reactions were incubated at 50°C for 20 sec and 95°C for 10 min, followed by 40 cycles of denaturation at 95°C for 15 sec, then 1 min of annealing/extension at 60°C. The ΔΔCq method was used to determine relative number of copies (RQ) of miR (22). Data were normalized to a C. elegans synthetic miR sequence, cel-miR-39 (Qiagen, Inc.), which was spiked in as a control during RNA isolation.
Soluble PD-L1
Plasma levels of soluble PD-L1 (sPD-L1) were determined by an ELISA kit (MyBioSource, San Diego, CA, USA) as recommended by the manufacturer.
Statistical analysis
Data were summarized as percentages, means and standard deviation, or medians and ranges. Repeated-measures ANOVA (using PROC MIXED in SAS), considering treatment group (single vs. combination) and time period (pre-treatment, cycle 1, and cycle 2) as categorical (class) variables, as well as the treatment*time period interaction, were used to model levels of immune cells and factors and circulating miRs. We used post-hoc contrast statements on estimated least-squares means to compare the two treatment groups at specific time points, and to compare first and last time point measures within treatment group. A significant treatment*time interaction in a model means that the null hypothesis that the two treatment groups have similar biomarker patterns over the 3 time points can be rejected. For each outcome variable we also conducted a planned contrast comparing differences in estimated least squares means at cycle 2 compared to pretreatment levels within each treatment group separately (i.e., 2 contrasts per outcome variable). The null hypothesis being tested in these contrasts is that the difference between pretreatment and cycle 2 levels within a treatment group is zero. We applied a Bonferroni correction within each model to the two P-values obtained from the contrast statements. A two-sided alpha of 0.05 was used to evaluate main and interactive model effects, and a two-sided alpha of 0.025 was used for the contrast statements, per the Bonferroni method of adjusting for the two extra contrasts within each model. All statistical analyses were performed using SAS version 9.4 (SAS Institute, Inc., Cary, NC, USA) and StatXact version 10 (Cytel Inc., Cambridge, MA, USA). All tests were two-sided, and P<0.05 was considered to indicate a statistically significant difference.
Results
Clinical efficacy
All patients enrolled had a PS of 2. Ten were randomized to the pembrolizumab alone, the single-agent arm, and 10 to pembrolizumab, carboplatin, and paclitaxel, the combination arm. Patient characteristics are outlined in Table I. The mean number of 3-week cycles per patient was 7 (range, 2–14) in the single-agent arm and 9 (range, 4–16) in the combination arm. Adverse events are displayed in Table II. One patient in the single-agent arm discontinued treatment due to A-V block that was not considered related to treatment and that was successfully managed with pacemaker insertion. Two patients in the single-agent arm required replacement therapy due to treatment-induced hypothyroidism. One patient in the combination arm discontinued therapy due to Grade 3 fatigue. Four patients in the combination arm discontinued carboplatin due to allergic reactions at 3, 7, 9, and 10 months of treatment. The patient who had a reaction during the third month of treatment had received carboplatin prior. These patients were able to continue treatment with pembolizumab and weekly paclitaxel. One patient in the combination arm required replacement therapy due to treatment-induced hypothyroidism. Paclitaxel infusion reactions were not observed nor were pneumonitis or renal failure. Grade 4 and 5 adverse events were also not observed. Tumor response and disease control rates are summarized in Table III.
Immunologic effects
Circulating immune cells and soluble factors previously reported to be modulated by platinum and taxane chemotherapeutics and/or by PD-1 blockade were examined. Circulating CD14+HLA-DR−/low MDSC, which have been associated with therapeutic resistance in patients with NSCLC, were examined (23) Decreases in absolute numbers of this MDSC subpopulation were observed in the combination arm; significant changes were not observed in the single-agent arm (Fig. 1A). Significant changes in circulating CD4+FOXP3+ Treg cells were not observed in either arm (Fig. 1B). Expression of ICOS, a T cell costimulatory receptor related to CD28 expressed on activated T cells that has been associated clinical response in patients with NSCLC treated with PD-1 pathway blockade, was also examined (24). Increases in ICOS+CD8+ cell were observed in the combination arm but not in the single-agent arm (Fig. 1C). Significant changes in ICOS+CD4+ cells were not observed. Significant changes in circulating sPD-L1, which has been associated with immune suppression and clinical outcome, were also not observed (Fig. 2A) (25–28). Pre-treatment sPD-L1 levels tended to be higher in patients that manifested PD (346±85 pg/ml, n=5), compared to patients that manifested PR (272±70 pg/ml, n=8), but this difference was not statistically significant.
Circulating levels of specific miRs implicated in regulating antitumor immune responses were also examined (29). Prominent among these are miRs-146a, 155, 181a, 20a and 223, plasma levels of which have been associated with changes in immune effector and regulatory cells in cancer patients (30,31). Enhanced immunity effected by taxanes has been associated with increases in miR-146a and 155 (32,33). Increases in plasma levels of all the immune-regulatory miRs tested were observed with treatment in the combination arm; increases in miR-155, 181, and 223 were statistically significant (Fig. 2B).
Discussion
Patients who are able to care for themselves but are unable to perform work-related activities are considered to have a PS of 2. These patients constitute a significant proportion of patients with NSCLC. Poor PS patients with NSCLC, irrespective of age, have poorer outcomes as well as an increased incidence of adverse events with therapy. The feasibility of applying weekly low-dose carboplatin and paclitaxel with pembrolizumab in this patient population was examined by randomizing patients to the combination or to pembrolizumab alone. Weekly carboplatin, at AUC 3 or 2, and paclitaxel, at 75 or 100 mg/m2, respectively, has resulted in acceptable toxicity and response rates in patients with advanced NSCLC, including those with poor PS (34,35). Immune activation was demonstrated in patients with ovarian cancer with weekly carboplatin at AUC 2 and paclitaxel at 60 to 80 mg/m2 (20). Because of potentially superior immune effects, we examined lower dosing, carboplatin at AUC 1 and paclitaxel at 25 mg/m2. We found that administering this chemotherapy-immunotherapy regimen to patients with advanced NSCLC and PS 2 was well tolerated and immunologically and clinically active.
Treatments in both the combination and single-agent arms were well tolerated. The incidences of Grade 3 adverse events were low. Carboplatin hypersensitivity was observed in 4 of the 10 patients treated with the combination. Repeated exposure is the most important predictive factor for platinum hypersensitivity, and the patients who did manifest hypersensitivity did receive more than 6 months of repeated exposures (36). How PD-1 blockade may influence platinum hypersensitivity, which is mediated primarily by IgE and/or mast cells/basophils, is not known. The toxicity observed compares favorably with other chemotherapy-PD-1 inhibitor combinations tested in advanced NSCLC patients with good PS. In a study of two doses of nivolumab combined with standard-dose, platinum-based doublet chemotherapy, Grade 3 or 4 treatment-related adverse events led to discontinuation in eight (14%) of 56 patients, most commonly pneumonitis and acute renal failure (5). These included four of 14 patients in the 5 mg/kg nivolumab plus carboplatin-paclitaxel arm and two of 15 patients in the 10 mg/kg nivolumab plus carboplatin-paclitaxel arm. Hypersensitivity reactions occurred in 14 (25%) of patients, all of whom received 10 mg/kg nivolumab, including six of 15 administered carboplatin-paclitaxel, seven of 15 administered cisplatin-pemetrexed, and one of 12 administered cisplatin-gemcitabine. In KEYNOTE-21, which involved 123 patients, the incidence of Grade 3 or worse adverse events was 39% patients in the pembrolizumab, carboplatin, and pemetrexed group and 26% in the chemotherapy alone group. Infusion reactions were observed in only one (2%) of 59 in the pembrolizumab plus chemotherapy group vs. none in the chemotherapy alone group (6).
Circulating cell regulators of the immune effects of chemotherapy and PD-1 inhibitors were examined. Decreases in MDSC were observed in the combination arm; changes in Treg cells were not. That T cells were activated in the combination arm was supported by the increase in ICOS expression on CD4+ cells. Although these findings are statistically non-significant after applying the Bonferroni correction, given the small sample size, we consider the results to be mainly hypothesis generating and warrant further study in a larger group of patients. Increased expression was not observed on CD8+ cells and not in the single-agent arm. ICOS expression was reported to increase on CD8+ cells of patients with NSCLC responding to single-agent PD-1 or PD-L1 blocking antibodies (22). Increases in CD4+ ICOS have been associated with response to the anti-CTLA-4 antibody, ipilimumab, in patients with melanoma (37). Significant changes in circulating immune suppressor and effector cells were not observed in the single-agent arm. It has been noted that whereas changes in MDSC have been evident intratumorally in patients treated with PD-1 inhibitors, changes in peripheral blood MDSC have not (38). In patients with melanoma treated with nivolumab combined with a vaccine, a decline in circulating Treg cells during treatment was associated with clinical benefit (39).
Circulating soluble immune regulators were also examined. Levels of sPD-L1 have had predictive value in patients with melanoma treated with CTLA-4 or PD-1 blockade (24). High plasma levels of sPD-L1 have been associated with reduced survival in lung cancer (25,26). Although there is evidence that high baseline sPD-L1 is associated with disease progression, it remains unclear whether sPD-L1 levels are associated with clinical response to PD-1 blockade in patients with NSCLC (27). Patients in our study who manifested PD tended to have higher levels of sPD-L1 than patients who manifested PR, but differences were not statistically significant. Plasma miRs are emerging as a new class of biomarkers. Circulating levels of many miRs with immune-regulatory effects have demonstrated diagnostic or prognostic potential in NCSLC, including the miRs tested, miR-146a, 155, 181a, 20a, and 223 (40–45). As noted, enhanced immunity effected by taxanes in mice has been associated with increases in miR-146a and miR-155 (31,32). Cisplatin has been shown to increase miR-146a and to decrease miR-181a (46–49). Increases in plasma levels of miR-155, 181a and 223 were associated with disease control the combination arm. miR-155 and miR-223 are involved in the development of MDSC as are miR-146a and miR-20a (50–53). miR-155 and 181a are involved in T cell regulation (54). miRs with immune regulatory activities also regulate a variety of other cellular processes. Of note, miR-181a and miR-20a has been implicated in regulating the sensitivity of tumor cells to platinums and taxanes (55–58).
A variety of factors are involved in the poor systemic therapy response rates observed in patients with NSCLC with poor PS (9,10). Although this clinical trial was not designed to establish or compare response rates, 7 of 10 patients (70%) in the combination arm manifested a PR compared to 2 of 10 patients (20%) in the single-agent arm. Weekly low-dose carboplatin at AUC 1 and paclitaxel at 25 mg/m2 can be safely administered with pembrolizumab at standard dosing to patients with advanced NSCLC and poor PS. This regimen is immunologically active. Reductions in MDSC, increases in activated CD4+ T cells, and changes in immune-regulatory miRs are observed. The combination of this low-dose chemotherapy regimen and pembrolizumab is also clinically active and merits further study in this patient population.
Acknowledgements
Not applicable.
Funding
The present study was funded by Merck & Co. as a part of an investigator initiated clinical trial (Merck Investigator Studies Program grant no. 52346).
Availability of data and materials
All data generated or analyzed during this study are included in this published article.
Authors' contributions
MB, TA and PLT made substantial contributions to the conception and design of the study, interpreted the data, were involved in the drafting and revising of the manuscript critically for important intellectual content and gave final approval of the version to be published. BJL and WJP interpreted the data, assisting the drafting and revising of the manuscript critically for important intellectual content, and gave final approval of the version to be published. SA, MK, SG, JR and DP interpreted the data and critically revised the manuscript for important intellectual content.
Ethics approval and consent to participate
The present study was approved by Wake Forest Health Sciences Institutional Review Board (Clinical Trial Identifier, NCT02581943; Date of registration, 5/1/16). All patients provided written informed consent before undergoing any study-related procedures or testing.
Patient consent for publication
Not applicable.
Competing interests
The authors declare they have no competing interests.
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