Characterization of outcomes in patients with metastatic non-small cell lung cancer treated with programmed cell death protein 1 inhibitors past RECIST version 1.1–defined disease progression in clinical trials
Introduction
Lung cancer is a leading cause of cancer-related morbidity and mortality. Estimates for lung cancer in the United States for 2016 are 224,390 new cases and 27% of all cancer deaths [1]. A number of risk factors in the development of lung cancer have been identified; the leading cause is exposure to cigarette smoke [2]. In the second-line setting in patients with tumors that do not harbor EGFR, ALK, or ROS1 alterations, until 2015, docetaxel with or without ramucirumab, pemetrexed (non-squamous only), and erlotinib were the only therapies approved by the US Food and Drug Administration (FDA) [3], [4], [5]. However, between 2015–2016, the immune checkpoint inhibitors, nivolumab, pembrolizumab, and atezolizumab were approved for the second-line treatment of mNSCLC without ALK or EGFR mutations [6], [7], [8], [9], [10]. These PD-1 inhibitors block T-cell inhibitory signal pathways by preventing engagement of PD-1 to its ligands (PD-L1/2).
In clinical trials, the magnitude of tumor response with checkpoint inhibitors did not fully characterize the clinical benefit of these agents nor suggest that they would extend survival. This observation led to uncertainty on whether the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1–defined response or progression [11] are appropriate endpoints for immunotherapy trials. RECIST version 1.1 was developed to replace more cumbersome bi-dimensional criteria for tumor response used to assess the activity of cytotoxic chemotherapy, and predated therapies engaging the immune system. According to RECIST, a ≥20% increase in the size of tumor lesions or development of new lesions established disease progression. Therefore, pseudo-progression resulting from an influx of inflammatory cells in tumor sites could lead to treatment discontinuation [12], [13]. Also, some have suggested that patients without a traditional response, or with focal progression amenable to local therapy, or asymptomatic, slow progression, may derive clinical benefit from immunotherapy agents [14]. Anecdotal cases reported of “clinically important” decreases in tumor size following initial evidence of RECIST-defined disease progression has led to clinical trials permitting treatment past RECIST-defined progression (TPP) as long as certain criteria are met (eg, stable performance status, no impending organ dysfunction, tolerability, re-consent of the patient) [14].
With the advent of immunotherapies, further evaluation is needed in describing patterns of tumor response and their association with clinical benefit. In this manuscript, we describe the findings in patients treated beyond RECIST-defined disease progression (TPP) in a pooled dataset from clinical trials of patients with metastatic non-small lung cancer (mNSCLC) who received an anti–PD-1 monoclonal antibody submitted to the FDA. We conducted this analysis to understand the frequency of further tumor reduction after RECIST-defined progression and to characterize the patterns of progression in patients who receive TPP.
Section snippets
Search strategy and selection criteria
We searched for clinical trials evaluating anti–PD-1 antibodies for mNSCLC submitted to the FDA in support of initial or supplemental New Biologics License Applications between 2014 and 2016 that enrolled at least 100 patients with mNSCLC who had previously received at least one prior line of chemotherapy, regardless of PD-L1 expression in tumor, where patients received an anti–PD-1 antibody at the FDA-approved dose and schedule. In addition, the clinical protocols allowed patients to receive
Results
We identified three multicenter, international, open-label trials where 535 patients received an anti–PD-1 antibody. Patients initiated therapy between October 2012 and January 2014. Among the 535 patients (all patients who actually received anti–PD-1 therapy), at the time of analysis, 420 patients (78.5%) had progressive disease on study. The median duration of follow-up was approximately 16 months. In accordance with the clinical trial protocols, patients were imaged radiographically every 6
Discussion
Immunotherapies are revolutionizing treatment paradigms for an increasing number of cancer indications. Notably, PD-1 and/or PD-L1 inhibitors have been found to be efficacious and have received FDA approval in Hodgkin lymphoma, melanoma, renal cell carcinoma, head and neck carcinoma, and urothelial carcinoma, in addition to NSCLC, and are likely to be demonstrated as beneficial in additional cancer indications in the near future [7], [8], [9], [15], [16], [17], [18], [19], [20], [21]. In the
Conclusions
A small percentage of patients continuing anti–PD-1 therapy past RECIST-defined progression may subsequently have further tumor reduction of prolonged duration. The decision to treat patients past progression should be weighed against possible immune-mediated adverse reactions of anti–PD-1 antibodies, as well as other therapies that the patient may benefit from.
Conflicts of interest
None.
Acknowledgments
We would like to sincerely thank Kirsten Goldberg for her attentive editing of the manuscript.
There is no funding source for this work.
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