Tumor Response Dynamics of Advanced Non–small Cell Lung Cancer Patients Treated with PD-1 Inhibitors: Imaging Markers for Treatment Outcome

Abstract

Purpose We evaluated tumor burden dynamics in advanced non-small-cell lung cancer (NSCLC) patients treated with commercial PD-1 inhibitors to identify imaging markers associated with improved overall survival (OS). Experimental Design The study included 160 advanced NSCLC patients treated with commercial nivolumab or pembrolizumab monotherapy as a part of clinical care. Tumor burden dynamics were studied for the association with OS. Results Tumor burden change at best overall response (BOR) ranged from −100% to +278% (median: +3.5%). Response rate (RR) was 18% (29/160). Current and former smokers had a higher RR than never smokers (p=0.04). Durable disease control for at least 6 months was noted in 26 patients (16%), which included 10 patients with stable disease as BOR. Using a landmark analysis, patients with <20% tumor burden increase from baseline within 8 weeks of therapy had longer OS than patients with ≥20% increase (median OS:12.4 vs. 4.6 months, p<0.001). Patients with <20% tumor burden increase throughout therapy had significantly reduced hazards of death (HR=0.24, Cox p<0.0001) after adjusting for smoking (HR=0.86, p=0.61) and baseline tumor burden (HR=1.55, p=0.062), even though some patients met criteria for RECIST progression while on therapy. One patient (0.6%) had atypical response pattern consistent with pseudoprogression. Conclusions Objective response or durable disease control was noted in 24% of advanced NSCLC patients treated with commercial PD-1 inhibitors. A tumor burden increase of <20% from baseline during therapy was associated with longer OS, proposing a practical marker of treatment benefit. Pseudoprogression is rare in NSCLCs treated with PD-1 inhibitors.

Pseudoprogression in Previously Treated Patients with Non–Small Cell Lung Cancer Who Received Nivolumab Monotherapy

“…In a previous clinical trial of nivolumab, the frequency of radiologic pseudoprogression was approximately 5%. 10 More recent reports have shown that the frequency of radiologic pseudoprogression was 0% to 5% in real-world settings, 6,11,12 which is similar to our findings. However, to the best of our knowledge, our cohort was the largest to reveal the incidence of radiologic pseudoprogression in relatively small patient subsets.…”

Future Challenges in Cancer Resistance to Immunotherapy

“…The shift in focus from the direct targeting of the cancer cell towards the stimulation of the anti-tumor response has resulted in encouraging clinical results in humans, but also comes with new problems. Despite promising overall response rates (ORR) for treatment with CPIs, tumor vaccines and ACT or a combination of these, response rates to immunotherapy vary greatly between tumor subtypes, depending partly on their immunogenicities [30,[35][36][37][38][39][40][41][42][43][44]. Primary therapy resistance, defined as a lack of clinical benefit from immunotherapy on tumor growth, exists in a large proportion of patients.…”

Imaging of Precision Therapy for Lung Cancer: Current State of the Art

“…Immune-related tumor response and progression.-ICI therapy may lead to unique patterns of tumor response and progression at imaging in subsets of patients. The most welldescribed pattern is pseudoprogression, which includes (a) response after an initial increase in tumor burden, and (b) respose during or after the appearance of new lesions (36,37,(54)(55)(56)(57)(58). Although pseudoprogression is becoming increasingly known, it is important to recognize the low incidence of pseudoprogression, especially in patients with NSCLC treated with PD-1/PD-L1 inhibitors, with the frequency ranging from 0.6% to 5% (41,57,59).…”

“…The most welldescribed pattern is pseudoprogression, which includes (a) response after an initial increase in tumor burden, and (b) respose during or after the appearance of new lesions (36,37,(54)(55)(56)(57)(58). Although pseudoprogression is becoming increasingly known, it is important to recognize the low incidence of pseudoprogression, especially in patients with NSCLC treated with PD-1/PD-L1 inhibitors, with the frequency ranging from 0.6% to 5% (41,57,59). While imaging strategies that help reliably differentiate pseudoprogression from true progression in the early course of therapy remain to be established, accumulating evidence of the low incidence of pseudoprogression in patients with NSCLCs indicates that an increase in tumor burden is more likely to reflect true progression than pseudoprogression in most patients (36).…”