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Evidence of pseudoprogression in patients treated with PD1/PDL1 antibodies across tumor types.

ABSTRACT: BACKGROUND:PD(L)1 antibodies (anti-PD(L)-1) have been a major breakthrough in several types of cancer. Novel patterns of response and progression have been described with anti-PD(L)-1. We aimed at characterizing pseudoprogression (PSPD) among patients with various solid tumor types treated by anti-PD(L)-1. METHODS:All consecutive patients (pts) enrolled in phase 1 trials with advanced solid tumors and lymphomas treated in phase I clinical trials evaluating monotherapy by anti-PD(L)-1 at Gustave Roussy were analyzed. We aimed to assess prevalence and outcome of PSPD across tumor types. We also intended to describe potential clinical and pathological factors associated with PSPD. RESULTS:A total of 169 patients treated with anti-PD(L)-1 were included in the study. Most frequent tumor types included melanoma (n = 57) and non-small cell lung cancer (n = 19). At first tumor evaluation 77 patients (46%) presented with immune unconfirmed progressive disease. Six patients (8%) experienced PSPD: 2 patients with partial response; 4 patients with stable disease. Increase in target lesions in the first CT-scan was more frequently associated to PSPD (67% vs 33%; P = .04). Patients with a PSPD had a superior survival when compared to patients progressing (median OS: 10.7 months vs 8.7 months; P = .07). CONCLUSIONS:A small subset of PSPD patients may experience response after an initial progression. Assessment of the current strategy for immune-related response evaluations may require further attention.

SUBMITTER: Martin-Romano P

PROVIDER: S-EPMC7163099 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Importance:Longitudinal circulating tumor DNA (ctDNA) has been shown to predict response and survival in patients with metastatic melanoma treated with anti-programmed cell death 1 (PD-1) antibodies. Pseudoprogression, defined as radiologic finding of disease progression prior to response, has been a challenge to clinicians. Objective:To establish whether ctDNA at baseline and up to week 12 of treatment can differentiate between the radiologic findings of pseudoprogression and true progression in patients with metastatic melanoma. Design, Setting, and Participants:This explorative biomarker study examined circulating BRAF and NRAS mutations in a cohort of 125 patients with melanoma receiving PD-1 antibodies alone or in combination with ipilimumab between July 3, 2014, and May 24, 2016. Pseudoprogression was defined retrospectively as radiologic progression not confirmed as progressive disease at the next radiologic assessment. Plasma samples of ctDNA at baseline and while receiving treatment were taken for analysis prospectively over the first 12 weeks of treatment. Favorable ctDNA profile (undetectable ctDNA at baseline or detectable ctDNA at baseline followed by >10-fold decrease) and unfavorable ctDNA profile (detectable ctDNA at baseline that remained stable or increased) were correlated with response and prognosis. Main Outcomes and Measures:Early differentiation of pseudoprogression from true progression using longitudinal ctDNA profile. Results:According to guidelines by Response Evaluation Criteria in Solid Tumors (RECIST), progressive disease occurred in 29 of the 125 patients (23.2%). Of the 29 patients, 17 (59%) were 65 years or younger, 18 (62%) were men, 9 (31%) had pseudoprogression, and 20 (69%) had true progression. Of the 9 patients (7%) with confirmed pseudoprogression, all patients had a favorable ctDNA profile. At a median follow-up of 110 weeks, 7 of 9 patients (78%) were alive. All but 2 patients with true progression had an unfavorable ctDNA profile. Sensitivity of ctDNA for predicting pseudoprogression was 90% (95% CI, 68%-99%) and specificity was 100% (95% CI, 60%-100%). The 1-year survival for patients with RECIST-defined progressive disease and favorable ctDNA was 82% vs 39% for unfavorable ctDNA (hazard ratio [HR], 4.8; 95% CI, 1.6-14.3; P?=?.02). Overall survival was longer in patients with a partial response (54 of 125 patients [43%]) compared with patients with progressive disease and a favorable ctDNA profile (11 of 125 patients [9%]; HR, 0.09; 95% CI, 0.01-0.80; P?<?.01). Conclusions and Relevance:The results demonstrate that ctDNA profiles can accurately differentiate pseudoprogression from true progression of disease in patients with melanoma treated with PD-1 antibodies. Results of this blood test performed at regular intervals during systemic treatment reflect tumor biology and have potential as a powerful biomarker to predict long-term response and survival.

Project description:Introduction:Until recently, systemic chemotherapy was the only option for treating bladder cancer and outcomes remained dismal. After a long gap of no progress for 40 years, immuno-therapy with checkpoint inhibitors (PDL1 and PD1) has revolutionized the treatment paradigm of bladder cancer, with five approved agents to treat platinum-refractory bladder cancer since the first approval of atezolizumab in May 2016. Methods:This review summarizes the most recent data on approved checkpoint inhibitors currently used in management of advanced bladder cancer. Early- and late-phase trials of the five checkpoint inhibitors (pembrolizumab, nivolumab, atezolizumab, durvalumab, and avelumab) in advanced bladder cancer are reviewed in detail. This review also describes the potential application of PD1/PDL1 inhibitors in adjuvant and neoadjuvant settings and non-muscle-invasive bladder cancer, as well as with radiation in muscle-invasive bladder cancer treatment. The role of PDL1 and tumor-mutation burden and clinical considerations in choosing a particular immunotherapy are also discussed. Results:The approved checkpoint inhibitors (PD1 and PDL1 inhibitors) have similar efficacy and safety profiles in metastatic platinum-refractory bladder cancer, but they vary in dose and frequency and cost burden. However, only pembrolizumab has shown superiority over standard chemotherapy in a randomized Phase III setting so far. In addition, in the first-line setting for cisplatin-ineligible patients, both pembrolizumab and atezolizumab are US Food and Drug Administration-approved and well tolerated. There is a lack of consensus on the utility of testing for PDL1 as a predictive biomarker, as patients with no PDL1 expression also derive some clinical benefit. Tumor-mutation burden is another predictive biomarker, but needs further validation. Conclusion:Immunotherapy has offered a glimmer of hope to patients with bladder cancer. The current landscape is rapidly evolving, with novel immunotherapy-combination trials to improve outcomes further and evaluate predictive biomarkers to help identify patients most likely to benefit from such therapies.

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Evidence of pseudoprogression in patients treated with PD1/PDL1 antibodies across tumor types.

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