Evaluation of Immune-Related Response Criteria and RECIST v1.1 in Patients With Advanced Melanoma Treated With Pembrolizumab

Abstract

Purpose: We evaluated atypical response patterns and the relationship between overall survival and best overall response measured per immune-related response criteria (irRC) and Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST v1.1) in patients with advanced melanoma treated with pembrolizumab in the phase Ib KEYNOTE-001 study (clinical trial information: NCT01295827).

Patients and methods: Patients received pembrolizumab 2 or 10 mg/kg every 2 weeks or every 3 weeks. Atypical responses were identified by using centrally assessed irRC data in patients with ≥ 28 weeks of imaging. Pseudoprogression was defined as ≥ 25% increase in tumor burden at week 12 (early) or any assessment after week 12 (delayed) that was not confirmed as progressive disease at next assessment. Response was assessed centrally per irRC and RECIST v1.1.

Results: Of the 655 patients with melanoma enrolled, 327 had ≥ 28 weeks of imaging follow-up. Twenty-four (7%) of these 327 patients had atypical responses (15 [5%] with early pseudoprogression and nine [3%] with delayed pseudoprogression). Of the 592 patients who survived ≥ 12 weeks, 84 (14%) experienced progressive disease per RECIST v1.1 but nonprogressive disease per irRC. Two-year overall survival rates were 77.6% in patients with nonprogressive disease per both criteria (n = 331), 37.5% in patients with progressive disease per RECIST v1.1 but nonprogressive disease per irRC (n = 84), and 17.3% in patients with progressive disease per both criteria (n = 177).

Conclusion: Atypical responses were observed in patients with melanoma treated with pembrolizumab. Based on survival analysis, conventional RECIST might underestimate the benefit of pembrolizumab in approximately 15% of patients; modified criteria that permit treatment beyond initial progression per RECIST v1.1 might prevent premature cessation of treatment.

Fig 1.

Percent change from baseline in target lesions per immune-related response criteria by central review in patients with early (A) and delayed (B) pseudoprogression. Circles represent times of radiologic assessment. Open circles represent times at which the 25% threshold was crossed. Colors represent individual patients. The inset in (A) is an enlargement of the change from a baseline of 0% to 100% from weeks 0 to 24, with the 25% threshold indicated by the horizontal line. In (B), the patient represented by the top gray line did not have a best overall response of progressive disease because progressive disease was not confirmed at the second assessment (change from baseline, 22.1%). The patient represented by the dark blue line is considered to have delayed pseudoprogression because a return to nonprogressive disease could not be confirmed at the time of the data cutoff date.

Fig 2.

Distribution of target lesions in patients with atypical response patterns.

Fig 3.

Case studies of patients with early progression. (A) Scans at baseline and 12, 24, and 52 weeks in a 56-year-old woman with advanced melanoma. Per Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST v1.1) and immune-related response criteria (irRC), the patient experienced progressive disease at week 12. At week 24, response was partial response by irRC. Complete response was obtained at week 96 and has been ongoing for 28 months. (B) Scans at baseline and 12, 16, and 154 weeks in a 72-year-old woman with advanced melanoma. RECIST v1.1 identified stable disease at an earlier time point than irRC. At week 12, response was unconfirmed progressive disease by irRC but stable disease by RECIST v1.1. At week 16, response was stable disease by both criteria. As of the last assessment (treatment ongoing), patient remains with partial response.

Fig 4.

Percent change from baseline in target lesions in patients with best overall response of progressive disease per Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST v1.1) but nonprogressive disease by immune-related response criteria (irRC). Only patients with measurable disease at baseline and at least one postbaseline measurable scan are included (n = 73). Open circles represent times of radiologic assessment. (A) Unidimensional tumor measurements. (B) Bidimensional tumor measurements. (C) Unidimensional tumor measurements that show weeks 0 to 36 only. (D) Bidimensional tumor measurements that show weeks 0 to 36 only.

Fig 5.

Kaplan-Meier estimates of overall survival on the basis of best overall response per RECIST v1.1 and irRC in patients who survived ≥ 12 weeks (n = 592). irRC, immune-related response criteria; non-PD, nonprogressive disease; PD, progressive disease; RECIST v1.1, Response Evaluation Criteria in Solid Tumors, version 1.1.