Major pathologic response on biopsy (MPRbx) in patients with advanced melanoma treated with anti-PD-1: evidence for an early, on-therapy biomarker of response

Abstract

Background: With increasing anti-PD-1 therapy use in patients with melanoma and other tumor types, there is interest in developing early on-treatment biomarkers that correlate with long-term patient outcome. An understanding of the pathologic features of immune-mediated tumor regression is key in this endeavor.

Materials and methods: Histologic features of immune-related pathologic response (irPR) following anti-PD-1 therapy were identified on hematoxylin and eosin (H&E)-stained slides in a discovery cohort of pre- and on-treatment specimens from n = 16 patients with advanced melanoma. These features were used to generate an irPR score [from 0 = no irPR features to 3 = major pathologic response on biopsy (MPRbx, ≤10% residual viable tumor)]. This scoring system was then tested for an association with objective response by RECIST1.1 and overall survival in a prospectively collected validation cohort of pre- and on-treatment biopsies (n = 51 on-treatment at 4-week timepoint) from melanoma patients enrolled on the nivolumab monotherapy arm of CA209-038 (NCT01621490).

Results: Specimens from responders in the discovery cohort had features of immune-activation (moderate-high TIL densities, plasma cells) and wound-healing/tissue repair (neovascularization, proliferative fibrosis) compared to nonresponders, (P ≤ 0.021, for each feature). In the validation cohort, increasing irPR score associated with objective response (P = 0.009) and MPRbx associated with increased overall survival (n = 51; HR 0.13; 95%CI, 0.054-0.31, P = 0.015). Neither tumoral necrosis nor pretreatment histologic features were associated with response. Eight of 16 (50%) of patients with stable disease showed irPR features, two of which were MPRbx, indicating a disconnect between pathologic and radiographic features at the 4-week on-therapy timepoint for some patients.

Conclusions: Features of immune-mediated tumor regression on routine H&E-stained biopsy slides from patients with advanced melanoma correlate with objective response to anti-PD-1 and overall survival. An on-therapy biopsy may be particularly clinically useful for informing treatment decisions in patients with radiographic stable disease. This approach is inexpensive, straightforward, and widely available.

Keywords: MPR; MPRbx; PD-1; melanoma; pathologic response; pathology.

© The Author(s) 2019. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.

Figures

Figure 1.

Representative photomicrographs showing histologic features in on-treatment specimens from melanoma patients receiving anti-PD-1. (A) On-treatment specimens from responders showed features of neovascularization (left; arrow on inset points to a small vessel), plasma cell infiltration (middle), and proliferative fibrosis (right; inset shows high fibroblast: collagen ratio). An asterisk labels a lymphoid aggregate. (B) Features that were not associated with response to anti-PD-1 included necrosis (left), tumoral melanosis (middle), and residual viable tumor (right). All panels, hematoxylin and eosin staining.

Figure 2.

Heat maps of individual histologic features in a discovery cohort of on-treatment melanoma specimens by response status. Green indicates feature is present. Red indicates feature is absent. Responding lesions show features (in bold) of dense TIL infiltration (including some lymphoid aggregates), neovascularization, proliferative fibrosis, and plasma cells. These features were used to generate an irPR score. The earliest on-treatment specimen from a responder (Patient #1) was taken 14 days after only one dose of anti-PD-1 therapy. The full constellation of pathologic findings associated with response was already evident at this time point. aAssessed on closest scan to biopsy. PR, partial response; CR, complete response; PD, progressive disease; SD, stable disease; (−) no TIL; (+) grade 1 TIL, mild; (++) grade 2 TIL, moderate; (+++) grade 3 TIL,  high.

Figure 3.

Discordant radiographic and pathologic findings in Patient #9 with SD. Top: Pre-treatment CT scan (left) indicating lesion of interest (yellow arrowhead), pre-treatment biopsy shown at low-power (middle; 100×) and high-power (right; 100×) showing viable melanoma. Bottom: On-treatment CT scan (left) showing stable radiographic size of lesion of interest (yellow arrowhead). On-treatment biopsy shown at low-power (middle; 100×) and at high-power (right; 400×) show features of immune-mediated regression with no remaining residual viable tumor apparent in the specimen despite no change in size by radiography.

Figure 4.

irPR scores associate with objective response and long-term survival. (A) Scores of irPR, but not necrosis, associate with objective response and clinical benefit in a validation cohort. (B) Long-term overall survival (OS) associates with MPRbx (irPR score = 3). In the validation cohort (n = 51 on-treatment specimens), OS was markedly increased in patients with irPR scores of 3, as compared to scores 0–2 (P = 0.015, log-rank test).