Tumour-infiltrating lymphocytes in advanced HER2-positive breast cancer treated with pertuzumab or placebo in addition to trastuzumab and docetaxel: a retrospective analysis of the CLEOPATRA study

Abstract

Background: High quantities of tumour-infiltrating lymphocytes (TILs) in primary HER2-positive breast cancer are associated with improved prognosis and response to therapy. We aimed to investigate the prognostic role of host antitumour immunity as represented by baseline quantities of TILs in patients with advanced HER2-positive breast cancer treated with either pertuzumab or placebo in addition to trastuzumab and docetaxel.

Methods: CLEOPATRA was a randomised phase 3 study comparing the addition of either pertuzumab or placebo to first-line therapy with trastuzumab and docetaxel for patients with locally recurrent, unresectable, or metastatic HER2-positive breast cancer. We assessed the quantity of stromal TILs in prospectively collected tumour samples and investigated their association with progression-free survival, overall survival, clinicopathological characteristics, and pertuzumab treatment. We estimated hazard ratios (HR) and 95% CIs with multivariate Cox regression models fitting stromal TILs as a continuous variable (per 10% increment). The CLEOPATRA trial is registered with ClinicalTrials.gov, number NCT00567190.

Findings: Tumour samples from 678 (84%) of 808 participants were evaluable for TILs, including 519 (77%) archival samples, 155 (23%) freshly obtained samples (collected 45 days or fewer before randomisation), and four samples of unknown archival status. Median follow-up was 50 months (IQR 41-54) for progression-free survival and 51 months (IQR 46-57) for overall survival. 519 progression-free survival events occurred and 358 patients died. The median TIL value was 10% (IQR 5-30). Freshly obtained tumour samples had significantly lower TIL values than did archival samples (10·00% [95% CI 5·00-20·00] vs 15·00% [5·00-35·00]; p=0·00036). We detected no significant association between TIL values and progression-free survival (adjusted HR 0·95, 95% CI 0·90-1·00, p=0·063). However, for overall survival, each 10% increase in stromal TILs was significantly associated with longer overall survival (adjusted HR 0·89, 95% CI 0·83-0·96, p=0·0014). The treatment effect of pertuzumab did not differ significantly by stromal TIL value for either progression-free survival (pinteraction=0·23) or overall survival (pinteraction=0·21).

Interpretation: In patients with advanced HER2-positive breast cancer treated with docetaxel, trastuzumab, and pertuzumab or placebo, higher TIL values are significantly associated with improved overall survival, suggesting that the effect of antitumour immunity extends to the advanced setting. Future clinical studies in this cancer subtype should consider TILs as a stratification factor and investigate whether therapies that can augment immunity could potentially further improve survival.

Funding: F Hoffmann-La Roche-Genentech and the Breast Cancer Research Foundation.

Conflict of interest statement

Declaration of interests

JE-W, EC, and AK are employees of F Hoffmann-La Roche. AK is an employee and reports personal fees from F Hoffmann-La Roche. JE-W is an employee and reports personal fees from Roche-Genentech. EC is an employee of Roche Products, and has an issued patent “Uses for and article of manufacture including HER2 dimerisation inhibitor pertuzumab 13/649591”. SS reports grants, personal fees and non-financial support from Roche-Genentech; personal fees from Clinigen Group, AstraZeneca, OncoPlex Diagnostics, and Pieris Pharmaceuticals; grants and personal fees from Pfizerand EliLilly; and grants from Puma Biotechnology and Merrimack Pharmaceuticals; and has received honoraria and her institution has received research funding from Roche-Genentech. SL reports grants from Roche-Genentech. SL’s institution receives research support from Roche-Genentech. All other authors declare no competing interests.

Copyright © 2017 Elsevier Ltd. All rights reserved.

Figures

Figure 1. Trial profile

Treatment naive was defined as no previous treatment with chemotherapy or trastuzumab (one previous endocrine therapy was allowed) and treatment experienced was defined as previous (neo)adjuvant chemotherapy, trastuzumab, or both. TILs=tumour-infiltrating lymphocytes. *20 paired cases of primary and metastatic cancer were counted only once.

Figure 2. Stromal TILs and survival

Kaplan-Meier curves are stratified by mean stromal TIL value (≤20% vs >20%). All analyses were done in the intention-to-treat population of patients with evaluable TILs. Plots show progression-free survival in the whole cohort (A) and in patients grouped by stromal TIL value and treatment group (all patients also received trastuzumab and docetaxel; B), and overall survival in the whole cohort (C) and in patients grouped by stromal TIL value and treatment group (D). HR=hazard ratio for patients with >20% TILs vs those with ≤20% TILs. NR=not reached. TIL= tumour-infiltrating lymphocyte.

Figure 3. Stromal TILs and effect of pertuzumab

Forest plots show the HR for each 10% increment in TILs according to treatment group. These HRs were derived with a Cox regression model. pinteraction values represent the test for interaction between TILs and pertuzumab effect—ie, to test if there is a significant difference between the HR point estimates of the effect of the number of TILs on progression-free survival (A) and overall survival (B) by treatment group. All analyses were done in the intention-to-treat population of the cohort with evaluable TILs. Overall HRs were adjusted for clinicopathological factors. TIL=tumour-infiltrating lymphocyte. HR=hazard ratio.