Background: The primary analysis of the randomized, double-blind, placebo-controlled APHINITY trial, published in 2017, including 4804 patients (pts) with HER2-positive, early breast cancer with 45.4 months' median follow-up, demonstrated that adjuvant pertuzumab (P) added to trastuzumab and chemotherapy, statistically significantly improved invasive disease-free survival (IDFS) compared with placebo (Pla) added to trastuzumab and chemotherapy overall and for pts with node-positive (N+) disease. In 2019, updated descriptive analyses of IDFS with 74.1 months' median follow-up, demonstrated sustained benefit of adding P both overall (HR, 0.76; 95% CI, 0.64-0.91), and for N+ disease (HR, 0.72; 95% CI, 0.59-0.87), while confidence intervals remained wide for the node-negative (N-) cohort (HR, 1.02; 95% CI, 0.69-1.53). There is great interest to explore how these significant overall results translate into absolute treatment benefits for different patient subpopulations.

Methods: Subpopulation Treatment Effect Pattern Plot (STEPP) is an exploratory, graphical method that plots estimates of treatment effect for overlapping patient subpopulations defined by a covariate of interest. Four continuous covariates of interest are considered for defining subpopulations in this report: i) a clinical composite risk score (see below), ii) TILs percentage, iii) HER2 FISH copy number, and iv) a clinical-biological composite risk score combining the previous three factors. Pts with lowest values for the covariate comprise the extreme left STEPP subpopulation, and pts with highest values comprise the extreme right subpopulation. The clinical composite risk score for IDFS based on the overall cohort was calculated using a Cox regression model including the following prespecified clinical characteristics: number of positive nodes, tumor size, age, and centrally-reviewed hormone receptor status. Composite risk scores were scaled between 0 and 100 with higher scores reflecting higher risk of an IDFS event. An example of low clinical risk factors would be T1N0 and aged 40-64; while high risk would be T3N2 or higher and ages <40 or ≥65. At 74.1 months' median follow-up, the composite risk of an IDFS event did not depend on hormone receptor status. Differences in Kaplan-Meier estimates of 6-year IDFS percents (P minus Pla) were used as estimates of treatment effect for each subpopulation. The overall analyses (N=4804) used 9 overlapping subpopulations with ~1000 pts in each, the N- analyses (N=1799) used 5 subpopulations with ~500 pts in each, and the N+ analyses (N=3005) used 7 subpopulations with ~750 pts in each. Intermediate (middle) subpopulations were the 5th, 3rd, and 4th, respectively.

Results: Table of 6-year IDFS percents (%) from Aphinity STEPPs, Overall and for N- and N+ cohorts. For each analysis, results are shown for the two subpopulations at either extreme of the STEPP (i.e. lowest and highest risk or values) as well as the intermediate STEPP subpopulation.

Conclusions: Based on the two extreme and one intermediate subpopulations of the STEPP analyses shown in the table, the intermediate clinical composite risk subpopulation and the highest TILs percentages had the largest absolute improvements in 6-year IDFS percents for P compared with Pla.

Table of 6-year IDFS percents (%) from Aphinity STEPPs, Overall and for N- and N+ cohorts.
6-year IDFS %Overall (N=4804)Node-Negative (N=1799)Node-Positive (N=3005)
PPlaΔ±SEPPlaΔ±SEPPlaΔ±SE
Overall Average Results 90.6 87.8 2.8±0.9 95.0 94.9 0.1±1.1 87.9 83.4 4.5±1.2 
          
Clinical composite risk          
Lowest risk (0 - 21) 95.3 96.2 -0.9±1.3 96.1 96.5 -0.4±1.5 
Intermediate (39 - 63) 92.6 87.3 5.3±1.9 95.0 91.0 4.0±3.0 93.6 86.7 6.9±2.3 
Highest risk (81 - 100) 80.5 75.8 4.7±2.8 - - - 79.4 75.4 4.0±3.2 
          
TILs percentage          
Lowest values (0-9) 90.4 87.8 2.6±2.0 94.7 95.2 -0.5±2.0 87.2 82.6 4.6±2.7 
Intermediate (13-21) 89.4 87.7 1.7±2.1 94.2 94.1 0.1±2.2 85.4 84.8 0.6±2.7 
Highest values (≥31) 95.6 89.3 6.3±1.7 98.1 94.9 3.2±1.7 92.3 84.9 7.4±2.4 
HER2 copy number          
Lowest values (1-8) 87.1 86.4 0.7±2.2 92.7 94.8 -2.1±2.2 84.1 82.1 2.0±2.8 
Intermediate (9.5-11) 91.8 89.0 2.8±1.9 94.9 96.1 -1.3±1.9 90.7 83.3 7.4±2.5 
Highest values (13-32) 90.5 88.9 1.6±2.0 96.0 95.1 0.9±2.0 87.7 85.3 2.4±2.6 
Clinical-biological composite risk          
Lowest risk (0-21) 96.7 96.4 0.3±1.2 98.2 95.7 2.5±1.6 - - - 
Intermediate (40-60) 93.4 89.5 3.9±1.9 91.7 92.7 -1.0±2.5 94.2 88.8 5.4±2.2 
Highest risk (79-100) 80.1 75.9 4.2±2.7 - - - 79.5 75.2 4.3±3.2 
Table of 6-year IDFS percents (%) from Aphinity STEPPs, Overall and for N- and N+ cohorts.
6-year IDFS %Overall (N=4804)Node-Negative (N=1799)Node-Positive (N=3005)
PPlaΔ±SEPPlaΔ±SEPPlaΔ±SE
Overall Average Results 90.6 87.8 2.8±0.9 95.0 94.9 0.1±1.1 87.9 83.4 4.5±1.2 
          
Clinical composite risk          
Lowest risk (0 - 21) 95.3 96.2 -0.9±1.3 96.1 96.5 -0.4±1.5 
Intermediate (39 - 63) 92.6 87.3 5.3±1.9 95.0 91.0 4.0±3.0 93.6 86.7 6.9±2.3 
Highest risk (81 - 100) 80.5 75.8 4.7±2.8 - - - 79.4 75.4 4.0±3.2 
          
TILs percentage          
Lowest values (0-9) 90.4 87.8 2.6±2.0 94.7 95.2 -0.5±2.0 87.2 82.6 4.6±2.7 
Intermediate (13-21) 89.4 87.7 1.7±2.1 94.2 94.1 0.1±2.2 85.4 84.8 0.6±2.7 
Highest values (≥31) 95.6 89.3 6.3±1.7 98.1 94.9 3.2±1.7 92.3 84.9 7.4±2.4 
HER2 copy number          
Lowest values (1-8) 87.1 86.4 0.7±2.2 92.7 94.8 -2.1±2.2 84.1 82.1 2.0±2.8 
Intermediate (9.5-11) 91.8 89.0 2.8±1.9 94.9 96.1 -1.3±1.9 90.7 83.3 7.4±2.5 
Highest values (13-32) 90.5 88.9 1.6±2.0 96.0 95.1 0.9±2.0 87.7 85.3 2.4±2.6 
Clinical-biological composite risk          
Lowest risk (0-21) 96.7 96.4 0.3±1.2 98.2 95.7 2.5±1.6 - - - 
Intermediate (40-60) 93.4 89.5 3.9±1.9 91.7 92.7 -1.0±2.5 94.2 88.8 5.4±2.2 
Highest risk (79-100) 80.1 75.9 4.2±2.7 - - - 79.5 75.2 4.3±3.2 

Citation Format: Richard D. Gelber, Xin Victoria Wang, Bernard F. Cole, David Cameron, Fatima Cardoso, Vivianne Tjan-Heijnen, Ian Krop, Sherene Loi, Roberto Salgado, Astrid Kiermaier, Elizabeth Frank, Debora Fumagalli, Carmela Caballero, Evandro de Azambuja, Marion Procter, Emma Clark, Eleonora Restuccia, Sarah Heeson, Jose Bines, Sibylle Loibl, Martine Piccart-Gebhardt. 6-year absolute invasive disease-free survival (IDFS) benefit of adding adjuvant pertuzumab to trastuzumab and chemotherapy for patients with early HER2-positive breast cancer: A STEPP analysis of the APHINITY (BIG 4-11) trial [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS10-01.