Patient-Reported Outcomes (PROs) in NRG Oncology RTOG 1010: Phase III Trial Evaluating the Addition of Trastuzumab to Trimodality Treatment of HER2 Overexpressing (HER2+) Esophageal Adenocarcinoma (EAC)

Purpose/Objective(s)

NRG/RTOG 1010 evaluated the benefit of trastuzumab for patients (pts) with HER2+ localized EAC receiving trimodality therapy. Adding trastuzumab did not improve disease-free (primary endpoint) or overall survival, nor treatment toxicity (Lancet Oncology 2022). The primary PRO objective was improvement (impr) in the FACT-Esophageal Cancer Subscale (ECS) score with trastuzumab at restaging prior to surgery. A secondary objective was to assess if impr in ECS score is associated with pathologic complete response (pCR).

Materials/Methods

Pts with HER2+ EAC (T1N1-2; T2-3N0-2) were stratified by presence of adenopathy & randomized 1:1 to weekly paclitaxel, carboplatin with 50.4 Gy radiation (CRT) followed by surgery ± trastuzumab (CRT+T), 4mg/kg week 1, 2mg/kg/weekly x 5 during CRT, 6 mg/kg x1 prior to surgery, and then 6mg/kg every 3 weeks (wks) x 13. The ECS, v4, was done at baseline, 6-8 wks post-CRT and at 1 & 2 years. Impr in ECS and its Swallowing Index (SI) & Eating Index (EI) were defined as increases of 5, 2 & 2 points, respectively, from baseline. PRO sample size provided ≥ 80% power with 1-sided 0.05 alpha & a chi-squared test to determine if the proportion of pts categorized as improved at 6-8 wks is ≥ 25% higher for the CRT+T arm. Correlation between pCR & impr in ECS score was evaluated via chi-squared test.

Results

From 2010-2015, 203 HER2+ pts were randomized; 194 eligible. Of 171 PRO consenting pts, the ECS was completed by 162 (95%) at baseline, 108 (64%) 6-8 wks, 82 (49%) 1 year & 55 (33%) at 2 years. The main reason for FACT-E noncompliance was pt death. Patient & tumor characteristics were similar between arms. Median age was 63 years; 86% male; 96% white; 65% Zubrod 0, 80% cT3 & 71% cN1-2 (AJCC 7^th ed). For ECS scores at 6-8 wks, the mean change (Δ) was higher (better) from baseline at 4.6 (95% CI: 1.3, 7.8) for the CRT+T arm vs 0.9 (95% CI: -2.7, 4.6) for the CRT arm; the proportion of pts with an impr in 6-8 wks ECS was higher on the CRT+T arm (46% vs 38% on the CRT arm) although not significantly different (p=0.39). Table 1 shows ECS, SI & EI scores for all timepoints. At 6-8 wks, 30% with a pCR had an impr in ECS vs 45% of nonpCR pts (p=0.18). There were no significant correlations between pCR and ECS, SI & EI impr at any time points.

Conclusion

The addition of trastuzumab to trimodality therapy for localized HER2+ EAC did not significantly improve survival or PROs. ECS score improvement following therapy was not associated with a pCR. The higher proportion of pts with improved ECS at 6-8 weeks and 2 years in the CRT+T arm is interesting and suggests that HER2 may still be an important target to explore.