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Meta-Analysis
. 2024 Oct 1;10(10):1331-1341.
doi: 10.1001/jamaoncol.2024.3456.

Neoadjuvant Immune Checkpoint Inhibitors Plus Chemotherapy in Early Breast Cancer: A Systematic Review and Meta-Analysis

Guillermo Villacampa  1   2 , Victor Navarro  2 , Alexios Matikas  3   4 , Joana Mourato Ribeiro  5   6 , Francesco Schettini  7   8   9 , Pablo Tolosa  1   10 , Olga Martínez-Sáez  7   8 , Rodrigo Sánchez-Bayona  1   10 , Juan M Ferrero-Cafiero  1 , Fernando Salvador  1 , Andri Papakonstantinou  3   4 , Aleix Prat  7   8   9   11   12 , Mafalda Oliveira  1   13 , Tomas Pascual  1   7   8   9
Affiliations
Meta-Analysis

Neoadjuvant Immune Checkpoint Inhibitors Plus Chemotherapy in Early Breast Cancer: A Systematic Review and Meta-Analysis

Guillermo Villacampa et al. JAMA Oncol. .

Abstract

Importance: Recent studies have investigated the combination of immune checkpoint inhibitors (ICIs) with (neo)adjuvant chemotherapy in early-stage breast cancer. However, there is an ongoing debate about the optimal approach for integrating this strategy.

Objectives: To evaluate the association of neoadjuvant ICIs with pathologic complete response (pCR) across molecular phenotypes, to quantify the survival benefits of ICIs beyond pCR status, and to estimate the incidence of specific adverse events.

Data sources: The PubMed database was searched on December 10, 2023, to identify all potential eligible studies.

Study selection: Randomized clinical trials (RCTs) that assessed (neo)adjuvant ICI plus chemotherapy in early breast cancer.

Data extraction and synthesis: Data from the eligible RCTs were extracted by 2 reviewers. An extracted individual patient data meta-analysis and a trial-level random-effect meta-analysis were performed.

Main outcome(s) and measure(s): Outcomes were pCR, event-free survival (EFS) in patients with and without pCR, and adverse events. Hazard ratios were estimated using stratified Cox proportional hazards regression models.

Results: Nine RCTs involving 5114 patients met the inclusion criteria (2097 triple-negative breast cancer [TNBC], 1924 hormone receptor-positive [HR+]/ERBB2-negative [ERBB2-], and 1115 ERBB2+ tumors). In TNBC, the addition of ICIs was associated with an improved pCR rate regardless of programmed cell death ligand 1 (PD-L1) status (absolute improvement, >10%). In HR+/ ERBB2- tumors, the administration of ICIs was associated with improved pCR only in the PD-L1-positive (PD-L1+) population (absolute improvement, +12.2%), whereas no benefit was observed in ERBB2+ tumors. In patients with TNBC achieving a pCR, the addition of ICIs was associated with improved EFS (hazard ratio, 0.65; 95% CI, 0.42-1.00), resulting in a 5-year EFS of 92.0% with ICIs compared with 88.0% without them. In patients with residual disease, ICIs also showed better EFS (hazard ratio, 0.77; 95% CI, 0.61-0.98), resulting in a 5-year EFS of 63.3% with ICIs and 56.1% without them. Adjuvant ICI did not show numerical improvement in patients with either pCR or residual disease (all hazard ratios >1). During the neoadjuvant treatment, the incidence of grade 3 or greater immune-related adverse events with ICI was 10.3%.

Conclusions and relevance: These findings suggest that neoadjuvant ICI therapy improves efficacy outcomes in early-stage TNBC and PD-L1+ HR+/ERBB2- tumors with an acceptable safety profile; however, no benefit was observed with adjuvant ICI. Given the financial and toxicity costs associated with ICIs, future research should prioritize identifying patients most likely to benefit from the addition of ICIs to neoadjuvant chemotherapy.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Villacampa reported receiving personal fees from Pfizer, Merck Sharpe and Dohme, GlaxoSmithKline, Pierre Fabrer, AstraZeneca, and Reveal Genomics outside the submitted work. Dr Matikas reported being a speaker or consultant (no personal fees) for Roche, Seagen, and Veracyte and research funding paid to his instution from Merck, Novartis, AstraZeneca, and Veracyte outside the submitted work. Dr Schettini reported receiving personal fees from Novartis, Gilead, Daiichy Sankyo and receiving travel expenses from Novartis, Gilead, and Daiichy Sankyo outside the submitted work. Dr Tolosa reported receiving personal fees from Pfizer, Novartis, Astra-Zeneca, and Eli Lilly outside the submitted work. Dr Martínez-Sáez reported receiving personal fees from Roche, Novartis, Reveal Genomics, Eisai, and Daiichi Sankyo outside the submitted work. Dr Sánchez-Bayona reported receiving travel grants from Pfizer, Gilead, AstraZeneca, and Novartis; receiving honoraria for speaker or advisory board participation from Novartis, Lilly, AstraZeneca, Daiichi Sankyo, Gilead, Roche, GlaxoSmithKline, Clovis Oncology, Seagen, and Accord; and having nonfinancial interests as a member of the ESMO Young Oncologists Committee and scientific secretary of the Spanish Society of Medical Oncology. Dr Prat reported receiving advisory and consulting fees from Roche, Pfizer, Novartis, Amgen, BMS, Puma, Oncolytics Biotech, MSD, Guardant Health, Peptomyc and Lilly, lecture fees from Roche, Pfizer, Novartis, Amgen, BMS, Nanostring Technologies, and Daiichi Sankyo; institutional financial interests from Boehringer, Novartis, Roche, Nanostring, Sysmex Europa GmbH, Medica Scientia Innovation Research, SL, Celgene, Astellas, and Pfizer; being a stockholder in and consultant for Reveal Genomics and SL; and having a patent for HER2DX licensed to Reveal Genomics, a patent for TNBCDX pending, and a patent for DNADX licensed to Reveal Genomics. Dr Oliveira reported receiving grants from AstraZeneca, Ayala Pharmaceuticals, Boehringer-Ingelheim, Gilead, Novartis, Roche, Seagen, Zenith Epigenetics, and PUMA Biotechnology; personal fees from AstraZeneca, Gilead, Novartis, Roche, Seagen, Daiichi Sankyo/AstraZeneca, iTEOS, Lilly, Merck Sharpe and Dohme, Pierre-Fabre, Relay Therapeutics, Eisai, Libbs, and Pfizer; and travel expenses from AstraZeneca, Gilead, Pierre-Fabre, and Eisai outside the submitted work. Dr Pascual reported receiving personal fees from Novartis, Pfizer, AstraZeneca, Veracyte, and Lilly outside the submitted work. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Pathologic Complete Response (pCR) by Molecular Phenotype Groups and Programmed Cell Death Ligand 1 (PD-L1) Expression
ERBB2+ indicates ERBB2 positive; HR+/ERBB2−, hormone receptor positive/ERBB2 negative; ICIs, immune checkpoint inhibitors; ITT, intention to treat; TNBC, triple-negative breast cancer.
Figure 2.
Figure 2.. Event-Free Survival (EFS) Outcomes in Patients With Triple-Negative Breast Cancer
The Kaplan-Meier curves were generated with the extracted individual patient data from the KEYNOTE-522, IMpassion031, GeparNuevo, and I-SPY2 trials. The EFS hazard ratio (HR) in the I-SPY2 study could not be estimated because no events were observed in the arm without immune checkpoint inhibitor (ICI) therapy. pCR indicates pathologic complete response.
Figure 3.
Figure 3.. Contribution of Adjuvant Immune Checkpoint Inhibitor (ICI) Therapy in Patients With Triple-Negative Breast Cancer Who Achieved Pathologic Complete Response (pCR)
The Kaplan-Meier curves were generated with the extracted individual patient data from the KEYNOTE-522, IMpassion031, GeparNuevo, and I-SPY2 trials. EFS indicates event-free-survival; HR, hazard ratio.
Figure 4.
Figure 4.. Contribution of Adjuvant Immune Checkpoint Inhibitor (ICI) Therapy in Patients With Triple-Negative Breast Cancer With Residual Disease
The Kaplan-Meier curves were generated with the extracted individual patient data from the KEYNOTE-522, IMpassion031, GeparNuevo, and I-SPY2 trials. EFS indicates event-free-survival; HR, hazard ratio.
See this image and copyright information in PMC

Comment in

References

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