Immune checkpoint inhibitors (ICI) have been incorporated into standard treatment regimens for patients with early and advanced triple-negative breast cancer (TNBC).1,2 Unlike in TNBC, the first studies to test the efficacy of ICI in patients with metastatic estrogen receptor-positive (ER+) disease showed limited efficacy, probably reflecting the lower immunogenicity of these tumors compared with TNBC.3, 4, 5 However, building on the knowledge that primary tumors are often less immunosuppressed than pretreated malignancies, and that combining ICI with cytotoxic agents may elicit antitumor immune responses, early studies have explored this strategy in the preoperative setting.6,7 A pathological complete response (pCR) rate of 16% was observed among 43 patients with Luminal B-like breast cancer treated with neoadjuvant chemotherapy (NACT), followed by nivolumab in combination with endocrine therapy (ET) in the GIADA trial.8 In the I-SPY2 trial, the addition of pembrolizumab to NACT increased estimated pCR rates from 13% to 30% in 40 patients with ER+/human epidermal growth factor receptor 2 (HER2)-negative (HER2−) MammaPrint-high breast cancer, suggesting that at least a subgroup of patients with ER+ disease could derive benefit from the addition of immune checkpoint blockade.9
In this context, the results of two large placebo-controlled, phase III studies evaluating the addition of ICI to NACT in patients with high-risk ER+ early breast cancer were recently reported. The KEYNOTE-756 trial enrolled 1278 patients with T1c-2 (≥2 cm) cN1-2 or T3-4 cN0-2, grade 3, ER+/HER2− invasive ductal carcinoma (invasive lobular carcinoma excluded), randomized 1 : 1 to neoadjuvant pembrolizumab or placebo, both administered with weekly paclitaxel for 12 weeks, followed by four cycles of doxorubicin/epirubicin and cyclophosphamide.10 After surgery (± radiotherapy), patients received pembrolizumab or placebo for nine cycles in combination with ET. The study's co-primary endpoints were pCR and event-free survival (EFS). An increase in pCR rate favoring the pembrolizumab-containing arm was demonstrated (24.3% versus 15.6%, P = 0.00005), corresponding to an absolute difference of 8.5% [95% confidence interval (CI) 4.2% to 12.8%] between the arms.10 EFS results are immature and have not yet been presented. Similarly, the CheckMate 7FL study randomized patients with T1c-2 and N1-2 or T3-4 and N0-2, grades 2-3, ER+/HER2− invasive breast cancer to receive preoperative nivolumab or placebo in combination with anthracycline- and paclitaxel-based NACT, followed by post-operative ET with nivolumab or placebo.11 Although the study design initially included pCR and EFS as co-primary endpoints, due to changes in the treatment landscape [including introduction of adjuvant cyclin-dependent kinases 4 and 6 (CDK4/6) inhibition] a protocol amendment changed the primary endpoint to be pCR only, with EFS being an exploratory endpoint, and accrual stopped after the randomization of 521 patients.11 The addition of nivolumab to NACT was associated with an increase in pCR from 13.8% to 24.5% (P = 0.0021), corresponding to a delta of 10.5% (95% CI 4.0% to 16.9%).11 Patients enrolled in the immunotherapy arms experienced higher rates of grade 3-4 adverse events, treatment discontinuations, and immune-related adverse events compared with those in the placebo arms (Table 1).10,12
Table 1.
Efficacy and safety results of KEYNOTE-756 and CheckMate 7FL trials
| Arm | KEYNOTE-756 |
CheckMate 7FL |
||
|---|---|---|---|---|
| Pembrolizumab | Placebo | Nivolumab | Placebo | |
| Randomly allocated patients | 635 | 643 | 263 | 258 |
| pCR rate | 24.3% | 15.6% | 24.5% | 13.8% |
| pCR rate (absolute difference) | 8.5% | 10.5% | ||
| All AEs (any grade) | 98% | 99% | 98% | 98% |
| Grade ≥3 AEs | 52% | 46% | 42% | 38% |
| Serious AEs | 19% | 10% | 23% | 13% |
| AEs leading to treatment discontinuation | 19% | 10% | 10% | 3% |
| Grade 5 AEs | 1 (0.2%) | 0 | 2 (0.8%) | 0 |
| IrAEs | 33% | 7% | NR | NR |
| Grade ≥ 3 irAEs | 7% | 1% | NR | NR |
| Most common AEs | Alopecia (64%) Nausea (48%) Anemia (32%) Fatigue (30%) Diarrhea (27%) |
Alopecia (61%) Nausea (50%) Anemia (26%) Fatigue (28%) Diarrhea (20%) |
Alopecia (49%) Nausea (45%) Anemia (36%) Fatigue (32%) Diarrhea (22%) |
Alopecia (48%) Nausea (37%) Anemia (29%) Fatigue (26%) Diarrhea (23%) |
AEs, adverse events; irAEs, immune-related adverse events; NR, not reported; pCR, pathological complete response.
Despite the gains observed in pCR, evaluation of long-term outcomes will ultimately be necessary to guide the incorporation of this strategy into clinical practice. This is especially important because the reliability of pCR as a surrogate endpoint for long-term outcomes has been questioned both in the ER+ population and in immunotherapy trials.13 In the CheckMate 7FL trial, this may be a particularly relevant limitation, as EFS was shifted from co-primary to an exploratory endpoint.
Considering the risk of immune-related adverse events in patients treated with ICI, the search for predictive biomarkers is of the utmost importance. In both the KEYNOTE-756 and CheckMate 7FL studies, a greater magnitude of pCR benefit was observed in patients with higher programmed death-ligand 1 (PD-L1) expression and lower ER expression, although few patients (<10%) with ER-low disease were included in either study.12,14 In KEYNOTE-756, the PD-L1 positivity rate was 76% based on the DAKO 22C3 assay using combined positive score criteria, while CheckMate 7FL reported a 35% positivity rate according to the Ventana SP142 assay for immune cell infiltration, with this discrepancy likely due to differences in the scoring methods.12,14 In the CheckMate 7FL study, median stromal tumor-infiltrating lymphocytes (TILs) was 1% (range 1%-98%) and an incrementally increasing benefit of ICI was also observed in patients with higher TILs.12 In this trial, lower progesterone receptor (PR) expression (<10%) was also associated with higher pCR rates. In line with observations from other studies, these findings emphasize the significant heterogeneity among patients with ER+ disease and underscore the potential for identifying predictive biomarkers. Similarly to what was observed in the CheckMate 7FL trial, lower PR expression was associated with higher pCR rates among patients with ER-positive breast cancer treated with ICI in both the GIADA and I-SPY2 trials.8,15 In the GIADA trial, which enrolled patients with Luminal B-like breast cancer defined as ER+ with high Ki67 and/or histologic grade 3, PAM50 analysis classified 25% of participants as Luminal A, 56% as Luminal B, and 19% as basal.8 Notably, the pCR rate was significantly higher in patients with the basal subtype (50%) compared with those with Luminal A (9%) and Luminal B (8%).8 Initially developed to assess chemotherapy versus ET sensitivity, gene expression profiles have also been shown to predict benefit from ICI. In the I-SPY2 study, patients classified as MammaPrint ultrahigh (MP2) showed a significant response to durvalumab and olaparib, with an estimated pCR rate of 64% compared with 22% in the control group, while no pCR benefit was seen in the MP1 group (9% versus 10%).15 Similar findings were observed in patients treated with pembrolizumab in I-SPY2, where MP2 status was significantly associated with higher pCR rates.16 The immune infiltrate also appears to play a critical role in modulating the response to immunotherapy among patients with ER+ disease, with a higher magnitude of pCR benefit observed in those with higher stromal TILs in both the CheckMate 7FL and GIADA trials.8,12 Interestingly, PD-L1 expression has been shown to be predictive of response to immunotherapy in metastatic, but not in early, TNBC.17 The reasons why PD-L1 status may predict response to ICI in early ER+ but not in TNBC remain unclear, although previous studies have shown that in patients with ER+ breast cancer, PD-L1 positivity was associated with higher recurrence scores by OncotypeDx and TIL levels.15,18,19 Taken together, these findings suggest that patients with lower ER/PR signaling, higher immune infiltrates and PD-L1 expression, and elevated MammaPrint/OncotypeDx scores represent a population in which the addition of ICI may significantly improve outcomes. While no single biomarker alone was able to accurately identify patients who would benefit from ICI, their integration could achieve a sufficient level of precision to select the ideal candidates for this strategy. Indeed, the identification of an optimal predictive biomarker will likely require the integration of multiple tumor and microenvironmental characteristics, including immune infiltrates, PD-L1 expression, hormone receptor expression, molecular subtypes, and gene expression profiles.20
Another active question is the role of post-operative administration of ICI, particularly as adjuvant abemaciclib is a standard adjuvant treatment option for patients with high-risk node-positive ER+ breast cancer. The significant overlap between the inclusion criteria of studies evaluating ICI and CDK4/6 inhibitors in the early setting (Table 2) is a point of concern given the difficulty of administering these two agents concurrently due to excessive toxicity.21,22 If the benefit of both classes of drugs is confirmed in an overlapping population, a sequencing strategy could be considered, for example starting a CDK4/6 inhibitor after the completion of adjuvant ICI. While sequencing strategies may be considered, it is crucial to prioritize the identification of biomarkers to determine which patients will benefit most from each approach, as the populations that benefit from each strategy may differ. Importantly, as the patients enrolled in the KEYNOTE-756 and CheckMate 7FL studies did not receive adjuvant CDK4/6 inhibition, the EFS results observed in these studies will not reflect the potential additional benefit from ICI in patients treated with CDK4/6 inhibitors.
Table 2.
Eligibility criteria in studies evaluating CDK4/6 inhibitors and immunotherapy in early estrogen receptor-positive breast cancer
| Stage |
Eligibility criteria |
||||||
|---|---|---|---|---|---|---|---|
| T | N | MonarchE | NATALEE | KEYNOTE-756a | CheckMate 7FLb | ||
| I | IA | T1 | N0 | ✖ | ✖ | ✖ | ✖ |
| IB | T0 | N1mi | ✖ | ✖ | ✖ | ✖ | |
| IB | T1 | N1mi | ✔c | ✖ | ✔e | ✔e | |
| II | IIA | T0 | N1 | ✖ | ✔ | ✖ | ✖ |
| IIA | T1 | N1 | ✔c | ✖ | ✔e | ✔e | |
| IIA | T2 | N0 | ✖ | ✔d | ✖ | ✖ | |
| IIB | T2 | N1 | ✔c | ✔ | ✔ | ✔ | |
| IIB | T3 | N0 | ✖ | ✔ | ✔ | ✔ | |
| III | IIIA | T0 | N2 | ✖ | ✔ | ✖ | ✖ |
| IIIA | T1 | N2 | ✔ | ✔ | ✔e | ✔e | |
| IIIA | T2 | N2 | ✔ | ✔ | ✔ | ✔ | |
| IIIA | T3 | N1 | ✔ | ✔ | ✔ | ✔ | |
| IIIA | T3 | N2 | ✔ | ✔ | ✔ | ✔ | |
| IIIB | T4 | N0 | ✖ | ✔ | ✔ | ✔ | |
| IIIB | T4 | N1 | ✔ | ✔ | ✔ | ✔ | |
| IIIB | T4 | N2 | ✔ | ✔ | ✔ | ✔ | |
| IIIC | Any T | N3 | ✔ | ✔ | ✖ | ✖ | |
KEYNOTE-756: histological grade 3 required.
CheckMate 7FL: grade 3 or grade 2 with an estrogen receptor expression between 1% and 10%.
If G3 or Ki67 ≥20%.
If G3, or G2 and Ki67 ≥20%, or high genomic risk.
If tumor size ≥2 cm.
Moving forward, refining the selection of patients with ER+ breast cancer who may derive the greatest benefit from preoperative ICI will be an essential next step in this field, and EFS results from the trials detailed above, as well as ongoing studies, will help to better understand the role of ICI in molecularly selected populations. The phase III SWOG S2206 (NCT06058377) trial is testing the addition of durvalumab to NACT in patients with stage II-III ER+, HER2− breast cancer and a MammaPrint ultrahigh score. Other immunotherapy priming strategies being evaluated include the incorporation of radiotherapy into neoadjuvant chemo-immunotherapy regimens in patients with high-risk ER+ disease defined by clinicopathological parameters and high genomic risk [P-RAD (NCT04443348) and Neo-CheckRay (NCT03875573) trials].23,24 This approach may be particularly promising in less immune-reactive subgroups, as demonstrated by the Neo-CheckRay trial, where the addition of immunotherapy to preoperative chemo-radiotherapy led to a 31% increase in pCR rates among patients with PD-L1-negative tumors.25 While the follow-up of the phase III studies continues, we await the presentation of long-term outcomes and additional biomarker analyses. The identification of subgroups more sensitive to intensified ET with CDK4/6 inhibitors, ICI, or both will allow personalized treatment selection and sequencing strategies to optimize outcomes.
Acknowledgments
Funding
None declared.
Disclosure
GNM reported travel support from AstraZeneca. AGW reported research support (to institution) from Genentech, Gilead, Macrogenics, and Merck; speakers’ fee from AstraZeneca; and consulting or advisory roles for AstraZeneca and AMBRX. SMT reported consulting or advisory roles for Novartis, Pfizer (SeaGen), Merck, Eli Lilly, AstraZeneca, Genentech/Roche, Eisai, Sanofi, Bristol Myers Squibb, CytomX Therapeutics, Daiichi Sankyo, Gilead, Zymeworks, Zentalis, Blueprint Medicines, Reveal Genomics, Sumitovant Biopharma, Umoja Biopharma, Artios Pharma, Menarini/Stemline, Aadi Bio, Bayer, Incyte Corp, Jazz Pharmaceuticals, Natera, Tango Therapeutics, Systimmune, eFFECTOR, Hengrui USA, Cullinan Oncology, Circle Pharma, Arvinas, BioNTech, Johnson&Johnson/Ambrx, Launch Therapeutics, Zuellig Pharma, and Bicycle Therapeutics; research funding from Genentech/Roche, Merck, Exelixis, Pfizer, Lilly, Novartis, Bristol Myers Squibb, Eisai, AstraZeneca, Gilead, NanoString Technologies, Seattle Genetics, OncoPep, Daiichi Sankyo, and Menarini/Stemline; and travel support from Eli Lilly, Sanofi, Gilead, Jazz Pharmaceuticals, Pfizer, and Arvinas. ELM reported consulting for AstraZeneca, Eli Lilly, and Novartis.
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