Updates from clinical trials from two HR+ breast cancers with neoadjuvant immune checkpoint inhibition

By Dr. Shipra Gandhi
of Roswell Park Comprehensive Cancer Center


Data from two phase III trials showed that adding immune checkpoint inhibition in the neoadjuvant setting in HR positive breast cancer was associated with increases in pCR rates. This was presented at ESMO congress 2023. Updated biomarker subgroup analyses were presented at San Antonio Breast Cancer Symposium 2023.


CheckMate 7FL (CM 7FL; NCT04109066) is a prospective, phase 3, randomized, multicenter, double-blind trial investigating nivolumab in combination with neoadjuvant chemotherapy and adjuvant endocrine therapy in patients with high-risk, estrogen receptor-positive (ER+), human epidermal growth factor receptor 2-negative (HER2−) primary breast cancer (BC). pCR (ypT0/Tis ypN0) rates with neoadjuvant nivolumab plus chemotherapy were significantly improved compared with control (24.5% versus 13.8%; odds ratio [OR] 2.05; 95% CI 1.29–3.27; p=0.0021).


KEYNOTE-756 (NCT03725059) is a global phase 3 study of neoadjuvant pembrolizumab or placebo + chemotherapy followed by adjuvant pembrolizumab or placebo + endocrine therapy in patients with early-stage high-risk ER + /HER2 –  breast cancer. KEYNOTE-756 showed a significantly increased rate of pCR with pembrolizumab plus chemotherapy versus placebo plus chemotherapy (24.3% versus 15.6%; treatment difference 8.5%, 95% confidence interval [CI] 4.2–12.8; p=0.00005).


Updated analysis from SABCS 23 showed that most of the benefit from neoadjuvant checkpoint inhibition was limited to tumors with aggressive biology, like, node positive disease, higher PD-L1 and lower ER expression.


Checkmate 7FL: Benefit of adding nivolumab to neoadjuvant chemotherapy for ER+ BC is mostly evident in patients with PDL1-high tumors, TILS> 5% and ER <=50%.


KEYNOTE-756: Larger pembrolizumab benefit in node+, higher PD-L1 and lower ER <10%.


Is this data practice-changing at this time? NO


Some questions remaining:
1. We need to await event free survival data before putting these results into practice.
2. Are there certain subgroups that derive maximum benefit from neoadjuvant checkpoint inhibition?
3. Should we send PD-L1 upfront in these patients?
4. Given increased hepatotoxicity with combining checkpoint inhibitors with CDK4/6 inhibitors, how will this fit into current treatment paradigm in the adjuvant setting?


Some comments from experts from Twitter:


Naoto T Ueno, MD, PhD: “KEYNOTE-756 confirms once again the benefit drives from less than ER 10%. I suggest that we call less than ER 10% as TNBC.”


George W Sledge, MD: “With both neoadjuvant Nivo and Pembro in ER pos BC pCR rates increase strongly as PD-L1 increases. Two questions: should we use PD-L1 as a predictive biomarker, and should we use either of these drugs in the absence of solid EFS improvements?”


Qamar Khan, MD: “EFS data absolutely needed! Also, ER 1-10 belong in TNBC trials not here. 1-10 % group is making results look better than they are.”


Dr. Sarah Sammons: “Low PR and presence of any TILs also helps us identify patients that may benefit.”


Jason A. Mouabbi, MD: “IMO until we have the EFS data, the KN-756 will not change our practice”


Jason A. Mouabbi, MD: “CheckMate 7FL: Addition of IO improved pCR in G3 PgR negative even if ER > 10% PgR negative tumors have been shown to have a poorer prognosis compared to PgR positive with some studies showing that its prognosis is similar to that of TNBC IMO: G3 ER+ PgR- should be treated like TNBC with chemoimmunotherapy.”


1. Cardoso F, O’Shaughnessy J et al. Phase 3 study of neoadjuvant pembrolizumab or placebo plus chemotherapy, followed by adjuvant pembrolizumab or placebo plus endocrine therapy for early-stage high-risk ER+/HER2− breast cancer: KEYNOTE-756. SABCS 2023
2. Loi S et al. Biomarker Results in High-risk Estrogen Receptor Positive, Human Epidermal Growth Factor Receptor 2 Negative Primary Breast Cancer Following Neoadjuvant Chemotherapy ± Nivolumab: an Exploratory Analysis of CheckMate 7FL. SABCS 2023.


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