LBA13 - Nivolumab and ipilimumab in early-stage triple negative breast cancer (TNBC) with tumor-infiltrating lymphocytes (TILs): First results from the BELLINI trial

Background

Immune checkpoint blockade (ICB) added to neoadjuvant chemotherapy (CTx) improves outcome for early stage TNBC patients, but it is largely unknown which patients truly benefit from ICB and for whom CTx can be de-escalated. Moreover, the addition of anti-CTLA4 to anti-PD1 has not been explored in early TNBC. In the first two cohorts of the adaptive phase II BELLINI trial we test the hypothesis that 4 weeks of neoadjuvant nivolumab (nivo) ± low dose ipilimumab (ipi, 1mg/kg) can induce immune responses in TNBC harboring TILs (TILs≥5%).

Methods

Stage I-III TNBC patients were treated with nivo (2 cycles, n=16) or nivo/ipi (2 cycles nivo, 1 cycle ipi, n=15) before start of neoadjuvant CTx or surgery. Primary endpoint is immune activation defined as 2-fold change (2FC) in CD8⁺ T cells or 2FC IFNG expression increase after 4 weeks. Secondary endpoints included safety, radiological response (RECIST1.1) and translational analyses. According to Simon’s two-stage design, immune activation in 30% of the patients allows expansion of a cohort.

Results

A partial radiological response (PR) after 4 weeks was evident in 7/31 (23%) patients, of which 3 received nivo and 4 nivo/ipi. In the 3 patients that went for surgery after ICB, we observed 1 pCR and 1 near-pCR. Only 6% of the patients developed a grade 3-4 adverse event. Immune activation was detected in 18/31 patients (58%), of which 9 received nivo and 9 nivo/ipi. All patients with a PR had TIL levels above 40%. Patients with a PR had higher baseline expression of IFNG (p=0.014). While baseline CD8⁺ T cell levels did not correlate with response, spatial analyses revealed that having CD8⁺ T cells more adjacent to tumor cells was strongly associated with response (p=0.0014). ctDNA clearance at 4 weeks was evident in 24% of the patients.

Conclusions

The majority of TNBC patients with TILs showed increased immune activation after only 4 weeks of ICB and a substantial fraction experienced a clinical response, highlighting the potential of ICB without CTx for TNBC patients.

Clinical trial identification

EudraCT: 2018-004188-30.

Editorial acknowledgement

Legal entity responsible for the study

Netherlands Cancer Institute.

Funding

Bristol-Myers Squibb, NWO (VIDI), Natera.

Disclosure

R.F. Salgado: Non-Financial Interests, Institutional, Invited Speaker: Merck, BMS; Financial Interests, Institutional, Sponsor/Funding: Merck, Puma Biotechnology, Roche; Financial Interests, Institutional, Advisory Board: BMS; Financial Interests, Personal, Advisory Role: Roche. K. Van De Vijver: Non-Financial Interests, Institutional, Advisory Board: GSK, AstraZeneca, ExactSciences. E. Kalashnikova: Financial Interests, Personal, Full or part-time Employment: Natera; Financial Interests, Personal, Stocks/Shares: Natera. S. Willingham: Financial Interests, Personal, Full or part-time Employment: Natera; Financial Interests, Personal, Stocks/Shares: Natera. G.S. Sonke: Financial Interests, Institutional, Sponsor/Funding: Merck, Agendia, AstraZeneca, Roche, Novartis; Non-Financial Interests, Institutional, Advisory Role: Novartis, Seattle Genetics, Biovica. C.U. Blank: Financial Interests, Institutional, Advisory Board: BMS, MSD, Roche, Novartis, GSK, AZ, Pfizer, Lilly, GenMab, Pierre Fabre; Financial Interests, Personal, Expert Testimony: Third Rock Ventures; Financial Interests, Personal, Stocks/Shares: Uniti Cars, co-founder Immagene BV; Financial Interests, Institutional, Invited Speaker: BMS, Novartis, NanoString, 4SC. R. Mann: Financial Interests, Institutional, Advisory Role: BD, Bayer, Screenpoint, Seno Medical, Koning, Medtronic. S.C. Linn: Financial Interests, Institutional, Sponsor/Funding: Roche, AstraZeneca, BMS, Tesaro, Merck, Immunomedics, Eurocept, Agendia, Novartis; Financial Interests, Institutional, Advisory Role: Daiichi Sankyo. M. Kok: Financial Interests, Institutional, Sponsor/Funding: BMS, Roche, AstraZeneca; Non-Financial Interests, Institutional, Advisory Role: BMS, Roche, MSD, Daiichi Sankyo. All other authors have declared no conflicts of interest.