At the 2023 European Society for Medical Oncology Annual Congress in Madrid, Spain, Sherene Loi, MBBS, PhD, Peter MacCallum Cancer Centre, Melbourne, Australia, shared results from the CheckMate 7FL trial. This placebo-controlled, global, phase 3 trial evaluated nivolumab vs placebo plus neoadjuvant chemotherapy among patients with high-risk, estrogen receptor-positive (ER-positive), HER2-negative primary breast cancer.

Dr Loi concluded, “This sets a new paradigm for the use of immunotherapy in this group of patients, potentially the PD-L1 positive patients are deriving the most benefit.”

Transcript:

Hi, I'm Sherene Loi. I'm from the Peter McCallum Cancer Center in Melbourne, Australia, and I'm here at ESMO 2023. I presented the CheckMate 7FL study, which was a randomized, multicenter, global, phase 3 study of nivolumab or placebo in combination with neoadjuvant chemotherapy, followed by adjuvant endocrine therapy in patients with high-risk estrogen receptor positive, HER2-negative primary breast cancer.

As background and rationale for the study, ER-positive, HER2-negative breast cancer is the most common breast cancer subtype. It's very heterogeneous. We know patients are high-risk if they have high tumor stage, grade 3, younger age, or lower ER expression. We know that we can give them neoadjuvant chemotherapy and [pathological complete response] pCR is associated with excellent outcomes. PD-1 targeted agents are in use and approved for use in patients with triple negative breast cancer and are associated with improved pCR rates.There's only been one previous small study in ER-positive disease looking at these agents, and that also showed an increase in the pCR rate.

The CheckMate 7FL study's main objective was to evaluate nivolumab in this setting in combination of neoadjuvant chemotherapy. The study design was placebo-controlled, so patients were randomized to receive nivolumab or placebo, followed by 4 cycles of weekly paclitaxel followed by AC. This could be dose stents or 3 times weekly, followed by surgery, and then adjuvant endocrine therapy with nivolumab or placebo for a year. With regards to inclusion criteria, patients needed to be ER-positive, HER2-negative, newly diagnosed, primary breast cancers. They could have cT1 or T2, but they needed to be node positive or they could have T3/T4 tumors and have any nodal status. Importantly, they needed to be grade 3 ductal histology, as determined by the local pathologist. The main stratification factor was PD-L1 status. This was determined centrally using the SP 142 assay of 1% or more.

Now the study was modified. Originally it was designed to have 1000 patients and a co-primary end point of pCR and [event-free survival] EFS. However, in October 2021, adjuvant abemaciclib was approved for use in the adjuvant setting, and abemaciclib cannot be combined with nivolumab. Patients were expected to withdraw to access abemaciclib, so the co-primary end point of EFS was at risk. A decision was made and a protocol amendment, which was to focus solely on the pCR end point and new recruitment was halted at that stage. There was around about 500 patients for the modified intent to treat primary analysis of pCR. pCR in the PD-L1 positive population as a secondary endpoint was then the next endpoint and event-free survival became exploratory because we were limited in power.

The results were that in using pCR in the intent to treat population, nivolumab increased the pCR rate from 12% to 22%. This was an absolute difference of 10%, and this was statistically significant so the primary end point was met. But importantly, in the PD-L1 positive population, the pCR was also increased, and this was from 20% to 44% — an absolute difference of 24%, so this is a huge difference for PD-L1 positive patients. In contrast, patients with PD-1 negative tumors, their increase was only 3.6%. The benefit was far greater in patients who are PD-L1 positive.

With regards to safety, this was roughly the same according to treatment arm with no new signals, so the adverse events were largely related to chemotherapy. There were immune events as expected, and this was roughly the same frequency as we would expect, so thyroid dysfunction and adrenal insufficiency in hypophysitis. And there were more treatment discontinuations in the nivolumab arm, 10% versus 2% in the placebo arm.

Overall, I think this sets a new paradigm for the use of immunotherapy in this group of patients, potentially the PD-L1 positive patients are deriving the most benefit. We need to follow them up long term to see if this benefit translates into improved, invasive disease-free survival or better long term clinical outcomes. I suspect they will, but of course that takes time to follow up. Yeah, so that’s really exciting.

Source:

Loi S, Curigliano G, Salgado R, et al. A randomized, double-blind trial of nivolumab (NIVO) vs placebo (PBO) with neoadjuvant chemotherapy (NACT) followed by adjuvant endocrine therapy (ET) ± NIVO in patients (pts) with high-risk, ER+ HER2− primary breast cancer (BC). Presented at 2023 ESMO Annual Congress; October 20-23, 2023; Madrid, Spain. Abstract LBA20.