Further Data Necessary to Gauge Value of Immune Checkpoint Inhibitors to Treat Patients With Early-Stage TNBC

While existing data suggest immunotherapy may be a viable option as neoadjuvant treatment for patients with early-stage triple-negative breast cancer (TNBC), more data is necessary to determine if immune checkpoint inhibitors add to the pathologic complete response (pCR) and, as a result, to event-free survival (EFS) of this patient cohort.

The presentation from the 38th Annual Miami Breast Cancer Conference highlighted 3 trials— KEYNOTE-522 (NCT03036488), IMpassion031 (NCT03197935), and NeoTRIPaPDL1 (NCT02620280)—as potential breakthroughs for immunotherapy as neoadjuvant treatment.¹

“We just have to be careful in anything we do of chasing the bright shiny object,” Adam Brufsky, MD, PhD, of the UPMC Hillman Cancer Center, explained in his presentation of the data. “Nonetheless, this is something that clearly appears to have a benefit here. And I think scientifically, what we really need to do is understand why PD1-L1 and why [tumor infiltrating lymphocytes (TILs)] gives a higher pCR rate with standard chemotherapy.”

First, the KEYNOTE-522 trial compared pembrolizumab (Keytruda) plus chemotherapy with placebo plus chemotherapy in the neoadjuvant setting for patients with newly diagnosed TNBC. The study also examined pembrolizumab versus chemotherapy in the adjuvant setting for the same cohort of patients.²

The patients were allocated to either the pembrolizumab arm (n = 784) or the placebo arm (n = 390). Median follow-up was 15.3 months for the pembrolizumab arm and 15.6 months for the placebo arm.

The primary end point of pCR was 13.6% higher in the pembrolizumab arm (64.8%) than in the placebo arm (51.2%; 95% CI, 5.4-21.8; P = .00055). More, when analyzed by both PD-L1–positive and -negative status, the pCR difference was 14.2% (95% CI, 5.3%-21.1%) and 18.3% (95% CI, -3.3%-36.8%) in favor of the pembrolizumab arm, respectively. EFS at an 18-month follow-up was 91.3% for the pembrolizumab arm and 85.3% in the placebo arm (HR, 0.63; 95% CI, 0.43-0.93).

Next, the double-blind, placebo-controlled, phase 3 Impassion031 trial evaluated atezolizumab (Tecentriq) plus chemotherapy compared with placebo plus chemotherapy for patients who did not receive prior treatment for early TNBC.³

The pCR rate at the data cutoff, which equated to about 20 months of follow-up for the entire cohort, for the atezolizumab arm was 57.6% compared with 41.1% for the placebo arm, which equated to a difference of 16.5% (95% CI, 5.9-27.1; P = .0044). In the PD-L1–positive population, the pCR benefit remained in the atezolizumab arm, with a rate of 19.5% (95% CI, 4.2-34.8) versus 13.3% (95% CI, -0.9-27.5) for patients with PD-L1-negative status (P = .021).

“Two things are being told to us here,” Brufsky explained. “One, that PD-1/L1 appears to be a predictive biomarker for response to chemotherapy; and number 2, you are getting additional benefit on top of that by using a checkpoint inhibitor.”

Lastly, the phase 3 NeoTRIPaPDL1 trial compared carboplatin plus nab-paclitaxel (Abraxane) with or without atezolizumab to treat patients with early high-risk and locally advanced TNBC.⁴

In this research, there was only a marginal difference in pCR rate between the atezolizumab and chemotherapy arms (52.3% vs 47.7%, respectively). Brufsky hypothesized that the imbalances of TILs may explain the marginal difference in pCR rates. Specifically, if patients had TILs infiltrating the tumors at 40% or more, there was a substantial improvement in pCR rates for both the atezolizumab and chemotherapy arms (71% vs 63%, respectively).

Brufsky summarized a number of key takeaways from these pieces of research. First, the chemotherapy backbone including anthracyclines and cyclophosphamides are key components for a benefit from neoadjuvant immune checkpoint inhibitors.

More, while baseline PD-L1 status of tumor or immune cells was not predictive for the benefit from immune checkpoint inhibitors, other variables like TILs and TIL/PD-L1 dynamics may play a role.

“Given the long-term toxicity, like irreversible hypothyroidism and the immature survival data, do not currently use immune checkpoint inhibitors in daily practice,” concluded Brufsky.

References:

1. Brufsky A. Evolving Strategies in Neoadjuvant/Adjuvant Treatment of Early-Stage Triple-Negative Breast Cancer. Presented at: 38th Annual Miami Breast Cancer Conference. Virtual.

2. Schmid P, Cortes J, Pusztai L, et al. Pembrolizumab for Early Triple-Negative Breast Cancer. N Engl J Med. 2020;382(9):810-821. doi: 10.1056/NEJMoa1910549.

3. Mittendorf EA, Zhang H, Barrios CH, et al. Neoadjuvant atezolizumab in combination with sequential nab-paclitaxel and anthracycline-based chemotherapy versus placebo and chemotherapy in patients with early-stage triple-negative breast cancer (IMpassion031): a randomised, double-blind, phase 3 trial. Lancet. 2020;396(10257):1090-1100. doi: 10.1016/S0140-6736(20)31953-X.

4. Pérez-García J, Soberino J, Racca F, et al. Atezolizumab in the treatment of metastatic triple-negative breast cancer. Expert Opin Biol Ther. 2020;20(9):981-989. doi: 10.1080/14712598.2020.1769063.