Combinations of Neoadjuvant IO and Chemo Grow in Popularity for Early-Stage TNBC

Hope S. Rugo, MD, FASCO

The use of immunotherapy for the treatment of early-stage triple-negative breast cancer (TNBC) has become a more prominent strategy, according to, Hope S. Rugo, MD, FASCO. However, questions about the best chemotherapy backbone and how to select patients still linger.

“We’ve made a lot of progress in TNBC. It’s an incredibly exciting time,” said Rugo, professor of medicine and director of breast oncology and clinical trials education at the University of California, San Francisco Helen Diller Family Comprehensive Cancer Center to the audience at the 39th Annual Miami Breast Cancer Conference®. She is the 2020 Giants of Cancer Care® award winner for education and delivered the Giants of Cancer Care® Lecture during the conference.

“Even the NCCN [National Comprehensive Cancer Network] recommends neoadjuvant therapy for all but the smallest tumors—T1C and up—because we can alter outcomes for patients who have the highest risk subset of breast cancer,” she added. “pCR [pathologic complete response] is associated with a markedly improved outcome, but we’re learning more how to look at this in a little more detail…Neoadjuvant therapy allows individualization of response and gives us the opportunity to study more ways to improve outcome.”

Although there are some exceptions, Rugo said that TNBC tends to be heterogeneous, highly proliferative, and generally responsive to chemotherapy. Other important factors including immune activation, tumor infiltrating lymphocytes, and PD-L1 expression. TNBC is associated with a high risk for recurrence and poor median survival following a diagnosis of metastases. It is also associated with a high mutation rate compared with other breast cancers, making it particularly important for investigators to optimize therapies, Rugo said.

Immunotherapy/chemotherapy combinations, first used in the metastatic setting, have made their way into the neoadjuvant treatment setting for those with TNBC. Investigators believe these combinations can extend long-term survival when used prior to resection. “I think that the direction of neoadjuvant therapy now is to replace our adjuvant trials with neoadjuvant trials, and power them to look both at pCR and event-free survival [EFS],” she said.

Investigators explored that hypothesis in early-stage TNBC during the phase 3 KEYNOTE-522 (NCT03036488). In results published in February 2022, the estimated 36-month EFS was 84.5% (95% CI, 81.7%-86.9%) for patients assigned to neoadjuvant pembrolizumab (Keytruda) plus chemotherapy (n = 784) compared with 76.8% (95% CI, 72.2%-80.7%) for those assigned to placebo plus chemotherapy (n = 390).2

Investigators assigned patients to 200 mg pembrolizumab every 3 weeks or placebo. All participants received 4 cycles of carboplatin plus paclitaxel, followed by 4 cycles of doxorubicin or epirubicin plus cyclophosphamide. After surgery, adjuvant pembrolizumab was continued for 9 cycles or until disease recurrence or intolerable toxicity.

Previous results from the primary EFS analysis found that 15.7% of patients in the experimental arm experienced EFS events compared with 23.8% in the control arm (HR, 0.63; 95% CI, 0.48-0.82; P = .00031). At a median follow-up of 39.0 months, the pembrolizumab regimen resulted in a 37% reduction in the risk of EFS events vs the chemotherapy/placebo regimen (HR, 0.63; 95% CI, 0.48-0.82; P = .00031).3

The FDA approved pembrolizumab in 2021 based on results from KEYNOTE-522 trial, making pembrolizumab the first immunotherapy for this indication.

Investigators also evaluated this approach in the phase 3 IMpassion031 (NCT03197935) found that neoadjuvant atezolizumab (Tecentriq) and nab-paclitaxel (Abraxane) plus doxorubicin and cyclophosphamide significantly improved pCR in patients with stage II or stage III TNBC compared with placebo plus chemotherapy. The pCR rates were 57.6% vs 41.1%, respectively (P = .0044).4

Among the intention-to-treat population (N = 333), 165 patients were randomly assigned to receive intravenous atezolizumab at 840 mg every 2 weeks plus nab-paclitaxel at 125 mg/m² every week for 12 weeks followed by doxorubicin at 60 mg/m² and cyclophosphamide at 600 mg/m² every 2 weeks for 8 weeks. The remaining patients randomly were assigned to receive placebo plus the chemotherapy regimen. All patients then underwent surgery.

Rugo noted that results from both trials showed that patients derived benefit from immunotherapy regardless of PD-L1 status. “PD-L1 expression itself in tumors predicts response to chemotherapy—makes perfect sense [that] if you have a more immune-active cancer, and the host can see that cancer is a foreign body and attack it more effectively, you’re going to get better response to chemotherapy even without the checkpoint inhibitor,” she said.

Rugo said that EFS and distant recurrence-free survival (DRFS) are closely aligned with overall survival (OS), as seen in the findings from KEYNOTE-522. Specifically, additional findings showed that at a median follow-up of 37.8 months (range, 2.7-48.0), 123 patients (15.7%) in the pembrolizumab arm and 93 patients (23.8%) in the placebo arm had an EFS event (HR 0.63; 95% CI, 0.48-0.82; P = .0003). These were defined as disease progression that precluded patients from undergoing definitive surgery, local or distant recurrence, a second primary cancer, or death from any cause. Moreover, the 36-month EFS rates were 84.5% (95% CI, 81.7%-86.9%) vs 76.8% (95% CI, 72.2%-80.7%), respectively. In terms of DRFS, 12.8% of patients in the pembrolizumab arm had an event vs 20.3 of patients in the placebo arm (HR, 0.61; 95% CI, 0.46-0.82). The 36-month DRFS rates were 87.0% vs 80.7%, respectively.2,3

Moreover, residual cancer burden appears to play a prognostic role in TNBC treatment. In KEYNOTE-522, among patients who had a pCR, the 36-month EFS rate for those in the pembrolizumab arm (n = 494) was 94.4% compared with 92.5% among those in the placebo arm (n = 217). For those who did not achieve pCR, those in the pembrolizumab arm (n = 290) had a higher EFS rate (67.4%) than those in the placebo arm (n = 173; 56.8%).2,3

Further, results from the multicenter, platform adaptive, randomized I-SPY2 trial (NCT01042379), for which Rugo is a coauthor, showed that EFS worsened significantly per unit of residual cancer burden (RCB) in every subtype. The phase 2 was designed to evaluate novel agents added to standard neoadjuvant chemotherapy trial in patients with high-risk stage II/III breast cancer. In the analysis, residual cancer burden (RCB) was measured among those who did not achieve pCR to quantify the extent of residual disease. RCB I was defined as having minimal burden, whereas RCB III demonstrated extensive burden. The 3-year EFS rates for those who received 4 cycles of pembrolizumab added to standard neoadjuvant chemotherapy with RCB were as follows: RCB-I (n = 50) 83%, RCB-2 (n = 93) 72%, and RCB-III (n = 36) 41%. For those who had a pCR (n = 140), the 3-year EFS rate was 93%.5,6

Investigators concluded that the prognostic significance of RCB was consistent regardless of subtype and treatment.5

Investigators are currently analyzing data to determine if pembrolizumab has the same effect in the final EFS population of KEYNOTE-522, and hope to publish later this year. “The [OS data] is still early, but it is encouraging to see that there’s a trend towards an improvement.”

Finally, Rugo highlighted updated results from the GeparNuevo trial (NCT02685059) in which investigators evaluated the investigated the addition of durvalumab (Imfinzi) to standard neoadjuvant chemotherapy in patients with early TNBC.7 Patients received placebo or durvalumab for 2 weeks followed by nab-paclitaxel for 12 weeks, followed by epirubicin, cyclophosphamide, and durvalumab or placebo for 8 weeks prior to surgery.7

At a median follow-up of 43.7 months (range, 4.9-56.1), the 3-year EFS rate for those who received durvalumab was 85.6% compared with 77.2% for those who received placebo (HR, 0.48; 95% CI, 0.24-0.97; P = .0398). The addition of the immune-checkpoint inhibitor demonstrated benefit in 3-year distant disease-free survival rates (91.7% vs 78.4%) and OS rates (95.2% vs 83.5%).7 In an analysis of those who achieved pCR with durvalumab (n = 47) or placebo (n = 38), the 3-year invasive disease-free survival rates were (95.5% (95% CI, 83.0%-98.9%) vs 86.1% (95% CI, 69.8%-94.0%), respectively (HR, 0.22; 95% CI, 0.05-1.06; P = 0.038). For distant disease-free survival the rates were 100% (95% CI, 100%-100%) vs 86.1% (95% CI, 69.8%-94.0%), respectively, and for OS these rates were 100% (95% CI, 100%-100%) vs 88.9% (95% CI, 73.1%-95.7%).

Ongoing trials evaluating the utility of atezolizumab and pembrolizumab are also ongoing in this setting, Rugo noted. Despite having some information on prognostic features and promising data for the integration of neoadjuvant immunotherapy regimens there are still many unanswered questions in the space.

Rugo explained that ongoing efforts will better illuminate which patient populations will benefit most from the use of checkpoint inhibitors, what the optimal chemotherapy backbone is, and the optimal duration of checkpoint inhibitors if pCR is achieved. “Understanding who needs immunotherapy and managing toxicity are critical issues,” Rugo said.

_References

_{1. Rugo HS. Incorportaing immunotherapy into the treatment of early-stage TNBC. Presented at: 39th Annual Miami Breast Cancer Conference®. March 3-6, 2022; Miami Beach, FL.}

_{2. Schmid P, Cortes J, Dent R, et al; KEYNOTE-522 Investigators. Event-free survival with pembrolizumab in early triple-negative breast cancer. N Engl J Med. 2022;386(6):556-567. doi:10.1056/NEJMoa2112651}

_{3. Schmid P, Cortes, J, Dent R, et al. KEYNOTE-522: Phase III study of neoadjuvant pembrolizumab + chemotherapy vs. placebo + chemotherapy, followed by adjuvant pembrolizumab vs. placebo for early-stage TNBC. Ann Oncol. 2021;32(9):P1198-P1200. doi:10.1016/j.annonc.2021.06.014}

_{4. 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 randomized, double-blind, phase 3 trial. Lancet. 2020;396(10257):1090-1100. doi:10.1016/S0140-6736(20)31953-X.}

_{5. Symmans WF, Yau C, Chen YY, et al. Assessment of residual cancer burden and event-free survival in neoadjuvant treatment for high-risk breast cancer: an analysis of data from the I-SPY2 randomized clinical trial. JAMA Oncol. 2021;7(11):1654-1663. doi:10.1001/jamaoncol.2021.3690}

_{6. Nanda R, Liu MC, Yau C, et al. Effect of pembrolizumab plus neoadjuvant chemotherapy on pathologic complete response in women with early-stage breast cancer: an analysis of the ongoing phase 2 adaptively randomized I-SPY2 trial. JAMA Oncol. 2020;6(5):676–684. doi:10.1001/jamaoncol.2019.6650}

_{7. Loibl S, Schneeweiss A, Huober JB, et al. Durvalumab improves long-term outcome in TNBC: results from the phase II randomized GeparNUEVO study investigating neodjuvant durvalumab in addition to an anthracycline/taxane based neoadjuvant chemotherapy in early triple-negative breast cancer (TNBC). J Clin Oncol. 2021;39(suppl 15):506. doi:10.1200/JCO.2021.39.15_suppl.506}