Navigating Neoadjuvant, Adjuvant Immunotherapy and ADCs in Metastatic TNBC

Although checkpoint inhibition has been shown to benefit some patients with metastatic triple-negative breast cancer (TNBC), there is not yet a role for immune-based treatment in the neoadjuvant setting, explained Rita Nanda, MD, during an OncLive® Institutional Perspectives in Cancer webinar on breast cancer.

“Historically, breast cancer has not been viewed as an immunogenic disease. Many other diseases like melanoma and lung cancer have been shown to be much more immunogenic…However, a number of studies have suggested that at least a subset of breast cancer may be immunogenic and therefore amenable to checkpoint inhibition,” said Nanda, an associate professor of medicine and director of the Breast Oncology Program at the University of Chicago Medicine.

“The rationale [for immunotherapy] has been the strongest in triple-negative breast cancer, and [it is the disease subtype] with the highest unmet need,” Nanda added.

During the meeting, Nanda also provided an overview of the emergence of antibody-drug conjugates (ADCs) in TNBC and shed light on novel ADCs in clinical development.

Introduction of Immunotherapy Ignites a New Wave of Metastatic TNBC Treatment

Single-agent immunotherapy with pembrolizumab (Keytruda), atezolizumab (Tecentriq), and avelumab (Bavencio) has demonstrated modest benefit for patients.^1-3 However, responses to checkpoint inhibitor monotherapy tend to be durable in responders and can be enriched based on line of therapy, tumor-infiltrating lymphocyte expression, and PD-L1 status, Nanda explained.

Findings from the phase 3 KEYNOTE-119 trial (NCT02555657) failed to demonstrate an improvement in overall survival (OS) with pembrolizumab monotherapy vs chemotherapy in patients with previously treated metastatic TNBC.⁴

However, a trend toward improvement in overall response rate (ORR) and OS was observed with pembrolizumab in patients whose tumor mutational burden (TMB) was 10 mutations/megabase (mut/Mb) or greater.⁵ Although these findings are intriguing, additional data are needed because patients with a TMB of 10 mut/Mb or greater comprised only 10.2% (n = 26) of the total patient population (n = 253).

To build upon the modest benefits observed with single-agent immunotherapy, combination strategies with immunotherapy and chemotherapy, other targeted agents, or radiation therapy have been evaluated in clinical trials, Nanda said.

IMpassion130 (NCT02425891) was a large phase 3 study that randomized patients with metastatic or inoperable, locally advanced TNBC to atezolizumab plus nab-paclitaxel (Abraxane; n = 451) or placebo plus nab-paclitaxel (n = 451).⁶ Findings from the study demonstrated a modest progression-free survival (PFS) improvement with atezolizumab vs placebo in the intention-to-treat (ITT) population (HR, 0.80; 95% CI, 0.69-0.92; P = .0021) and the PD-L1–positive population, measured by immunohistochemistry (HR, 0.63; 95% CI, 0.50-0.80; P < .0001).

Based on these findings, the FDA approved atezolizumab plus nab-paclitaxel in March 2019 for the treatment of patients with unresectable locally advanced or metastatic PD-L1–positive TNBC.⁷

The final analysis of the IMpassion130 trial showed that the median OS was 25.4 months with atezolizumab vs 17.9 months with placebo (HR, 0.67; 95% CI, 0.53-0.86).⁸ The 3-year OS rates were 36% and 22%, respectively.

Another phase 3 study, IMpassion131 (NCT03125902), randomized patients with metastatic TNBC to atezolizumab plus paclitaxel vs placebo plus paclitaxel but failed to demonstrate a statistically significant PFS or OS benefit with the immunotherapy-based combination vs placebo as frontline therapy in PD-L1–positive patients.⁹

“The reasons [why IMpassion131 was a negative trial] remain unclear. People have postulated whether this patient population could have been different or whether the chemotherapy backbone matters, but there is a lot we still don’t understand about this trial and why it was negative. It will be interesting to continue to see the data as they mature,” Nanda said.

In April 2021, the FDA's Oncologic Drugs Advisory Committee (ODAC) voted 7 to 2 favoring to maintain the indication of atezolizumab/nab-paclitaxel regimen as a treatment for adult patients with unresectable locally advanced or metastatic, PD-L1–positive TNBC. The meeting was part of a 3-day public review of 6 indications for checkpoint inhibitors granted under the FDA’s accelerated approval process, which later failed to reach thresholds for statistical significance for key end points in confirmatory clinical trials.

The phase 3 KEYNOTE-355 trial (NCT02819518) randomized patients with TNBC to pembrolizumab plus physician’s choice of chemotherapy (n = 566) or placebo plus chemotherapy (n = 281).¹⁰ The results demonstrated a statistically significant PFS improvement in patients with a PD-L1 combined positive score (CPS) of 10 or greater (38% of the ITT population; HR, 0.65; P = .0012). Moreover, PFS favored the pembrolizumab arm vs placebo across all PD-L1–positive expression levels, and the chemotherapy backbone did not appear to influence response to pembrolizumab.

Although OS data are pending, in November 2020, the FDA granted an accelerated approval to pembrolizumab plus chemotherapy for the treatment of patients with locally recurrent unresectable or metastatic TNBC whose tumors express PD-L1 (CPS ≥10).¹¹

The Benefit of Neoadjuvant Immunotherapy Remains Inconclusive in Early-Stage TNBC

The adaptative, randomized I-SPY2 trial (NCT01042379) was one of the first studies to report on the utility of immunotherapy in the neoadjuvant setting for patients with TNBC, Nanda explained. The results of one arm of the study showed an improvement in estimated pathologic complete response (pCR) rate with a trend toward improvement in event-free survival (EFS) with pembrolizumab plus standard of care chemotherapy.¹²

The larger, phase 3 KEYNOTE-522 trial (NCT03036488) confirmed some of the findings from I-SPY2, demonstrating a 14% absolute improvement in pCR rates with the addition of neoadjuvant and adjuvant pembrolizumab to standard of care chemotherapy vs placebo for patients with newly diagnosed TNBC.¹³ Notably, the benefit was observed irrespective of PD-L1 status.

Additionally, the results of the KEYNOTE-522 study demonstrated a 91% EFS rate in the pembrolizumab arm vs 85% with placebo (HR, 0.63; 95% CI, 0.43-0.93).

However, the FDA’s ODAC voted 10 to 0 against the approval of pembrolizumab in combination with chemotherapy as neoadjuvant therapy for high-risk, early-stage TNBC.¹⁴ The ODAC group voted to defer regulatory action on the biologics license application for pembrolizumab in this setting, citing that the survival findings were immature and required longer follow-up.

As such, neoadjuvant immunotherapy does not currently have a role outside of a clinical trial for patients with early-stage TNBC, Nanda said.

Notably, the IMpassion031 trial (NCT03197935) utilized a similar trial design as the KEYNOTE-522 study but randomized patients with previously untreated stage II and III TNBC to neoadjuvant and adjuvant atezolizumab plus chemotherapy vs placebo plus chemotherapy.¹⁵ The results demonstrated a 16.5% absolute improvement in pCR with atezolizumab vs placebo (P = .0044), and the pCR benefit was observed irrespective of PD-L1 status.

“PD-L1 positivity or negativity is not a useful biomarker in this early-stage setting, and there are some real toxicities that are associated with using these agents in the neoadjuvant setting. We need to better understand who these individuals are who benefit from this strategy so we can tailor therapy appropriately,” Nanda said.

Sacituzumab Govitecan Approval Paves the Way for Novel ADCs in TNBC

Another exciting advancement in the TNBC paradigm has been the introduction of ADCs, Nanda said.

Most notably, sacituzumab govitecan-hziy (Trodelvy), a Trop-2–directed ADC, received an accelerated approval from the FDA in April 2020 for the treatment of adult patients with metastatic TNBC who have received at least 2 prior therapies for metastatic disease.¹⁶

The regulatory decision was based on findings from the phase 1/2 IMMU-132 trial (NCT01631552), in which sacituzumab govitecan elicited an objective response rate of 33.3% (95% CI, 24.6%-43.1%) and a median duration of response of 7.7 months.¹⁷

Moreover, the clinical benefit rate, which comprised complete responses, partial responses, and cases of stable disease lasting 6 months or longer, was 45.4%.

On April 7, 2021, the FDA granted a regular approval to the ADC for patients with unresectable locally advanced or metastatic TNBC who have received at least 2 prior systemic therapies, at least one of which was in the metastatic setting.¹⁸

The full indication was based on findings from the confirmatory phase 3 ASCENT trial (NCT02574455). The results revealed a median PFS of 5.6 months with sacituzumab govitecan vs 1.7 months with physician’s choice treatment in patients with metastatic disease (HR, 0.41; 95% CI, 0.32-0.52; P < .0001). The median OS was 12.1 months and 6.7 months, respectively (HR, 0.48; 95% CI, 0.38-0.59; P < .0001).¹⁹

A biomarker analysis revealed that patients derived PFS and OS benefit from sacituzumab govitecan vs placebo regardless of Trop-2 expression, although the degree of benefit did increase with higher Trop-2 expression.²⁰

“There is no role for testing for Trop-2 expression levels in determining who is eligible for treatment with sacituzumab govitecan. That is the wonderful thing about [the ADC]: it is a treatment that all patients, regardless of a biomarker, as long as they are triple negative, can benefit from,” Nanda said.

Other ADCs are currently in clinical development, including ladiratuzumab vedotin (SGN-LIV1A), fam-trastuzumab deruxtecan-nxki (Enhertu), and vic-trastuzumab duocarmazine (SYD985), concluded Nanda.

References

1. Nanda R, Chow LQM, Dees EC, et al. Pembrolizumab in patients with advanced triple-negative breast cancer: phase Ib KEYNOTE-012 study. J Clin Oncol. 2016;34(21):2460-2467. doi:10.1200/JCO.2015.64.8931
2. Emens LA, Cruz C, Eder JP, et al. Long-term clinical outcomes and biomarker analyses of atezolizumab therapy for patients with metastatic triple-negative breast cancer. JAMA Oncol. 2019;5(1):74-82. doi:10.1001/jamaoncol.2018.4224
3. Dirix LY, Takacs I, Jerusalem G, et al. Avelumab, an anti-PD-L1 antibody, in patients with locally advanced or metastatic breast cancer: a phase 1b JAVELIN Solid Tumor study. Breast Cancer Res Treat. 2018;167(3):671-686. doi:10.1007/s10549-017-4537-5
4. Winer EP, Lipatov O, Im SA, et al. Pembrolizumab versus investigator-choice chemotherapy for metastatic triple-negative breast cancer (KEYNOTE-119): a randomised, open-label, phase 3 trial. Lancet Oncol. 2021;22(4):499-511. doi:10.1016/S1470-2045(20)30754-3
5. Winer EP, Lipatov O, Im SA, et al. Association of tumor mutational burden (TMB) and clinical outcomes with pembrolizumab (pembro) versus chemotherapy (chemo) in patients with metastatic triple-negative breast cancer (mTNBC) from KEYNOTE-119. J Clin Oncol. 2020;38(suppl 15):1013. doi:10.1200/JCO.2020.38.15_suppl.1013
6. Schmid P, Rugo HS, Adams S, et al. Atezolizumab plus nab-paclitaxel as first-line treatment for unresectable, locally advanced or metastatic triple-negative breast cancer (IMpassion130): updated efficacy results from a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2020;21(1):44-59. doi:10.1016/S1470-2045(19)30689-8
7. FDA approves atezolizumab for PD-L1 positive unresectable locally advanced or metastatic triple-negative breast cancer. News release. FDA. Published March 8, 2019. Accessed May 3, 2021. https://bit.ly/370skLR.
8. Emens LA, Adams S, Barrios CH, et al. IMpassion130: Final OS analysis from the pivotal phase III study of atezolizumab + nab-paclitaxel vs placebo + nab-paclitaxel in previously untreated locally advanced or metastatic triple-negative breast cancer. Ann Oncol. 2020;31(suppl 4):S1148. doi:10.1016/j.annonc.2020.08.2244
9. Miles DW, Gligorov J, André F, et al. Primary results from IMpassion131, a double-blind placebo-controlled randomised phase III trial of first-line paclitaxel (PAC) ± atezolizumab (atezo) for unresectable locally advanced/metastatic triple-negative breast cancer (mTNBC). Ann Oncol. 2020;31(suppl 4):S1147-S1148. doi:10.1016/j.annonc.2020.08.2243
10. Cortes J, Cescon DW, Rugo HS, et al. Pembrolizumab plus chemotherapy versus placebo plus chemotherapy for previously untreated locally recurrent inoperable or metastatic triple-negative breast cancer (KEYNOTE-355): a randomised, placebo-controlled, double-blind, phase 3 clinical trial. Lancet. 2020;396(10265):1817-1828. doi:10.1016/S0140-6736(20)32531-9
11. FDA grants accelerated approval to pembrolizumab for locally recurrent unresectable or metastatic triple negative breast cancer. News release. FDA. Published November 13, 2020. Accessed May 3, 2021. https://bit.ly/3ufiOhv.
12. 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
13. 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
14. Oncologic Drugs Advisory Committee (ODAC) Meeting. FDA. February 9, 2021. Accessed May 4, 2021. https://collaboration.fda.gov/pehwal2fk5bd
15. 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. 396(10257):1090-1100. doi:10.1016/S0140-6736(20)31953-X
16. FDA grants accelerated approval to sacituzumab govitecan-hziy for metastatic triple negative breast cancer. News release. FDA. Published April 22, 2020. Accessed May 3, 2021. https://bit.ly/3eOGPpj.
17. Bardia A, Mayer IA, Vahdat LT, et al. Sacituzumab govitecan-hziy in refractory metastatic triple-negative breast cancer. N Engl J Med. 2019;380(8):741-751. doi:10.1056/NEJMoa1814213
18. FDA grants regular approval to sacituzumab govitecan for triple-negative breast cancer. News release. FDA. Published April 7, 2021. Accessed May 3, 2021. https://bit.ly/3tfgRk6.
19. Bardia A, Tolaney SM, Loirat D, et al. ASCENT: A randomized phase III study of sacituzumab govitecan (SG) vs treatment of physician's choice (TPC) in patients (pts) with previously treated metastatic triple-negative breast cancer (mTNBC). Ann Oncol. 2020;31(4):S1149-S1150. doi:10.1016/j.annonc.2020.08.2245
20. Hurvitz SA, Tolaney SM, Punie K, et al. Biomarker evaluation in the phase 3 ASCENT study of sacituzumab govitecan versus chemotherapy in patients with metastatic triple-negative breast cancer. Cancer Research. 2021;81(suppl 4):GS3-06. doi:10.1158/1538-7445.SABCS20-GS3-06