Breast Cancer Awareness Month: Recent Developments and Future Directions for Immunotherapy Treatment

Margaret E. Gatti-Mays, MD, MPH, FACP

Margaret E. Gatti-Mays, MD, MPH, FACP, is an assistant professor in the Division of Medical Oncology at The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute (OSUCCC – James), where she specializes in immunotherapy, adverse events from immunotherapy, and rare subtypes of breast cancer like small-cell breast cancer.

As a member of the Translational Therapeutics Research Program at the OSUCCC – James and the Pelotonia Immuno-oncology Institute (PIIO), her clinical research is focused on finding ways to use immunotherapy in breast cancer through evaluating novel immunotherapy agents and therapeutic combinations based on preclinical data. Dr Gatti-Mays is also studying immune-related adverse events (irAEs) in patients who have received treatment with immunotherapy. This includes learning more about who develops irAEs, which irAEs allow for continued treatment, and how irAEs impact the quality of life of patients who have good responses to treatment.

While the age of immunotherapy started in 2011 with the approval of ipilimumab (Yervoy) for metastatic melanoma, breast cancer did not have a breast-cancer specific immunotherapy regimen until 2019 when atezolizumab (Tecentriq) plus nab-paclitaxel was approved for use in PD-L1 positive, metastatic triple negative breast cancer.^1,2

Now, we have breast cancer-specific approvals in the neoadjuvant³ and metastatic⁴ settings with many promising agents that target pathways other than PD-1, PD-L1 as monotherapy and in combination with other therapeutics on the horizon. It is an exciting time in breast immunotherapy and the future is full of hope.

Impacts on Standard of Care

Pembrolizumab (Keytruda) plus chemotherapy (nab-paclitaxel, paclitaxel or gemcitabine/carboplatin) is now the standard of care for the first-line treatment of PD-L1 positive (defined as Dako 22C3 CPS ≥ 10), metastatic triple-negative breast cancer (TNBC) based on the KEYNOTE-355 clinical trial (NCT02819518), which showed a significant improvement in progression-free survival (PFS) by 4.1 months (9.7 vs 5.6 months) as well as an improvement in overall survival (OS) by almost 7 months (23 vs 16.1 months).⁴ Until recently, atezolizumab and nab-paclitaxel was also approved for use in first-line, PD-L1–positive (defined as SP142 immune cells ≥ 1%) metastatic TNBC based on the IMpassion130 trial (NCT02425891),^2,5 which showed improved PFS but not significantly improve OS. This approval was voluntarily withdrawn in August 2021 by Genentech after a subsequent confirmatory trial, IMpassion131 (NCT03125902) of atezolizumab plus paclitaxel failed to meet the primary survival end point.⁶

There are also tumor agnostic approvals where pembrolizumab can be used in later-line settings in various solid tumor types including breast cancer but these indications are not specific to TNBC. These 2 tumor agnostic approvals are pembrolizumab for use in patients with tumor mutational burden (TBM) high tumors (defined as ≥ 10 mutations/megabase)⁷ and in patients with tumors that are microsatellite instability-high (MSI-H).⁸ These tumor agnostic indications represent a small percentage of patients with breast cancer, but for those who meet criteria, it is reasonable to consider pembrolizumab monotherapy as a treatment option.

Immunotherapy has greatly impacted the standard of care in aggressive forms of breast cancer like TNBC, where survival has generally been limited to 1 to 2 years in the metastatic setting. The deep and durable responses seen in some patients has significant prolonged life for some patients in this population. The recently released survival analysis of KEYNOTE-355 (NCT02819518) presented at the 2021 European Society for Medical Oncology (ESMO) Congress showed that the addition of pembrolizumab increased median survival from 16.1 months with chemotherapy alone to 23 months.⁹ This survival improvement by 7 months is significant, although we still need to do better for our patients and expand the benefit of immunotherapy to more patients with advanced breast cancer.

While immune checkpoint inhibitors are the most commonly researched and discussed immunotherapy, antibody drug conjugates (ADCs) have also made significant advances in improving clinical outcomes in patients with advanced breast cancers. The ASCENT trial (NCT02574455) evaluated sacituzumab govitecan (Trodelvy), which targets TROP2, against standard chemotherapy.¹⁰ In this trial, heavily pretreated patients (median of 3 prior therapies) with TNBC who received sacituzumab govitecan had longer PFS (5.6 months vs 1.7 months with standard chemotherapy) and improved OS (12.1 months vs 6.7 months with standard chemotherapy) in patients with TNBC.

Immunotherapy is not limited to TNBC. The recent DESTINY-Breast03 trial (NCT03529110) presented at the 2021 ESMO Congress showed a remarkable improvement in PFS of the ADC trastuzumab deruxtecan (Enhertu) compared with T-DM1 (trastuzumab emtansine; Kadcyla), another ADC.¹¹ When compared to the current second line standard of care, trastuzumab deruxtecan far outperformed T-DM1 with a 12-month PFS rate of 75.8% vs 34.1%. This resulted in the FDA granting breakthrough designation to trastuzumab deruxtecan for the second line therapy in October 2021 for patients with pretreated, metastatic HER2-positive breast cancer.

Ongoing Trials and Promising Directions

While many consider immunotherapy to primarily refer to monoclonal antibodies which target immune checkpoint inhibitors like PD-1, PD-L1, and CTLA4, there are many more exciting subcategories of immunotherapy that are being evaluated in breast cancer. These include other T cell checkpoint targets like OX40, GITR and 4-1BB, novel ADCs, immunocytokines, therapeutic cancer vaccines, and cellular therapies like chimeric antigen receptor (CAR) T cells or natural killer (NK) cells.

In addition, as we develop a greater understanding of the dynamic changes within the tumor microenvironment, the focus on treatments is shifting away from monotherapy approaches and to multimodality regimens which aim to mold the breast tumor and the surrounding tumor microenvironment into a more immunopermissive environment.

Potential Upcoming FDA Approvals

2020 to 2021 has been a banner year for breast immunotherapy. There are several ongoing clinical trials evaluating approved agents either in combination with other agents or evaluating approved against agents used earlier in the standard-of-care algorithm. For example, the recently presented data at the 2021 ESMO Congress and the subsequent FDA breakthrough designation lead to trastuzumab deruxtecan becoming the second-line therapy for metastatic HER2-positive disease and it will replace T-DM1 in this space. Furthermore, I don’t think we have seen the last of atezolizumab for metastatic TNBC, as this regimen has been effective for many patients with advanced TNBC.

Despite a lag between the onset of the age of immunotherapy and the regular utilization of immunotherapy in breast cancer, it is now clear that immunotherapy has a place in the treatment of breast cancer. The future of immunotherapy is full of hope as I believe the benefit of immunotherapy will be able to be expanded to more patients with breast cancer through innovation combinations and novel immunotherapy therapies.

_References:

_{1. Narayan P, Wahby S, Gao JJ, et al. FDA approval summary: atezolizumab plus paclitaxel protein-bound for the treatment of patients with advanced or metastatic TNBC whose tumors express PD-L1. Clin Cancer Res. 2020;26(10):2284-2289. doi:10.1158/1078-0432.CCR-19-3545}

_{2. Schmid P, Adams S, Rugo HS, et al. Atezolizumab and nab-paclitaxel in advanced triple-negative breast cancer. N Engl J Med. 2018;379(22):2108-2121. doi:10.1056/NEJMoa1809615}

_{3. 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}

_{4. 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}

_{5. Emens LA, Adams S, Barrios CH, et al. First-line atezolizumab plus nab-paclitaxel for unresectable, locally advanced, or metastatic triple-negative breast cancer: IMpassion130 final overall survival analysis. Ann Oncol. 2021;32(8):983-993. doi:10.1016/j.annonc.2021.05.355}

_{6. Miles D, Gligorov J, André F, et al. Primary results from IMpassion131, a double-blind, placebo-controlled, randomised phase III trial of first-line paclitaxel with or without atezolizumab for unresectable locally advanced/metastatic triple-negative breast cancer. Ann Oncol. 2021;32(8):994-1004. doi:10.1016/j.annonc.2021.05.801}

_{7. Marabelle A, Le DT, Ascierto PA, et al. Efficacy of Pembrolizumab in patients with noncolorectal high microsatellite instability/mismatch repair-deficient cancer: results from the phase II KEYNOTE-158 study. J Clin Oncol. 2020;38(1):1-10. doi:10.1200/JCO.19.02105}

_{8. Marcus L, Lemery SJ, Keegan P, Pazdur R. FDA approval summary: pembrolizumab for the treatment of microsatellite instability-high solid tumors. Clin Cancer Res. 2019;25(13):3753-3758. doi:10.1158/1078-0432.CCR-18-4070}

_{9. Rugo HS, Cortés J, Cescon DW, et al. LBA16 - KEYNOTE-355: Final results from a randomized, double-blind phase 3 study of first-line pembrolizumab + chemotherapy vs placebo + chemotherapy for metastatic TNBC. Ann Oncol. 2021;32(suppl 5):S1283-S1346. doi:10.1016/annonc/annonc741}

_{10. Bardia A, Hurvitz SA, Tolaney SM, et al; ASCENT Clinical Trial Investigators. Sacituzumab govitecan in metastatic triple-negative breast cancer. N Engl J Med. 2021;384(16):1529-1541. doi:10.1056/NEJMoa2028485}

_{11. Cortes J, Kim S, Ching W, et al. LBA1 - Trastuzumab deruxtecan (T-DXd) vs trastuzumab emtansine (T-DM1) in patients (Pts) with HER2+ metastatic breast cancer (mBC): Results of the randomized phase III DESTINY-Breast03 study. Ann Oncol. 2021;32(suppl 5):S1283-S1346. doi:10.1016/annonc/annonc741}