Immunotherapy in the Treatment of Breast Cancer

Educational Objectives

The goal of this program is to improve management of breast cancer using immunotherapeutic strategies. After hearing and assimilating this program, the clinician will be better able to:

1. Summarize efficacy and adverse events of immunotherapy for treatment of breast cancer in the metastatic and neoadjuvant settings.
2. Identify factors that have been associated with response to immunotherapy in patients with breast cancer.
3. Utilize therapeutic strategies to improve efficacy of immunotherapy in breast cancer.

Summary

Characteristics of triple negative breast cancer (TNBC): may be the most immunogenic of all breast cancers and, compared with other types of breast cancer, has higher levels of tumor infiltrating lymphocytes (TILs), programmed death-ligand 1 (PD-L1) expression, and genomic instability, with a high proportion of nonsynonymous mutations

Immunotherapy monotherapy for TNBC: studies of patients with previously treated TNBC (atezolizumab monotherapy in TNBC and KEYNOTE-086 trial of pembrolizumab for advanced TNBC) showed response rates of <10%; patients who received these agents as their first line of therapy for advanced disease had a response rate of ≈25%; agents were generally well tolerated with manageable side effects

Biomarkers of response: PD-L1 status — did not predict response to atezolizumab, although positivity may be associated with a trend toward improvement in overall survival (OS); PD-L1 tests use different antibodies, immune compartments in the tumor microenvironment (TME), and cut points; trials of atezolizumab primarily used an in vitro diagnostic assay for PD-L1 (eg, VENTANA SP142 assay) with a cut point for positivity of ≥1% of immune cells stained positive; study of atezolizumab found a higher response rate and improvement in OS in patients with PD-L1 positive disease, and patients with high level of TILs in their tumor microenvironment (TME) were more likely to have a response to therapy and improvement in OS; in the KEYNOTE-086 trial, earlier line of therapy and high level of tumor infiltrate in TME approached response rates of ≈40%

Take-home messages: level of TIL, PD-L1 positivity, and line of therapy were associated with response in monotherapy trials; although response rate of 25% in the frontline setting was similar to that with chemotherapy, immunotherapy may yield a more durable response; chemotherapy can also lead to adverse events, eg, neuropathy, hand-foot syndrome, or hair loss, that are not observed with immunotherapy

Checkpoint inhibitors with chemotherapy: chemotherapy drugs used in treatment of breast cancer (eg, taxanes, anthracyclines, and alkylating agents) can stimulate an immune response by activating the immune system, leading to an activation of dendritic cells or suppression of myeloid-derived suppressor cells and T regulatory cells

IMpassion130 trial: patients previously untreated for TNBC in the metastatic setting were randomized to receive nab-paclitaxel with or without atezolizumab; a ≈2-mo improvement in progression-free survival (PFS) was observed with the addition of atezolizumab in the intent-to-treat population (with a slightly greater improvement in patients with PD-L1 positive disease), and a 10-mo improvement in OS was observed in patients with PD-L1 positive disease; results led to the approval of nab-paclitaxel with atezolizumab for patients with PD-L1 positive metastatic TNBC; however, PD-L1 positivity varies among sites of tumor tissue (eg, tends to be higher in tissue from the breast and lymph nodes than in tissue from the liver or skin), and analyses suggest that cut point of ≥1% on the VENTANA SP142 assay is optimal for determining eligibility for treatment

KEYNOTE-355 trial: compared addition of pembrolizumab or placebo to chemotherapy in high-risk patients (ie, may have had a recurrence ≥6 mo from the completion of early-stage therapy); cut point for PD-L1 positivity was ≥10% based on combined positive score assay (tumor and immune cells) and 22c3 antibody; positive outcomes were reported in the cohort with PD-L1 positive disease; different chemotherapy backbones were used based on previous therapy and timing of disease relapse, and patients who had received therapy for early-stage disease were randomized to receive paclitaxel, nab-paclitaxel, or gemcitabine and carboplatin

TONIC trial: response rate of 35% was observed following 2 doses of induction chemotherapy with doxorubicin given 1 wk apart followed by nivolumab

SAPPHIRE trial: patients with metastatic or locally advanced breast cancer that was HER2-negative (hormone receptor [HR]-positive disease was allowed) who had a response or stable disease to 6 to 8 cycles of chemotherapy were randomized; patients with a genomically targetable alteration in their tumor were randomized to receive targeted therapy or maintenance of chemotherapy; patients without a molecularly targetable abnormality were randomized 2 to 1 to receive maintenance therapy with durvalumab or continuation of chemotherapy; patients with TNBC were more likely to have PD-L1 positive disease than those with HR-positive disease; no improvement in PFS or OS was observed for patients who switched to maintenance durvalumab; trend toward improvement in outcomes was observed in patients with TNBC and patients with PD-L1 positive tumors who were randomized to or crossed over to receive durvalumab

Strategies to Increase Efficacy of Immunotherapy

Rationale: tumors can escape the immune system and thrive; majority of breast cancers have a low immune infiltrate; immune-excluded tumors have immune cells that surround the periphery of the tumor and are unable to infiltrate the TME; use of checkpoint inhibitors may be helpful in tumors with an inflamed TME

Poly (adenosine diphosphate-ribose polymerase) (PARP) inhibition: stimulates immunity, causes DNA damage, increases neoantigen load of the tumor, and activates the STING pathway through the activation of type I interferon, suggesting that combination with immunotherapy is a rational therapeutic strategy

TOPACIO trial: rate of clinical benefit was 40% with niraparib and pembrolizumab; ≈50% of patients who had a benefit did not have a BRCA1 or BRCA2 mutation, suggesting that the combination of PARP inhibition with checkpoint blockade may be a rational strategy for a broad base of patients with advanced breast cancer

MEDIOLA trial: patients with a BRCA mutation received olaparib monotherapy for 1 mo, followed by olaparib plus durvalumab; of the 30 evaluable patients, ≈50% had BRCA1 mutations and ≈50% had BRCA2 mutations, and patients had HR-positive breast cancer or TNBC; patients who received combination in the first-line setting for advanced-stage disease tended to have a greater benefit

OlympiAD trial: led to the Food and Drug Administration (FDA) approval of olaparib for patients with BRCA1- and BRCA2-associated metastatic disease

ETCTN trial: investigating combinations of PARP inhibitors and checkpoint inhibitors; randomizes patients with BRCA1- or BRCA2-associated metastatic breast cancer to receive olaparib or olaparib plus atezolizumab

COLET trial: investigated a regimen of taxane-based chemotherapy, atezolizumab, and cobimetinib (MEK inhibitor), with the goal of increasing the proportion of patients who benefit from checkpoint blockade; good responses were observed (independent of PD-L1 status) in patients with treatment-naive TNBC who received paclitaxel or nab-paclitaxel with atezolizumab and cobimetinib in the frontline setting

Pathway involving PI3K, AKT, and PTEN: active in large proportion of breast cancers and can lead to suppression of an immune response; AKT inhibition may lead to expansion of tumor-specific lymphocytes and was shown to be tolerable, with tumor responses observed in the majority of patients enrolled in a phase 1 study

Trials of neoadjuvant therapy: GeparNuevo trial — a nonsignificant trend toward a higher rate of pathologic complete response (pCR) was observed in patients who received durvalumab with chemotherapy, as well as in patients who received durvalumab monotherapy prior to chemotherapy; neoadjuvant I-SPY 2 trial — goal was to identify novel combination strategies that are worth pursuing in randomized phase 3 trials; pembrolizumab was graduated to the phase 3 KEYNOTE-756 trial for patients with high-risk HR-positive breast cancer based on estimated rates of pCR; unexpected immune-related toxicities were observed, including thyroid abnormalities (which were easily managed by hormone replacement therapy) and adrenal insufficiency (also observed in the KEYNOTE-522 trial); KEYNOTE-522 trial — higher rate of pCR was observed with addition of pembrolizumab to chemotherapy, regardless of PD-L1 status, in patients with TNBC

Factors predicting pCR: disease stage — patients with higher-stage disease (eg, with positive lymph nodes) appear to derive a greater benefit from immunotherapy; PD-L1 status — no indication that it is related with outcomes in the neoadjuvant setting

Immune-related adverse events: rates of adrenal insufficiency in the KEYNOTE-522 trial were lower than those in the I-SPY 2 trial but higher than those observed in the metastatic setting; in the I-SPY 2 trial, cases of adrenal insufficiency occurred after surgery, and 5 of 6 patients presented >3 mo from completion of checkpoint inhibition

NeoTRIP trial: addition of atezolizumab to a standard neoadjuvant chemotherapy for 8 cycles, followed by anthracycline-based therapy, did not improve pCR over atezolizumab plus chemotherapy, and response was not affected by PD-L1 status or disease stage; increase in liver enzymes on liver function tests were observed in patients who received atezolizumab

Readings

Adams S, Schmid P, Rugo HS, et al. Pembrolizumab monotherapy for previously treated metastatic triple-negative breast cancer: cohort A of the phase II KEYNOTE-086 study. Ann Oncol. 2019; 30:397-404; doi: 10.1093/annonc/mdy517; Cortes J, Cescon DW, Rugo HS, et al. KEYNOTE-355: randomized, double-blind, phase III study of pembrolizumab + chemotherapy versus placebo + chemotherapy for previously untreated locally recurrent inoperable or metastatic triple-negative breast cancer. J Clin Oncol. 2020; 38:1000; doi: 10.1200/JCO.2020.38.15_suppl.1000; Keenan TE, Tolaney SM. Role of immunotherapy in triple-negative breast cancer. J Natl Compr Canc Netw. 2020;18(4):479-489. doi:10.6004/jnccn.2020.7554; Mittendorf EA, Philips AV, Meric-Bernstam F, et al. PD-L1 expression in triple-negative breast cancer. Cancer Immunol Res. 2014; 2:361-370; doi: 10.1158/2326-6066.CIR-13-0127; 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; O'Meara T, Marczyk M, Qing T, et al. Immunological differences between immune-rich estrogen receptor-positive and immune-rich triple-negative breast cancers. JCO Precis Oncol. 2020; 4:PO.19.00350; doi: 10.1200/PO.19.00350; Park YH, Lal S, Lee JE, et al. Chemotherapy induces dynamic immune responses in breast cancers that impact treatment outcome. Nat Commun. 2020; 11:6175; doi: 10.1038/s41467-020-19933-0; Pérez-García J, Soberino J, Racca F, et al. Atezolizumab in the treatment of metastatic triple-negative breast cancer. Expert Opin Biol Ther. 2020; 20:981-989; doi: 10.1080/14712598.2020.1769063; Robson M, Im S, Senkus E, et al. Olaparib for metastatic breast cancer in patients with a germline BRCA mutation. N Engl J Med. 2017; 377:523-533; doi: 10.1056/NEJMoa1706450; Schmid P, Adams S, Rugo HS, et al. Atezolizumab and nab-paclitaxel in advanced triple-negative breast cancer. N Engl J Med. 2018; 379:2108-2121; doi: 10.1056/NEJMoa1809615; Voorwerk L, Slagter M, Horlings HM, et al. Immune induction strategies in metastatic triple-negative breast cancer to enhance the sensitivity to PD-1 blockade: the TONIC trial. Nat Med. 2019; 920-928; doi: 10.1038/s41591-019-0432-4.

Disclosures

In adherence to ACCME Standards for Commercial Support, Audio Digest requires all faculty and members of the planning committee to disclose relevant financial relationships within the past 12 months that might create any personal conflicts of interest. Any identified conflicts were resolved to ensure that this educational activity promotes quality in health care and not a proprietary business or commercial interest. For this program, the following has been disclosed: Dr. Nanda was on the advisory board for Aduro, G1 Therapeutics, Genentech, MacroGenics, Merck, and Pfizer; was on the drug safety monitoring board for G1 Therapeutics; and received research grants from AstraZeneca, Celgene, Corcept Therapeutics, Genentech/Roche, Immunomedics, Merch, OBI Pharma, Odonate Therapeutics, Pfizer, and Seattle Genetics. The members of the planning committee reported nothing to disclose.

Acknowledgements

Dr. Nanda was recorded at the Scripps Cancer Center’s 40th Annual Conference: Hematology and Oncology 2020, held February 15, 2021, in San Diego, CA, and presented by Scripps Health, Department of CME. For information on future CME activities from this presenter, please visit scripps.org. Audio Digest thanks the speakers and meeting presenters for their cooperation in the production of this program.

CME/CE INFO

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Lecture ID:

ON122401

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