Immunotherapy Approaches for Breast Cancer Patients in 2023

Abstract

Immunotherapy, particularly agents targeting the immunoregulatory PD-1/PD-L1 axis, harnesses the power of the immune system to treat cancer, with unique potential for a durable treatment effect due to immunologic memory. The PD-1 inhibitor pembrolizumab combined with neoadjuvant chemotherapy followed by adjuvant pembrolizumab improves event-free survival and is a new standard of care for high-risk, early-stage triple-negative breast cancer (TNBC), regardless of tumor PD-L1 expression. For metastatic TNBC, pembrolizumab combined with chemotherapy is a new standard of care for the first-line therapy of PD-L1⁺ metastatic TNBC, with improvement in overall survival. The PD-L1 inhibitor atezolizumab combined with nab-paclitaxel is also approved outside the United States for the first-line treatment of metastatic PD-L1⁺ TNBC. Current research focuses on refining the use of immunotherapy in TNBC by defining informative predictive biomarkers, developing immunotherapy in early and advanced HER2-driven and luminal breast cancers, and overcoming primary and secondary resistance to immunotherapy through unique immune-based strategies.

Breast cancer is often immunologically cold with low tumor mutational burden (TMB). However, tumor-infiltrating lymphocytes (TILs) are present in some breast cancers. TILs are enriched in more aggressive, highly proliferative breast cancers, particularly triple-negative breast cancers (TNBCs) and HER2⁺ breast cancers (Stanton et al. 2016). Key questions are (1) Why do some patients develop immune infiltrates and others do not? and (2) How can we most effectively harness antitumor immunity for breast cancer treatment? Recent work demonstrates that immune checkpoint inhibitors (ICIs) targeting the programmed cell death 1 receptor (PD-1) or its ligand programmed death ligand 1 (PD-L1) is effective in the treatment of both early- and late-stage TNBC, resulting in multiple health authority approvals around the world. Intense investigation into the potential efficacy of immunotherapy for other breast cancer subtypes is ongoing.

IMMUNE INFILTRATE IN BREAST CANCER

Although normal breast tissue does not typically contain high levels of immune cells, breast cancers sometimes harbor TILs. Immune infiltrates are composed primarily of T effector and effector memory cells (Savas et al. 2018). As the quantity of intratumoral immune infiltrates increases, the ratio of CD8⁺ to CD4⁺ T cells increases, reflecting an evolving cytotoxic T-cell response. Tissue-resident memory T cells have been identified in high-TIL TNBCs, signifying the importance of the local T-cell memory response. High levels of TILs present in breast cancer at diagnosis is strongly prognostic, particularly in TNBC. Although not yet incorporated into standard staging systems, the levels of TILs can effectively up- or down-stage anatomic staging (Loi et al. 2022a). Furthermore, intratumoral T cells most often express the immune checkpoints PD-1 and CTLA-4, but not TIM-3 or LAG-3, with tissue-resident memory T cells expressing PD-1, CTLA-4, TIM-3, LAG-3, and TIGIT in addition to cytotoxic T-cell markers (Savas et al. 2018). These observations underlie the rationale that immune checkpoint blockade can improve outcomes in patients with breast cancer. Notably, metastatic breast tumors have fewer TILs than primary tumors, suggesting increasing immune suppression with disease progression (Cimino-Mathews et al. 2016; Szekely et al. 2018).

EARLY-STAGE BREAST CANCER

Immunotherapy in Early TNBC

Several trials evaluating ICIs targeting PD-1/PD-L1 in early breast cancer have been reported. Given the high levels of TILs in triple-negative tumors, immunotherapy trials for early breast cancer have focused on TNBC. Importantly, preclinical data demonstrate improved responses to neoadjuvant relative to adjuvant ICI, suggesting that improved priming and expansion of T cells occurs when the primary lesion remains as a source of tumor antigens (Liu et al. 2016). For TNBC, a pathological complete response (pCR), the absence of invasive cancer at surgery after neoadjuvant treatment, strongly correlates with excellent clinical outcomes and is a common clinical end point in breast cancer clinical trials (Cortazar et al. 2014). Several trials have tested the combination of ICI and neoadjuvant chemotherapy in early TNBC, demonstrating significantly improved pCR and/or event-free survival (EFS) rates (Table 1).

Table 1.

Selected clinical trials in early triple-negative breast cancer (TNBC)

Clinical trial (sample size)	Design	Disease stage	ICI	Chemotherapy backbone	Adjuvant therapy	Results
KEYNOTE-522 (n = 1174)	Randomized phase III	cT1N1-2 cT2-4N0-2	Pembro	Carbo + paclitaxel, then AC	Pembro to complete 1 yr total (no cape allowed)	pCR in ITT 64.8% vs. 51.2%, P < 0.001
						3-yr EFS 84.5% vs. 76.8%, HR 0.63, P < 0.001
IMpassion031 (n = 333)	Randomized phase III	cT2-4N0-3	Atezo	Nab-paclitaxel, then AC	Atezo to complete 1 yr total (cape allowed)	pCR in ITT 58% vs. 41%, P = 0.0044
						pCR in PD-L1+ 69% vs. 49%, P = 0.021
						EFS immature
NeoTripaPDL1 (n = 280)	Randomized phase III	cT1N1-3 cT2-4N0-3	Atezo	Carbo + nab-paclitaxel	AC/EC/FEC	pCR 48.6% vs. 44.4%, P = 0.48
						EFS immature
GeparNuevo (n = 174)	Randomized phase II	cT2-4N0-3	Durva	2 wk durva alone, then nab-paclitaxel, then AC	None	pCR 53.4% vs. 44.2%, OR 1.45
						3-yr DDFS 91.4% vs. 79.5%, HR 0.37, P = 0.0148
						3-yr OS 95.1% vs. 83.1%, HR 0.26, P = 0076
I-SPY2 (n = 29 TNBC) (69 total)	Randomized phase II	CT2-4dN0-3	Pembro	Paclitaxel, then AC	Physician's discretion	pCR 60% vs. 22% in TNBC
NCI10013 (n = 67)	Randomized phase II	cT2-4Nany	Atezo	Carbo + paclitaxel	ddAC	pCR 55.6% vs. 18.8%, P = 0.018
						pCR in mBRCA 80% vs. 50%
NeoPACT (n = 117)	Single-arm phase II	Stage I–III	Pembro	Carbo + docetaxel	Physician's discretion	pCR 60%
						2-yr EFS 89%
CHARIOT (n = 34)	Single-arm phase II	Stage III >15 mm RD after AC × 4	Ipi + nivo	Paclitaxel (AC prior to randomization)	Nivo	pCR 24.2%
						1-yr EFS 85%
I-SPY2 (n = 21 TNBC) (73 total)	Randomized phase II	Stage II–III	Durva + olaparib	Paclitaxel, then AC	None	pCR 47% vs. 27% in TNBC

(ICI) Immune checkpoint inhibitor, (pembro) pembrolizumab, (atezo) atezolizumab, (durva) durvalumab, (nivo) nivolumab, (ipi) ipilimumab, (carbo) carboplatin, (AC) doxorubicin and cyclophosphamide, (EC) epirubicin and cyclophosphamide, (dd) dose dense, (pCR) pathological complete response, (EFS) event-free survival, (DDFS) distant disease-free survival, (OS) overall survival, (ITT) intent to treat, (RD) residual disease, (cape) capecitabine, (mBRCA) mutant breast cancer gene, (PD-L1) programmed death ligand 1, (HR) hazard ratio, (OR) odds ratio.

KEYNOTE-522 is a randomized phase III trial that tests the addition of pembrolizumab or placebo to neoadjuvant chemotherapy with carboplatin and paclitaxel sequenced with doxorubicin and cyclophosphamide (AC), followed by surgery and adjuvant pembrolizumab (Schmid et al. 2020b, 2022). Adding pembrolizumab to neoadjuvant chemotherapy significantly increased the pCR rate, and more importantly reduced the risk of recurrence for all patients (hazard ratio [HR] 0.63, P < 0.001), regardless of PD-L1 expression. Based on these data, the U.S. Food and Drug Administration (FDA) has approved neoadjuvant pembrolizumab with chemotherapy for patients with early TNBC. Multiple important questions remain: (1) What is the optimum chemotherapy backbone? (2) Can we de-escalate therapy for appropriate patients? (3) What is the proper role of adjuvant ICI therapy? and (4) What is the best way to select patients for neoadjuvant immunotherapy? Other clinical trials illustrating these issues are discussed below.

Benefit of Neoadjuvant Carboplatin

Three randomized trials (IMpassion031, I-SPY2, and GeparNuevo, testing atezolizumab, pembrolizumab, and durvalumab, respectively) have yielded positive results without adding carboplatin to sequential AC and taxane (Mittendorf et al. 2020; Nanda et al. 2020; Loibl et al. 2022). These trials also allowed or mandated dose-dense (2-wk) AC, rather than the 3-wk AC used in KEYNOTE-522. GeparNuevo demonstrated improved invasive and distant disease-free survival (iDFS and DDFS) and overall survival (OS) with neoadjuvant durvalumab and chemotherapy independent of pCR, and survival data from IMpassion031 are awaited. The BrighTNess trial previously demonstrated EFS benefit with carboplatin added to paclitaxel followed by 3-wk AC, but the CALGB 40603 trial did not, so the utility of carboplatin for early TNBC remains a topic of debate (Geyer et al. 2022; Shepherd et al. 2022). Moreover, whether intensification of chemotherapy with carboplatin is needed when pembrolizumab is added to neoadjuvant chemotherapy is unknown.

Defining the short- and long-term impact of chemotherapy on antitumor immunity will inform the optimum chemotherapy backbone for ICI. Different chemotherapy classes induce distinct types of tumor cell death with varying mechanisms of potential immunologic synergy with ICIs (Emens and Middleton 2015; Park et al. 2020). For example, anthracyclines can induce immunogenic cell death, which may enhance dendritic cell uptake of tumor antigens (Mattarollo et al. 2011; Montico et al. 2018). Taxanes inhibit microtubule formation and may bind to Toll-like receptor 4 (TLR4) to promote innate immunity (Pfannenstiel et al. 2010). This immune-modulating activity enhances natural killer cell function and decreases both T regulatory cells and myeloid-derived suppressor cells (MDSCs) (Muraro et al. 2015). DNA-damaging therapies also stimulate immune surveillance through necrotic cell death, a source of type I interferons. During mitosis, cells with double-stranded DNA breaks accumulate micronuclei sensed by the cyclic GMP-AMP synthase stimulator of the interferon genes (cGAS-STING) pathway, culminating in increased interferon signaling (Zierhut et al. 2019; Serpico et al. 2020).

While chemotherapy may enhance tumor immunogenicity, the potential for long-term negative impact on adaptive immunity has also been recognized. A reduction in the naive T-cell pool occurs with more intensive chemotherapy regimens (Verma et al. 2016; Gustafson et al. 2020) and may be worsened by adjuvant radiotherapy (Mozaffari et al. 2007, 2009; Venkatesulu et al. 2018). Lymphopenia is associated with adverse clinical outcomes and a higher risk of future cancers (Ménétrier-Caux et al. 2019). Further defining the immunomodulatory activity of distinct chemotherapies will help optimize ICI efficacy and maintain patients’ lymphocyte pool long term.

Less Cytotoxic Neoadjuvant Chemotherapy

It may be possible to reduce the intensity of the chemotherapy backbone with neoadjuvant ICI for two main reasons. First, attaining a pCR is associated with excellent outcomes regardless of the therapy used. Second, post-neoadjuvant treatment provides an opportunity to escalate or de-escalate subsequent therapy according to the pathologic response. Because adding ICI to neoadjuvant chemotherapy results in higher pCR rates, evaluating ICIs in combination with less toxic neoadjuvant chemotherapy regimens is an attractive strategy for reducing the risk of long-term cardiotoxicity and secondary hematological malignancies associated with anthracyclines in lower-risk patients with early TNBC. The single-arm phase 2 NeoPACT trial tested six cycles of neoadjuvant pembrolizumab, carboplatin, and docetaxel (Sharma et al. 2022), with a pCR rate of 60% and a 2-yr EFS rate of 88% without adjuvant pembrolizumab therapy. Patients with higher immune activation (TILs ≥30%) had higher pCR rates. The key to successful chemotherapy de-escalation to improve clinical outcomes and reduce toxicity lies in accurate selection of patients most likely to achieve pCR with ICIs.

Postoperative ICI Considerations

Post-neoadjuvant therapy provides an opportunity to escalate or de-escalate adjuvant therapy according to pathological response. The impact of continuing adjuvant pembrolizumab for patients who do not experience a pCR with neoadjuvant pembrolizumab and chemotherapy is unclear. The GeparNuevo trial demonstrated a statistically significant improvement in long-term clinical outcomes from neoadjuvant ICI despite not including an adjuvant ICI phase. In exploratory subgroup analysis, even patients who did not experience pCR had clinically meaningful improvements from durvalumab, including improved 3-yr iDFS (76.3% vs. 69.7%), DDFS (84.3% vs. 71.9%), and OS (92.0% vs. 78.8%), suggesting that clinical benefit can be derived from neoadjuvant-only administration of ICI even in the absence of pCR (Loibl et al. 2022). Notably, patients who do experience pCR with durvalumab in GeparNuevo had a 3-yr DDFS and OS of 100%, suggesting adjuvant ICI can be omitted in these patients. While this question remains to be answered, in the future other trials without the adjuvant ICI component will also provide long-term clinical outcome data that may give confidence in this approach to those that achieve pCR. Notably, those patients who achieved pCR or residual cancer burden class I (RCB-I) in KEYNOTE-522 with or without neoadjuvant pembrolizumab also had excellent clinical outcomes. In patients with RCB-II, pembrolizumab significantly improved 3-yr EFS (75.5% in the pembrolizumab arm vs. 55.9% in the placebo arm, HR 0.52, 95% CI 0.32–0.82) (Pusztai et al. 2022), although it is unknown whether this is mediated by the neoadjuvant or adjuvant pembrolizumab phase, or both. Taken together, these data from KEYNOTE-522 and GeparNuevo support a clinical trial to evaluate cessation versus continuation of adjuvant ICI in patients who achieve pCR and RCB-I. The Optimice-pCR trial is planned to address this question, randomizing patients with pCR following neoadjuvant chemo-immunotherapy to an additional 27 wk of pembrolizumab or observation.

Outside of these trials, patients with residual disease after neoadjuvant chemotherapy currently receive adjuvant capecitabine, or adjuvant olaparib when a germline BRCA1/2 alteration is present. Whether the incorporation of neoadjuvant or adjuvant pembrolizumab to these agents adds further benefit is unknown.

In KEYNOTE-522, patients with RCB-II had a partial pathological response to neoadjuvant treatment. The long-term improvements in this population imply that they have mounted meaningful antitumor immunity that results in improved clinical outcomes. In contrast, all patients with RCB-III in KEYNOTE-522 (5.1% and 6.7% of patients in the pembrolizumab and placebo arms, respectively) have very poor outcomes irrespective of treatment, implying primary resistance to both chemotherapy and immunotherapy (3-yr EFS 26.2% vs. 24.6% in the pembrolizumab and placebo arms, respectively [HR 1.24, 95% CI 0.69–2.23]). These patients are in critical need of novel non-cross-resistant therapies. New immunotherapeutic strategies that circumvent intrinsic immune resistance such as personalized cancer vaccines, adoptive T-cell therapy or immune agonists are particularly attractive.

Two trials (SWOG1418 and A-BRAVE) are evaluating the role of ICI in the adjuvant phase only specifically, with results pending (Conte et al. 2020). SWOG1418 is evaluating adjuvant pembrolizumab in patients who do not experience pCR with neoadjuvant chemotherapy (no prior ICI), while A-BRAVE is also evaluating adjuvant ICI in this group as well as those who receive no neoadjuvant therapy. These are important questions for patients who have not had the opportunity to access neoadjuvant ICI, as well as potentially tailoring treatment based on a pathological result post-neoadjuvant chemotherapy approach without ICI.

Toxicity Profiles

Relevant to breast cancer, women may be at higher risk of immune-related adverse events (irAEs) from immunotherapy than men (Özdemir et al. 2018; Miceli et al. 2021). For patients with curable disease, the risk of permanent or life-threatening treatment-related toxicity is set at a lower threshold than in the advanced disease setting, especially as some patients will be cured with chemotherapy alone. Although immunotherapy is generally well-tolerated and the most common irAEs are readily manageable, the idiosyncratic nature of permanent endocrinopathies such as primary adrenal insufficiency, hypophysitis, and autoimmune diabetes mellitus can be problematic. In KEYNOTE-522, any-grade irAE occurred in 33.5% of patients receiving pembrolizumab (compared to 11.3% in the placebo group), including hypothyroidism in 15.1%, primary adrenal insufficiency in 2.6%, and hypophysitis in 1.9% (Schmid et al. 2020a). Three immune-related deaths occurred in the pembrolizumab arm (pneumonitis, immune-related encephalitis, and pulmonary embolus). Adrenal insufficiency (due to hypophysitis or primary adrenal insufficiency) was reported in 8.7% of patients treated with pembrolizumab in I-SPY-2, higher that what has previously been reported for anti-PD-1 therapy (Nanda et al. 2020). Immunotherapy also has unknown survivorship implications. Recently, ICIs were reported to mediate ovarian inflammation and reduce oocyte reserves in a murine model (Winship et al. 2022). If confirmed in patients, this effect could have implications for women of reproductive age receiving immunotherapy in the curative setting, particularly given the detrimental impact of chemotherapy on fertility. Further clinical research assessing menstrual cycle patterns, menopausal status, fertility, and changes in sex steroid/gonadotropin levels with ICI treatment is needed.

Patient Selection

The major challenge to the optimal use of immunotherapy in early-stage TNBC is patient selection. PD-L1 protein expression is an established predictive biomarker of response to PD-1/PD-L1 inhibitors for metastatic TNBC, despite varying methods of PD-L1 assessment (Schmid et al. 2018; Cortes et al. 2020). In both KEYNOTE-522 and IMpassion031, improved pCR rates were associated with the use of pembrolizumab or atezolizumab, respectively, in both PD-L1⁺ and PD-L1-negative patients. In KEYNOTE-522 and GeparNuevo, clinical benefit with pembrolizumab or durvalumab and chemotherapy was also observed regardless of PD-L1 status. Hence, PD-L1-negative patients should not be excluded from receiving ICIs with neoadjuvant chemotherapy, as patients can generate an antitumor immune response that translates into clinical benefit regardless of PD-L1 status. Thus, there is currently no indication for assessing PD-L1 expression in a newly diagnosed patient with early-stage TNBC.

Why PD-L1 expression predicts immunotherapy response in metastatic disease but not in early-stage disease is unclear. However, higher tumor burdens are associated with poorer outcomes from ICI in the advanced setting (Tarantino et al. 2020). The NeoTrip trial included higher-stage N2/N3 primary disease and suggested greater clinical benefit from ICI in patients with PD-L1⁺ disease, although EFS outcomes are not yet reported (Gianni et al. 2022). In multivariate analysis, PD-L1 positivity was the most significant factor associated with pCR (odds ratio 2.08, P < 0.0001) in this trial. Data from patients presenting with stage 4 de novo disease treated with PD-1/PD-L1 agents may be helpful in understanding the impact of tumor burden relative to prior chemotherapy in the requirement for PD-L1 IHC expression.

Given long-term toxicity concerns, it is debated whether all early-stage patients need neoadjuvant ICI with their chemotherapy, particularly those presenting with node-negative disease. Clinical and preclinical data support that the addition of PD-1 targeting agents to chemotherapy as compared with chemotherapy alone significantly augments the antitumor T-cell response and results in long-term immune protection from recurrence. It is hoped that in the future these agents can be pharmacologically improved to just target tumor-specific T cells, which will hopefully alleviate many of the immune toxicity concerns.

Current Status and Future Directions

Adding ICI to neoadjuvant chemotherapy both achieves a pCR in more patients and improves long-term clinical outcomes even in patients with residual disease at surgery. High-risk patients (large tumor size or node-positive tumors) without a medical contraindication (active autoimmune disease, for example) should receive a PD-1/PD-L1 inhibitor in combination with neoadjuvant chemotherapy (Emens et al. 2021c). Future clinical trials aim to optimize the chemotherapy backbone and/or duration of immunotherapy according to the TIL level or PD-L1 expression. For example, it is plausible that some patients with stage I/II disease and high TIL or PD-L1⁺ disease could benefit from neoadjuvant taxane with short course ICI.

Biomarkers that predict response to neoadjuvant ICI are needed. On-treatment change in TILs and PD-L1 protein expression, immune gene signatures, homologous recombination deficiency (HRD), CD274 amplification, and TMB (Karn et al. 2020; Bianchini et al. 2021) have been evaluated and a few have been found to be predictive of benefit from ICI specifically. In GeparNuevo, only an increase in intratumoral TIL from baseline to cycle 1, day 15 significantly predicted benefit from durvalumab and not placebo (Loibl et al. 2019). High TMB and immune gene-expression profile were associated with increased odds of pCR in both treatment arms (Karn et al. 2020). Stromal TILs (sTILs) and up-regulation of immune signaling pathways at cycle 2, day 1 was associated with pCR in both atezolizumab and chemo-alone arms of NeoTrip (Bianchini et al. 2021). Spatial connectivity of PD-L1-expressing immune cells relative to epithelial cells appears to be relevant to response to atezolizumab in NeoTrip (Bianchini et al. 2022), suggesting that categorical or continuous characterization of individual immune markers such as PD-L1 and TILs may be too simplistic in this disease.

The pCR end point is not a perfect surrogate end point for either neoadjuvant chemotherapy alone (Conforti et al. 2022) or combined with ICI. Assessment of pathologic response as a surrogate for long-term outcome may be strengthened by combining it with biomarkers such as circulating tumor cells, circulating tumor DNA, and/or TILs in residual disease (Luen et al. 2019). Finally, the clinical benefit of adjuvant immunotherapy used alone or continued after neoadjuvant therapy remains an open question that will be informed by the results of current clinical trials.

Immunotherapy in Hormone Receptor-Positive (HR⁺) and HER2⁺ Early Breast Cancer

Immunotherapy is being actively investigated in HR⁺ and HER2⁺ breast cancer (Table 2). Patients with HER-2-driven disease have high levels of TILs and high pCR rates with neoadjuvant chemotherapy plus dual HER2 blockade. IMpassion050 investigated the addition of atezolizumab or placebo to neoadjuvant AC followed by paclitaxel, trastuzumab, and pertuzumab (Huober et al. 2022). There was no significant difference in pCR between the two arms regardless of PD-L1 expression, and EFS outcomes remain immature. Moreover, there were four deaths in the atezolizumab arm and none in the placebo arm; two deaths were attributed to treatment. Atezolizumab plus trastuzumab emtansine patients with residual disease after standard neoadjuvant therapy for HER2⁺ disease is being evaluated in the randomized phase III ASTEFANIA trial (NCT04873362).

Table 2.

Immune checkpoint inhibitor (ICI) trials in early HER2⁺ and HR⁺ breast cancer

Clinical trial (sample size)	Design	Disease type and stage	ICI	Chemotherapy backbone	Adjuvant therapy	Results
IMpassion050 (n = 454)	Randomized phase III	HER2+ cT2-4N1-3	Atezo	ddAC, then THP	Atezo + HP if pCR	pCR in ITT 62.4% vs. 62.7%, P = 0.9551
					T-DM1 if RD
I-SPY2 (n = 40 HR+) (69 total)	Randomized phase II	cT2-4dN0-3	Pembro	Paclitaxel, then AC	Physician's discretion	pCR 30% vs. 13% in HR+
GIADA (n = 43)	Single-arm phase II	Stage II–IIIA premenopausal luminal B	Nivo	EC × 3, OFS exemestane	OFS + exemestane	pCR 16.3%
I-SPY2 (n = 52) (73 total)	Randomized phase II	Stage II–III	Durva + olaparib	Paclitaxel, then AC	None	pCR 28% vs. 14% in HR+
KEYNOTE-756	Randomized phase III	T1c-2N1-2	Pembro	Paclitaxel, then AC	Pembro × 9 + ET	Primary end points pCR and EFS
		T3-4N0-2
		Grade 3				Completed accrual
Checkmate 7FL	Randomized phase III	T1c-2N1-2	Nivo	Paclitaxel, then AC	Nivo × 7 + ET	Terminated early due to a change in the standard of care
		T3-4N0-2
		Grade 3
		ER 1%–9%

(HER2) Human epidermal growth factor 2, (HR) hormone receptor, (atezo) atezolizumab, (pembro) pembrolizumab, (nivo) nivolumab, (durva) durvalumab, (AC) adriamycin and doxorubicin, (THP) paclitaxel, trastuzumab, and pertuzumab, (HP) trastuzumab and pertuzumab, (EC) epirubicin and cyclophosphamide, (OFS) ovarian function suppression, (ET) endocrine therapy, (ER) estrogen receptor, (pCR) pathologic complete response, (RD) residual disease, (EFS) event-free survival, (ITT) intent to treat.

HR⁺ breast cancer overall is associated with a good prognosis. However, certain patient subgroups have a worse prognosis, including those who are premenopausal, and/or whose disease is high grade, has greater nodal involvement, or has low estrogen receptor (ER) expression. High-grade disease is associated with higher TIL levels, even in HR⁺ disease. HR⁺ HER2-negative (HER2neg) patients were included in I-SPY2, with an improvement in pCR rates from 13% to 30% (Table 2; Nanda et al. 2020). The GIADA trial enrolled 43 patients with stage II–III luminal B breast cancer (HR⁺, HER2neg, Ki67 ≥ 20%, and/or grade 3) to receive three cycles of EC followed by eight cycles of 2-wk nivolumab, with a pCR rate of 16.3% (Dieci et al. 2022). Checkmate 7FL (NCT04109066) and KEYNOTE-756 (NCT03725059) are randomized phase III trials investigating either nivolumab or pembrolizumab, respectively, in combination with neoadjuvant AC- and taxane-based chemotherapy, followed by adjuvant ICI with endocrine therapy in high-grade HR⁺ breast cancers. Checkmate 7FL closed to accrual early after the MonarchE trial showed significant benefit for adjuvant abemaciclib (Harbeck et al. 2021), which cannot be safely combined with ICI. KEYNOTE-756 has completed accrual; pCR and EFS analyses are planned.

Combination Strategies

Combinations of PD-1/PD-L1 agents with other immune-modulatory agents may improve pCR rates for patients unlikely to respond to ICI alone (Table 3). The single-arm CHARIOT trial recruited 34 patients with stage III TNBC with poor response to neoadjuvant AC to receive combination ipilimumab and nivolumab with neoadjuvant weekly paclitaxel, resulting in pCR rates of 24.4%, 37.5%, and 23% in the overall, PD-L1⁺ and PD-L1-negative populations, respectively (Loi et al. 2022b). The combination of PARP inhibitors and immunotherapy is particularly attractive due to the prevalence of HRD in breast cancer. HRD is a genomic feature associated with increased immune activation via up-regulation of the cGAS/STING pathway (Parkes et al. 2022; van Vugt et al. 2022). I-SPY2 evaluated the PARP-inhibitor olaparib with durvalumab and paclitaxel, followed by AC, for patients with HER2neg early breast cancer, and demonstrated numerically improved pCR rates compared to chemotherapy alone in both the HR⁺ and TNBC cohorts (Pusztai et al. 2021).

Table 3.

Immune checkpoint inhibitor (ICI) trials for the first-line therapy of metastatic triple-negative breast cancer (TNBC)

Clinical trial (sample size)	Design	Patient population	ICI	Chemotherapy backbone	Results
KEYNOTE-355 (n = 847)	Randomized phase III	Untreated advanced TNBC TFI >6 mo	Pembro vs. placebo	Nab-paclitaxel Paclitaxel Gemcitabine + carboplatin	ITT: PFS 7.5 mo vs. 5.6 mo, HR 0.82, P = not tested
					ITT: OS 17.2 vs 15.5 mo, HR 0.89, P = not tested
					CPS >10: PFS 9.7 vs 5.6 mo, HR 0.65, P = 0.0012
					CPS ≥10: OS 23.0 vs. 16.1 mo, HR 0.73, P = 0.0185
IMpassion130 (n = 902)	Randomized phase III	Untreated advanced TNBC TFI ≥12 mo	Atezo vs. placebo	Nab-paclitaxel	ITT: PFS 7.2 mo vs. 5.5 mo, HR 0.80, P = 0.002
					ITT: OS 21.0 vs. 18.7 mo, HR 0.87, P = not tested
					PD-L1+: PFS 7.5 vs. 5.0 mo, HR 0.62, P < 0.001
					PD-L1+: OS 25.4 vs. 17.9 mo, HR 0.67, P = not tested
IMpassion131 (n = 651)	Randomized phase III	Untreated advanced TNBC TFI ≥12 mo	Atezo vs. placebo	Paclitaxel	PD-L1+: PFS 5.7 mo vs. 6.0 mo, HR 0.82, P = 0.002
					PD-L1+: OS 22.1 vs. 28.3 mo, HR 1.11 P = not tested

(TFI) Treatment-free interval, (pembro) pembrolizumab, (atezo) atezolizumab, (ITT) intent to treat, (PD-L1) programmed death ligand 1, (PFS) progression-free survival, (OS) overall survival, (HR) hazard ratio.

ADVANCED BREAST CANCER

Metastatic TNBC—First-Line ICIs

Metastatic TNBC has historically been treated with chemotherapy, with bevacizumab sometimes added ex-U.S. Recent clinical progress has expanded treatment options for patients, which now include targeted agents and immunotherapy (Huppert et al. 2022). The PARP inhibitors olaparib and niraparib (for germline BRCA-mutated breast cancer) and the antibody-drug conjugates sacituzumab govitecan (specific for the cell-surface antigen TROP2) and trastuzumab deruxtecan (specific for HER2 and active in patients with HER2-low TNBC) are targeted therapies available for routine use in the United States. Pembrolizumab with chemotherapy (based on KEYNOTE 355; Cortes et al. 2022) is a standard of care for the first-line treatment of metastatic PD-L1⁺ TNBC in the United States and globally, and atezolizumab with nab-paclitaxel (based on IMpassion 130) is approved for the first-line treatment of metastatic PD-L1⁺ TNBC (Schmid et al. 2018; Emens et al. 2021b) outside the United States. These trials are summarized in Table 3. In contrast to the neoadjuvant setting, PD-L1 expression is used to select patients with advanced TNBC for immunotherapy (the SP142 assay for atezolizumab and the 22C3 assay for pembrolizumab were used in the trials). These PD-L1 assays are not the same, as demonstrated in a systematic analysis of patient samples evaluating the association of PD-L1 status and clinical response from the IMpassion130 study (Rugo et al. 2021).

The combination of chemotherapy and pembrolizumab was evaluated in KEYNOTE 355, a global clinical study that randomized 847 patients with advanced TNBC to receive pembrolizumab or placebo and chemotherapy with nab-paclitaxel, paclitaxel, or gemcitabine and carboplatin (Cortes et al. 2020, 2022). Eligible patients had untreated advanced disease with a treatment-free interval from (neo)adjuvant therapy of ≥6 mo. Primary end points included PFS and OS in the overall patient population, and in patients with PD-L1 CPS scores of ≥10 or ≥1. Pembrolizumab given with chemotherapy improved both PFS (Δ4.1 mo, HR 0.65, P = 0.0012) and OS (Δ6.9 mo, HR 0.73, P = 0.0093) in PD-L1⁺ CPS ≥10 patients. Based on these data, pembrolizumab with chemotherapy is approved in the United States and globally for the first-line treatment of patients with advanced PD-L1⁺ TNBC.

IMpassion130 is a global clinical trial that enrolled 902 patients with advanced TNBC, randomizing them to nab-paclitaxel with atezolizumab or placebo (Schmid et al. 2018, 2020a; Emens et al. 2021b). Patients had treatment-naive metastatic disease, with a treatment-free interval of ≥12 mo from (neo)adjuvant therapy. Primary end points included PFS and OS in the overall and PD-L1⁺ patient groups. The study showed an improvement in PFS with the addition of atezolizumab to nab-paclitaxel in both the overall (Δ2.1 mo, HR 0.69, P = 0.0025) and PD-L1⁺ (Δ2.5 mo, HR 0.62, P < 0.0001) groups. A trend toward improved OS in the overall patient population was not statistically significant, but an exploratory OS analysis in PD-L1⁺ patients revealed a clinically meaningful OS improvement that was not formally tested due to the hierarchical statistical analysis plan for OS. These results resulted in accelerated approval by the U.S. FDA. The OS for PD-L1⁺ patients remained consistent over time, with improvements of 7.5 (HR 0.62), 7.0 (HR 0.71), and 7.5 (HR 0.67) mo at the first, second, and final analyses, respectively (median follow up 18.8 mo at final analysis). Extensive biomarker analyses of IMpassion130 tumor specimens revealed that enriching for PD-L1 was not associated with greater clinical benefit, and patients with PD-L1-negative disease had no treatment effect (Emens et al. 2021a). Only 9% of tumors expressed PD-L1 on tumor cells, and 2% of tumors expressed PD-L1 exclusively on tumor cells. Improved clinical outcomes were observed in tumors with CD8⁺ T cells and sTILs only if the tumors were PD-L1⁺. BRCA1/2 mutations were present in 14.5% (89/612) of patients, and not associated with PD-L1 status. PD-L1⁺ patients derived clinical benefit regardless of BRCA1/2 mutation status.

IMpassion 131, an independent companion trial designed to independently evaluate these findings, was a global clinical trial that enrolled a similar population of 651 patients (Miles et al. 2021). It randomized patients to receive atezolizumab or placebo combined with paclitaxel (Table 3). The percentages of PD-L1⁺ patients in IMpassion 130 and IMpassion 131 were 40% and 45%, respectively. Adding atezolizumab to paclitaxel did not improve PFS or OS in PD-L1⁺ patients (Δ0.3 mo, HR 0.82, P = 0.20, and Δ −6.2 mo, HR 1.11, respectively). The reasons for the discordant results between the trials are unclear. They may relate to the steroid exposure required for paclitaxel or unknown biological differences between the patient populations. Given the negative results of IMpassion 131 and the lack of statistically significant OS data from IMpassion 130, the approval of pembrolizumab left no clear regulatory path forward for atezolizumab combined with nab-paclitaxel in the United States, and the accelerated approval indication was withdrawn by the sponsor. Atezolizumab and nab-paclitaxel is approved by regulatory authorities outside the United States.

Metastatic TNBC—ICIs Second Line and Beyond

Immunotherapy has been less active in metastatic TNBC beyond the first-line setting (Table 4). The phase 3 KEYNOTE 119 study evaluated pembrolizumab monotherapy versus chemotherapy of physician's choice in a global, randomized, open label trial enrolling patients with TNBC after one to two prior systemic therapies for metastatic disease (Winer et al. 2021). Patients received either pembrolizumab or chemotherapy with capecitabine, eribulin, gemcitabine, or vinorelbine. Primary end points were OS in patients with PD-L1 CPS ≥10 and CPS ≥1 disease, and the overall patient population. Pembrolizumab did not improve OS relative to chemotherapy in any group, although exploratory analyses revealed a potential survival benefit in the CPS ≥20 subgroup. These findings indicate that novel treatment and/or patient-selection strategies are needed for patients with previously treated advanced TNBC.

Table 4.

Trials testing immune checkpoint inhibitors (ICIs) in metastatic triple-negative breast cancer (TNBC) beyond the first-line setting

Clinical trial (sample size)	Design	Patient population	ICI	Intervention	Results
KEYNOTE-119 (n = 622)	Randomized open label phase III	Advanced TNBC second or third line	Pembro	Pembro alone vs. physicians’ choice chemo: capecitabine, eribulin, gemcitabine, vinorelbine	OS:
					CPS ≥10: 12.7 vs. 11.6 mo, HR 0.78, P = 0.057
					CPS ≥1: 10.7 vs. 10.2 mo, HR 0.86, P = 0.073
					ITT: 9.9 vs. 10.8 mo, HR 0.97, P = nt
					CPS ≥20: 14.9 vs. 12.5 mo, HR 0.58, P = nt
TONIC (n = 67)	Noncomparative adaptive phase I/II	Metastatic TNBC	Nivo	Nivo alone vs. nivo beginning after 2 wk priming with: CY 50 mg orally daily	ORR:
					Overall 20%
					Nivo 17%
				Cis 2 × 40 mg/m2 IV	CY 8%
				Dox 2 × 15 mg IV	Cis 23%
				XRT 3 × 8 Gy	Dox 35%
					XRT 8%
FUTURE-C-PLUS (n = 48)	Single-arm phase II	Advanced CD8+ T-cell-enriched metastatic TNBC	Camre	Camrelizumab + famitinib, nab-paclitaxel	ORR 81.3%, PFS 13.6 mo
KEYNOTE-162 (TOPACIO) (n = 55)	Single-arm phase II	Metastatic TNBC	Pembro	Pembro + niraparib	ITT (n = 47 efficacy evaluable):
					ORR 21%
					DCR 49%
					PFS 2.3 mo
					mBRCA (n = 15):
					ORR 47% (n = 7)
					DCR 80% (n = 12)
					PFS 8.3 mo
					wtBRCA (n = 27):  ORR 11% (n = 3)  DCR 33% (n = 9)  PFS 2.1 mo
SAFIR02-BREAST IMMUNO (n = 199)	Randomized phase II	Metastatic HER2neg breast cancer, stable after six to eight cycles of chemotherapy	Durva	Maintenance therapy durva vs. chemo	Overall:
					PFS HR 1.40, P = 0.047
					OS HR 0.84, P = 0.423
					TNBC (n = 82)
					All OS HR 0.54, P = 0.0377, P = nt
					PD-L1+ (n = 32) OS HR 0.37, P = nt
					PD-L1– (n = 24) OS HR 0.49, P = nt
					CD274 gain/amplification (n = 23)
					OS HR 0.18, P = 0.0059
					CD274 normal/loss (n = 32)
					OS HR 1.12, P = 0.8139

(HER2neg) Human epidermal growth factor 2-negative, (pembro) pembrolizumab, (nivo) nivolumab, (camre) camrelizumab, (durva) durvalumab, (chemo) chemotherapy, (CY) cyclophosphamide, (Cis) cisplatin, (Dox) doxorubicin, (XRT) radiotherapy, (ITT) intent to treat, (PD-L1) programmed death ligand 1, (CPS) combined positive score, (ORR) objective response rate, (DCR) disease control rate, (PFS) progression-free survival, (OS) overall survival, (HR) hazard ratio, (Gy) gray, (IV) intravenous, (mBRCA) mutated breast cancer–related gene, (wtBRCA) wild-type breast cancer–related gene, (nt) not tested.

The TONIC study is a noncomparative, adaptive phase 1/2 clinical trial that evaluated nivolumab alone or after 2 wk priming with immunomodulatory doses of cyclophosphamide (50 mg orally daily), cisplatin (2 × 40 mg/m² intravenously), doxorubicin (2 × 15 mg intravenously), or radiation therapy (3 × 8 Gy) in 67 patients with metastatic TNBC, 24% of whom had no prior treatment for metastatic disease (Voorwerk et al. 2019). Biopsies were collected at baseline, and after priming and 3 wk of nivolumab. The overall objective response rate (ORR) by iRECIST was 20%, with ORRs of 23% and 35% with cisplatin and doxorubicin priming, respectively. Correlative studies revealed up-regulation of immune-related genes in the PD-1 and T-cell cytotoxicity pathways with both drugs, as well as inflammation and both JAK/STAT and TNF-α signaling with doxorubicin. Induction with low-dose doxorubicin followed by nivolumab versus nivolumab alone is currently being evaluated.

The FUTURE-C-PLUS trial evaluated the antiangiogenic agent famitinib combined with the PD-1 antibody camrelizumab and nab-paclitaxel as first-line therapy in 48 advanced CD8⁺ T-cell-enriched immunomodulatory TNBC patients (Wu et al. 2022). The ORR was 81.3%, with a median PFS of 13.6 mo. Clinical benefit was enhanced in CD8⁺ T-cell-enriched and PD-L1⁺ tumors, and the PKD1 somatic mutation was associated with resistance. The TOPACIO/KEYNOTE 162 trial is a single-arm trial that evaluated niraparib combined with pembrolizumab in 55 patients (47 efficacy evaluable) with metastatic TNBC (Vinayak et al. 2019). The ORR was 21%, with a disease control rate (DCR) of 49%. In 15 efficacy evaluable patients with a germline BRCA mutation, the ORR was 47% (n = 7) with a DCR of 80% (n = 12).

The randomized phase II SAFIR02 Breast Immuno trial tested maintenance therapy with chemotherapy versus durvalumab in patients with metastatic HER2neg breast cancer with stable disease after induction chemotherapy (Batchelot et al. 2021). There was no clinical activity of durvalumab in the overall population, but in 82 patients with TNBC, durvalumab improved OS (HR 0.54, P = 0.0377) and CD274 gain/amplification was identified as a potential biomarker of sensitivity.

Immunotherapy for Metastatic HER2⁺ Breast Cancer

The major challenge of developing immunotherapy for metastatic HER2⁺ breast cancer is the availability of multiple HER2-directed therapeutics with survival benefit. These highly effective drugs raise the bar for demonstrating enhanced clinical activity with immunotherapy combinations (Table 5), while simultaneously creating hope for curing patients with advanced HER2⁺ breast cancer. Several HER2-specific therapeutics have intrinsic immune-modulating activity, creating an opportunity for therapeutic synergy. A phase 1b study evaluated adding atezolizumab to ado-trastuzumab emtansine (TDM1) or trastuzumab/pertuzumab with docetaxel in patients with metastatic HER2⁺ breast cancer (Hamilton et al. 2021). The ORR with atezolizumab and TDM1 was 35% (7/20 patients) and with atezolizumab plus trastuzumab, pertuzumab, and docetaxel was 100% (6/6 patients). Immune cell PD-L1 expression increased in patients treated with atezolizumab with TDM1 independent of clinical response.

Table 5.

Selected trials testing immune checkpoint inhibitors (ICIs) in HER2⁺ and HR⁺ HER2-negative metastatic breast cancer

Clinical trial (sample size)	Design	Patient population	ICI	Intervention	Results
KATE2 (n = 202)	Randomized phase II	Metastatic HER2+ breast cancer previously treated with trastuzumab and taxane	Atezo	Atezo or placebo + T-DM1	ITT PFS 8.2 vs. 6.8 mo, HR 0.82, P = 0.33
					PD-L1+ PFS 8.5 vs. 4.1 mo, HR 0.62
					PD-L1– PFS 6.8 vs. 8.2, HR 1.06
PANACEA (n = 55)	Phase Ib/II parallel cohort	Metastatic HER2+ breast cancer progressed on trastuzumab	Pembro	Pembro + trastuzumab	PD-L1+ vs. PD-L1– cohorts:
					ORR 15% vs. 0%
					12-mo PFS 13% vs. 0%
					12-mo OS rate 65% vs. 12%
AIPAC (n = 227)	Randomized phase IIb	Metastatic HR+ breast cancer, first-line chemo	Efti	Paclitaxel with efti or placebo for six cycles, then maintenance efti vs. placebo	ORR 48.3% vs. 38.4%
					PFS at 6 mo 63% vs. 54%, HR 0.93, P = 0.341
SAFIR02-BREAST IMMUNO (n = 199)	Randomized phase II	Metastatic HER2neg breast cancer, stable after six to eight cycles of chemo	Durva	Maintenance therapy durva vs. chemo	Overall (117/199 HR+)
					PFS HR 1.40, P = 0.047
					OS HR 0.84, P = 0.423
					*Potential benefit in TNBC subset (n = 82)
Pembro + eribulin (n = 88)	Randomized phase Ib/II	Metastatic HR+ breast cancer	Pembro	Pembro + eribulin vs. eribulin	ORR 27% vs. 34%, P = 0.49
					PFS 4.1 vs. 4.2 mo, HR 0.80, P = 0.33
Treme + exemestane (n = 26)	Single-arm phase I	Advanced HR+ breast cancer	Treme	Treme + exemestane	Stable disease ≥12 wk in 42%
Pembro + tamoxifen + vorinostat (n = 34)	Randomized phase II	Advanced HR+ breast cancer	Pembro	Concurrent tamoxifen + vorinostat with pembro vs. one cycle of priming with tamoxifen + vorinostat followed by concurrent therapy with pembro	ORR 4%
					CBR 19%
MEDIOLA (n = 30)	Single-arm phase II	gmBRCA HER2neg metastatic breast cancer	Durva	4 wk olaparib priming followed by concurrent olaparib with durva	Overall ORR 63%
					HR+ (n = 13) ORR 69%

(HER2) Human epidermal growth factor 2, (HER2neg) human epidermal growth factor 2-negative, (HR) hormone receptor, (TNBC) triple-negative breast cancer, (atezo) atezolizumab, (pembro) pembrolizumab, (treme) tremelimumab), (durva) durvalumab, (chemo) chemotherapy, (efti) eftilagomad alpha, (T-DM1) trastuzumab emtansine, (ITT) intent to treat, (PD-L1) programmed death ligand 1, (CPS) combined positive score, (ORR) objective response rate, (DCR) disease control rate, (PFS) progression-free survival, (OS) overall survival, (HR) hazard ratio, (ORR) objective response rate, (gmBRCA) germline mutated breast cancer–related gene, (wtBRCA) wild-type breast cancer–related gene.

PANACEA evaluated the safety and clinical activity of trastuzumab and pembrolizumab in 55 patients with metastatic HER2⁺ breast cancer who had previously progressed on trastuzumab (Loi et al. 2019). The ORRs were 15.2% (7/42) in PD-L1⁺ and 0% (0/12) PD-L1-negative patients, respectively. Moreover, 12-mo PFS and OS rates were 13% versus 0% and 65% versus 12% in patients with PD-L1⁺ versus PD-L1-negative disease, respectively. sTILs tracked with clinical benefit in PD-L1⁺ patients.

KATE2 is a randomized phase 2 trial that added atezolizumab or placebo to TDM1 in 202 patients with HER2⁺ metastatic breast cancer previously treated with trastuzumab and a taxane (Emens et al. 2020). There was no significant difference in PFS or OS in the overall population, but exploratory analyses suggested improved PFS and OS in PD-L1⁺ patients. KATE3, a randomized phase 3 clinical trial is enrolling biomarker-selected patients with metastatic HER2⁺ breast cancer that is also PD-L1⁺ (NCT04740918).

Immunotherapy for Metastatic HR⁺ Breast Cancer

HR-expressing breast cancer tends to lack T cells and instead contains a significant population of myeloid cells. Given the distinct immunobiology of metastatic HR⁺ breast cancer, it is not surprising that ICIs alone have displayed limited clinical activity. Pembrolizumab alone in 25 patients with ER⁺, HER2neg, PD-L1⁺ metastatic breast cancer had an ORR of 12% (Rugo et al. 2018). Most trials for advanced HR⁺ breast cancer have thus focused on combination strategies (Table 5).

The anti-CTLA4-specific antibody tremelimumab combined with exemestane was evaluated in 26 patients with advanced HR⁺ breast cancer (Vonderheide et al. 2010). Peripheral ICOS⁺ T cells increased, with a best response of stable disease for ≥12 wk in 42% of patients. The combination of tremelimumab and durvalumab was tested in 18 patients with advanced HER2neg breast cancer, 11 of whom had HR⁺ disease (Santa-Maria et al. 2018). Although no responses occurred in ER⁺ disease, the ORR in TNBC was 17%.

Pembrolizumab was given with eribulin in 44 patients with advanced HR⁺ breast cancer, with an ORR of 41% (Perez-Garcia et al. 2021). A randomized study enrolled 88 patients with advanced HR⁺ breast cancer to receive eribulin with or without pembrolizumab, with crossover permitted (Tolaney et al. 2020). There was no improvement in ORR (27% vs. 34%, P = 0.49), PFS, or OS, and no association of PFS with PD-L1, sTILs, TMB, or genomic alterations. Computational analysis of 52 pretreatment tumors showed an association between immune infiltrates and antigen presentation pathways and clinical response, with resistant tumors characterized by heterogeneity and active estrogen signaling (Keenan et al. 2021).

Another study evaluated epigenetic modulation with pembrolizumab in metastatic ER⁺ breast cancer, randomizing 34 patients to receive tamoxifen and vorinostat with concurrent pembrolizumab (n = 18), or with pembrolizumab beginning after one cycle of priming with tamoxifen and vorinostat (n = 16) (Terranova-Barberio et al. 2020). The ORR was 4%, with a clinical benefit rate of 19%. Another study evaluated entinostat with nivolumab and low-dose ipilimumab in 24 patients with advanced HER2neg breast cancer; 12 had TNBC and 12 had HR⁺ breast cancer. The ORR was 30%, mostly in TNBC. The CD8⁺ T cells increased with therapy.

Eftilagomad alpha (efti, IMP321) is a soluble LAG-3 Ig fusion that binds to MHC class II molecules, promoting immune priming. The AIPAC trial randomized 227 patients with metastatic HR⁺ breast cancer to weekly paclitaxel with efti or placebo as first-line chemotherapy in endocrine-experienced patients (Wildiers et al. 2021). Paclitaxel was given with either efti or placebo for six cycles, and then maintenance efti or placebo was continued for 52 wk. There was no PFS difference (HR 0.93, P = 0.341), but efti and paclitaxel improved OS in patients <65 yr with low monocytes and more aggressive disease by about 8 mo (22.3 vs. 14.8 mo, P = 0.17). A follow-up phase 3 clinical trial is planned.

Biomarker-Defined Metastatic Breast Cancer beyond Subtype

The MEDIOLA study enrolled 30 patients with germline BRCA-mutated HER2neg metastatic breast cancer to receive olaparib priming for 4 wk, followed by durvalumab with olaparib starting at week 5; 17 patients had TNBC and the remainder were HR⁺ (Domchek et al. 2020). The overall ORR was 63%, with ORRs in TNBC and HR⁺ disease of 59% and 69%, respectively. The median duration of response was 9.2 mo. Nine patients had early disease progression at ≤28 wk. Potential mechanisms of resistance identified included BRCA2 reversion, lack of BRCA2 LOH, p53 mutation, and PD-L1/PD-L2 gene amplification.

The TAPUR study tests commercially available targeted agents in patients with advanced cancers and a predictive molecular alteration (Alva et al. 2021). This study treated 28 patients with metastatic breast cancer (any subtype) and a high TMB of 9–37 Mut/Mb. The ORR and DCR were 21% and 37%, respectively, and median OS was 30.6 wk (95% CI 18.3–103.3). There was no association between PFS and TMB.

The NIMBUS study tested nivolumab with low-dose ipilimumab in 30 patients with advanced HER2neg breast cancer and a TMB ≥9 mut/Mb; 21 had HR⁺ disease, and eight were treated first-line (Barroso-Sousa et al. 2022). The overall ORR was 17% (5/30 patients). Three patients had HR⁺ disease with TMBs of 110, 38, and 17.5, whereas two TNBC responders had TMBs of 10.9 and 9.1, with the first also PD-L1⁺. Patients with TMB ≥14 had an ORR of 60%, suggesting prospective trials are needed to determine the optimal TMB cutoff in breast cancer.

NOVEL EMERGING IMMUNOTHERAPIES

To date, pembrolizumab is the only immunotherapy approved for breast cancer in the United States, with its utility currently limited to TNBC. Key goals for the field are to enhance the activity of immunotherapy for TNBC, and to expand its use to other breast cancer subtypes. One major strategy is to combine ICIs with standard and novel breast cancer therapies. Attractive combinations include ICIs with newer antibody drug conjugates (sacituzumab govitecan, fam-trastuzumab deruxtecan, for example), radiotherapy, cyroablation, and new precision drugs targeting unique aspects of intrinsic tumor biology and/or the tumor immune microenvironment (key signaling pathways and metabolic circuits). Initial combinations have been discussed above. A second major strategy is the development of innovative immunotherapies, including novel immune checkpoint modulators, vaccines, adoptive cell therapies, and bispecific molecules.

Novel Immune Checkpoints

New immune checkpoints are under active investigation. The LAG-3-specific antibody relatlimab is now approved for melanoma in combination with nivolumab and represents the third type of ICI approved for clinical use (Tawbi et al. 2022). Clinical trials have tested antibodies specific for TIM-3 and TIGIT, but clinical activity has not been clearly demonstrated. Other promising novel immune checkpoints under active clinical investigation include CD40, OX-40, ICOS, B7-H3, and B7-H4.

Vaccines

Cancer vaccines have been tested with minimal clinical success. Therapeutic breast cancer vaccines were first tested in metastatic disease, and then in the adjuvant setting; all phase 3 clinical trials so far have been negative (Solinas et al. 2020). There is now increasing interest in applying cancer vaccines for disease interception and prevention, as disease burdens and immune suppression are both minimal.

Adoptive Cell Therapy

After ICIs, adoptive cellular therapy with CD19-specific CAR-T cells is the second major class of immunotherapy that has revolutionized cancer therapy. It is approved for patients with CD19-expressing hematologic malignancies. CAR-T cell therapy has been challenging to develop in solid tumors, due to on-target/off-tumor toxicity and lack of CAR-T cell trafficking into solid tumors. In contrast, therapy with autologous TILs is promising for solid tumors, including breast cancer (Zacharakis et al. 2022).

Bispecific Small Molecules

Bispecific small molecules are engineered to simultaneously recognize two distinct targets (Roussos Torres and Emens et al. 2022). The bispecific T-cell engager (CD3 × CD19) blinatumomab is a standard of care for the treatment of B-cell malignancies. Bispecific T-cell engagers under evaluation in clinical trials for breast cancer include CD3 × HER2 and CD3 × p-cadherin molecules. Dual affinity retargeting (DART) molecules simultaneously target two immune checkpoints, and DARTs tested in breast cancer so far are PD-1 × CTLA-4 and PD-1 × LAG-3 agents. Finally, bintrafusp alfa is a bifunctional fusion protein that simultaneously targets PD-L1 and transforming growth factor β. Early clinical trials demonstrated promising activity particularly in HPV-related cancers.

CONCLUDING REMARKS

We have made enormous progress in breast cancer immunotherapy over the last decade. Immunotherapy with pembrolizumab and chemotherapy is now approved for neoadjuvant therapy of high-risk early TNBC, regardless of PD-L1 expression, and for the first-line therapy of metastatic PD-L1⁺ TNBC. We have significant work ahead to clarify how best to use immunotherapy in breast cancer, and to extend the impact of immunotherapy to patients with HER2⁺ or HR⁺ disease. For early-stage TNBC, remaining questions include predictive biomarkers of response and resistance, the optimal neoadjuvant chemotherapy backbone, and strategies for the tailored management of residual disease and pCR after neoadjuvant immunotherapy. For metastatic TNBC, remaining needs are better predictive biomarkers beyond PD-L1 for ICIs, defining primary and secondary mechanisms of immunotherapy resistance, and new immunotherapy strategies for metastatic TNBC independent of PD-L1 expression, and for other breast cancer subtypes. Given the innovative immune-based agents already under development, the future of breast cancer immunotherapy is bright.