Excitement Grows About Immunotherapy Potential in Breast Cancer

Hope Rugo, MD

Although the first checkpoint inhibitor has just been approved for patients with breast cancer, findings from dozens of ongoing studies may eventually change the paradigm for large subsets of those with the malignancy. Two leading experts in the field, Hope S. Rugo, MD, FASCO, and Elizabeth Mittendorf, MD, PhD, discussed emerging trial data and the populations who might benefit the most from this modality during the 36th Annual Miami Breast Cancer Conference^® (MBCC).

The prospects for administering these therapies moved from the realm of pending trials into clinical practice with the FDA’s approval Friday of atezolizumab (Tecentriq) for patients with metastatic triple-negative breast cancer (TNBC). The PD-L1 inhibitor is approved in combination with nab-paclitaxel (Abraxane) for patients with unresectable locally advanced or metastatic PD-L1—positive TNBC.

“The approval of atezolizumab for breast cancer is really important because we have our first approved checkpoint inhibitor, or really immune agonoist for the treatment of breast cancer,” Rugo, an MBCC co-chair who was among the principal investigators in the study, said in an interview. “Now our big challenge is to try and figure out how to expand the use of this class of drugs to other patients and with other chemotherapy combinations.”

Mittendorf echoed those sentiments. “It’s obviously a tremendously exciting day but also a tremendously exciting time,” she said in an interview. “It’s going to be a very fast-paced time…Of course, triple negative is just 1 subtype of breast cancer and so there’s going to be tremendous enthusiasm for continuing to explore opportunities to make our other tumor types susceptible to immunotherapy as well.”

She said the next steps in the research include determining which patients are likely to respond beyond the PD-L1—positive group, how those without PD-L1–positive expression on immune cell infiltrates will be treated, and what subsequent therapies should be administered to PD-L1–positive patients who initially respond and then progress.

The atezolizumab combination was approved based on findings from the phase III IMpassion 130 study (NCT0242589), which randomized 902 patients with untreated metastatic TNBC to nab-paclitaxel with either atezolizumab or placebo. Patients must test positive for PD-L1 expression. The FDA designated the VENTANA PD-L1 SP142 assay, which was used in the study, as a companion diagnostic for the atezolizumab combination.

In the intent-to-treat population, median progression-free survival (PFS) was 7.2 months with the atezolizumab combination and 5.5 months among those who received nab-paclitaxel plus placebo (hazard ratio [HR] for progression or death, 0.80; 95% CI, 0.69-0.92; P =.002).¹ Median overall survival (OS) was 21.3 months with the atezolizumab regimen and 17.6 months with nab-paclitaxel alone (HR for death, 0.84; 95% CI, 0.69-1.02; P = .08).

For patients with PD-L1—positive tumors, the median PFS was 7.5 months with atezolizumab and 5.0 months with nab-paclitaxel alone (HR, 0.62; 95% CI, 0.49-0.78; P <.001). Median OS was 25.0 months and 15.5 months, respectively (HR, 0.62; 95% CI, 0.45-0.86). Positivity was defined as PD-L1 expression on tumor-infiltrating immune cells as a percentage of tumor area, with <1% categorized as negative and ≥1% as positive.¹ Rugo said the OS findings are an interim result based on 60% of the events, but that the trend would likely be maintained when the data are updated later this year.

Even at this juncture, however, the OS benefit for the combination “is the amazing part of this data,” she said. “A 9.5-month difference—it’s unequaled. We haven’t seen it anywhere else,” Rugo noted. “It tells us 2 things: 1 is we can change the survival in patients with metastatic triple-negative breast cancer who have immune cells positive for PD-L1. It also tells us we can change the environment of the cancer to change its responsivness to treatment so that other treatments have to be working better.”

The rationale for using immune checkpoint inhibitors as neoadjuvant therapy also is growing. “Over the last few years, we have come to understand that more aggressive forms of breast cancer have some degree of host immunity, and as those tumors progress and become more resistant, the host immunity tends to decrease. As the tumor becomes more resistant, it also is able to reduce the body’s immune response to the cancer,” Rugo said in an earlier interview.

Early Data and Ongoing Trials

"This means the first breast cancers that were studied in trials of immune checkpoint inhibitors —triple-negative (hormone- and HER2-receptor—negative), advanced, heavily pretreated, and very aggressive—were actually the least likely to respond," she said. "If we’d gotten unlucky in those early trials, we wouldn’t have seen enough response in those early trials to spur more research, but we got lucky. We saw some response, although it was less than 10%, and went on. Response rates rose to a fairly respectable 23% in trials that used checkpoint inhibitors as first-line therapy for advanced disease, and now there is growing evidence that these agents may work even better in the adjuvant or neoadjuvant setting."Early-stage trials and preliminary data from larger trials suggest that adding checkpoint inhibitors to neoadjuvant chemotherapy may improve outcomes. The 2018 European Society for Medical Oncology Congress featured interim data from the first 19 patients in a phase II trial of neoadjuvant atezolizumab plus nab-paclitaxel in TNBC (NCT02530489). Eligible patients had chemo-sensitive TNBC based on their response to anthracycline therapy. Participants received neoadjuvant atezolizumab plus nab-paclitaxel followed by atezolizumab for 3 months after surgery.²

The addition of atezolizumab to the neoadjuvant regimen resulted in residual cancer burden scores of 0 or 1 in 32% of study patients (6 of 19), which investigators said is typically about 5%. However, toxicity included 6 serious adverse events (AEs) in 3 patients: fever, elevated creatinine, and postsurgical pain. Atezolizumab was paused or discontinued in 6 patients.²

The phase I KEYNOTE-173 trial (NCT02622074) tested pembrolizumab (Keytruda), a PD-1 inhibitor, in combination with 1 of 6 chemotherapy regimens as neoadjuvant treatment for previously untreated locally advanced TNBC. Some of the chemotherapy regimens performed better than others, but the combination of neoadjuvant immunotherapy and chemotherapy, followed by surgery and more immunotherapy, was effective across the board: 60% of all patients (90% CI, 30%-85%) achieved pathologic complete response (pCR; defined as ypT0/Tis ypN0).³

Earlier data from the phase II I-SPY2 trial showed that the addition of pembrolizumab to standard neoadjuvant chemotherapy increased the estimated pCR response rate nearly 3-fold in patients with locally advanced TNBC (60% vs 20%) and nearly 3-fold in patients with locally advanced hormone receptor—positive/HER2-negative breast cancer (34% vs 13%).4 Participants had invasive breast cancer (tumor size, ≥2.5 cm).

Several larger trials are now testing neoadjuvant immunotherapy in women with aggressive breast cancers. The phase III KEYNOTE-522 trial (NCT03036488) is randomizing 1174 women with operable TNBC to 24 weeks of either chemotherapy and pembrolizumab or chemotherapy and placebo before definitive surgery and maintenance therapy with either pembrolizumab or placebo.

A phase II study (NCT03546686) is comparing the addition of nivolumab (Opdivo) plus ipilimumab (Yervoy) to cryoablation as preoperative therapy versus standard-of-care definitive surgery in patients with TNBC who have undergone neoadjuvant taxane-based chemotherapy and then surgery. Women in the experimental arm will also receive nivolumab after surgery. The trial, which is seeking to recruit 150 patients, has a primary endpoint of event-free survival after 36 months.

As clinical trial data continue to mature, investigators will get a sharper picture of the toxicities that may occur with checkpoint inhibition in breast cancer. Overall, the AEs most associated with immune checkpoint inhibitor therapy include colitis, pneumonitis, dermatologic AEs, and endocrine dysfunction.⁵

Breast Cancer Biology

"We are getting data from these trials, and from normal clinical practice, that emphasize the need for constant vigilance. They can create a very wide range of immune toxicities that can arise at nearly any time and quickly become life threatening," Rugo said. "I have been using these agents for years now, and I’m still seeing reactions that I’ve never seen before. I have a patient who received 1 dose of pembrolizumab and developed a full-body rash that has required 9 weeks of steroids and suspended treatment."Although immune checkpoint inhibition has been approved for about 15 tumor types, breast cancer initially was not considered immunogenic enough to respond to such treatments. “Unlike many solid tumors, breast cancer has not typically been responsive to modulation of the immune system,” Mittendorf and Rugo wrote in a joint MBCC abstract.

The agents work well in tumor types with higher immunogenicity and tumor mutational burden, which may help promote an antitumor immune response to neoantigens that can then be reactivated with monoclonal antibodies aimed at immune checkpoints, they noted. “In breast cancer, proliferative subsets, such as TNBC and HER2-positive disease, have a higher tumor mutational burden and could be more amenable to immunotherapy,” they said.

The use of PD-1 or PD-L1 inhibitors as monotherapy has demonstrated durable responses at low rates ranging from 4.8% to 19% in 4 phase I studies in patients with metastatic breast cancer, the abstract said.

Investigators are looking to combination regimens in an effort to enhance the effects of immune checkpoint inhibitors. Ongoing studies are evaluating immunotherapy combinations that include immune agonists, radiation therapy, PARP inhibitors, MEK inhibitors, HDAC inhibitors, HER2-targeted therapy ,and CDK4/6 inhibitors, as well as vaccines.

"Although rare durable responses have been seen [with monotherapy], it is clear that combination therapy is a critical next step in the study of immunotherapy for breast cancer," Mittendorf and Rugo said.

References

1. Schmid P, Adams S, Rugo HS, et al; IMpassion130 Trial Investigators. Atezolizumab and nab-paclitaxel in advanced triple-negative breast cancer. N Engl J Med. 2018;379(22):2108-2121. doi: 10.1056/NEJMoa1809615.
2. Litton JK, Moulder SL, Hess KR, et al. Neoadjuvant trial of nab-paclitaxel and atezolizumab (Atezo), a PD-L1 inhibitor, in patients (pts) with chemo-insensitive triple negative breast cancer (TNBC). Ann Oncol. 2018;29(suppl 8; abstr 224P). doi: 10.1093/annonc/mdy270.219.
3. Schmid P, Park YH, Muñoz-Couselo E, et al. KEYNOTE-173: phase 1b multicohort study of pembrolizumab (Pembro) in combination with chemotherapy as neoadjuvant treatment for triple-negative breast cancer (TNBC). In: Proceedings from the 2018 San Antonio Breast Cancer Symposium. 2019;79(suppl 4; abstr PD5-01). sabcs.org/SABCS/2018/AllAbstracts_2018-12-03_Updated.pdf.
4. Nanda R, Liu MC, Yau C, et al. Pembrolizumab plus standard neoadjuvant therapy for high-risk breast cancer (BC): results from I-SPY 2. J Clin Oncol. 2017(suppl; abstr 506). meetinglibrary.asco.org/record/153653/abstract.
5. Johnson DB, Chandra S, Sosman JA. Immune checkpoint inhibitor toxicity in 2018. JAMA. 2018;320(16):1702-1703. doi: 10.1001/jama.2018.13995.

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