Trials Consider Role of Immunotherapy in Breast Cancer

Elizabeth A. Mittendorf, MD, PhD

Elizabeth A. Mittendorf, MD, PhD

Mixed results have occured in recent trials testing immuotherapy in patients with breast cancer. Checkpoint inhibitors have been used as monotherapy in a pair of trials, reporting lackluster overall response rates (ORRs). When immunotherapy was paired with chemotherapy, on the other hand, it usually showed better results, and gave signals that immunotherapies combined with targeted agents could work better than immunotherapy alone.

“I think we have enough data at this point to say that monotherapy is not the way forward for checkpoint blockade in breast cancer patients,” said Elizabeth A. Mittendorf, MD, PhD, who reviewed data ahead of her presentation at the 2018 Miami Breast Cancer Conference^®titled, “Breast Cancer Immunotherapy Update."

“The tumor types where we have seen the most robust responses to immunotherapies used on their own—melanoma and lung cancer—have genetic mutations that occurred during exposure to the sun or tobacco,” Mittendorf said. “Breast tumors generally have far fewer mutations. They look more like normal tissue, so it’s harder to get the immune system to attack them. Immunotherapies such as checkpoint blockade, therefore, need help. If you think of checkpoint blockade as taking the brakes off T cells, if T cells aren’t present, what would we be taking the brakes off? We don’t quite know which other treatments will help the most by generating an initial immune response, but we’re making progress.”

Patients with breast cancer enrolled in basket trials of checkpoint blockade monotherapy in many tumor types, indicating that such therapy might work in approximately 20% of patients with breast cancer. Recent findings from subsequent trials with larger numbers of patients with breast cancer suggested the true response rate may be much lower.

In the KEYNOTE-086 study of pembrolizumab (Keytruda) in metastatic triple-negative breast cancers (TNBCs), patients were seperated into 2 cohorts. Cohort A¹consisted of 170 women with previously treated disease, only 1 woman who had achieved a complete response, and 8 women who had achieved any sort of response (ORR, 4.7%; 95% CI, 2.3%-9.2%).

ORR did not vary significantly for women whose tumors expressed PD-L1 (ORR, 4.8%) and those whose tumors did not (ORR, 4.7%). Figures were dramatically lower than those in the KEYNOTE-012 basket trial,²reporting responses for 5 of 32 patients with heavily pretreated TNBC (ORR, 18.5%) and stable disease in another 7 patients. For cohort B of KEYNOTE-086,³pembrolizumab was administered as first-line therapy to 84 patients whose metastatic TNBC expressed PD-L1, finding an ORR of 23%.

Similar results from a monotherapy trial of atezolizumab (Tecentriq)⁴were found, both in actual response rates and in the fact that pretreated patients were far less likely to respond than patients who were previously untreated. In the 115 women with TNBC, ORR was 10%. There were also high levels of PD-L1 expression (defined as ≥5% positive immune-infiltrating cells) which improved that figure, but the real predictor of response appeared to be previous treatment.

ORR was 26% in the 19 women whose cancers were previously untreated (95% CI, 9%-51%) while the ORR was 7% in the 93 women who had already tried at least 1 other treatment prior (95% CI, 2%-14%). Those who did respond to treatment tended to haver durable responses (median duration, 21.1 months). All responders, with the exception of only 11% as nonresponders, were still alive after 2 years. Median survival for the entire patient population in the trial was only 9.3 months which is about a normal survival rate for untreated patients.

However, trials combining checkpoint blockades with other medications have found higher response rates with a combination of pembrolizumab (Keytruda) while eribulin (Halaven)⁵has produced a 26.4% ORR in 106 patients with metastatic TNBC who enrolled in the ENHANCE1/KEYNOTE-150 phase Ib/II trial. The ORR was similar among the 65 untreated patients (29.2%; 95% CI, 18.6%-41.8%) and the 41 patients who had received 1 or 2 prior therapies (22.0%; 95% CI, 10.6%-37.6%). Previously treated women responded slightly better than treatment-naïve women who responded. There was a total median overall survival (OS) of 17.7 months (95% CI, 13.7-not estimable).

It’s possible that some responders have responded to chemotherapy alone rather than with the combination of immunotherapy and chemotherapy, but Mittendorf sees plenty of reason to believe that chemotherapy makes checkpoint blockade more effective.

High doses of strong chemotherapies can severely weaken immune systems, particularly when administered with steroids. However, recent research demonstrates that many chemotherapies have the opposite effect. Many common chemotherapies increase immune response against cancer by altering dying tumor cells in ways that make them visible to the immune system, which reducses the ability of tumors to suppress the immune system and stimulate T cells or other effector cells both directly and indirectly. These effects would, in turn, seem likely to increase the effectiveness of checkpoint blockades and other immunotherapies.

Other types of medications can enhance the effects of immunotherapies, such as PARP inhibitors which can hinder proteins that repair single-strand DNA breaks and are vital to the survival of many fastgrowing cancers. When PARP inhibitors block those repairs, broken DNA gets passed on in cell reproduction and mistakes will multiply. If DNA degrades enough, the tumor cells die on their own, but a smaller increase in DNA mutations might be able to attract a response from the immune system.

This theory is supported by phase II findings from the MEDIOLA trial of the PARP inhibitor olaparib (Lynparza) and the PD-L1 blockade with durvalumab (Imfinzi)⁶where there was an ORR of 52% (95% CI, 31%-72%) among 25 patients withBRCA-mutated, HER2-negative metastatic breast cancer. The disease control rate (DCR) at 12 weeks was the trial’s primary endpoint. A DCR of 75% was considered a predetermined measure of success. The actual DCR was 80%. The data was not mature enough yet at time of analysis to determine progression-free survival, OS, and duration of response.

Combination with immunotherapy and inhibitors of cyclindependent kinases 4 and 6 (CDK4/6) are another option to be looked at. Shom Goel, PhD, MB, and colleagues published a paper inNature^7,showing that at least 1 of such compounds increased immunity to breast cancer and other tumor types.

“The enhanced antitumor immune response has 2 underpinnings,” the authors wrote. “First, CDK4/6 inhibitors activate tumor cell expression of endogenous retroviral elements, thus increasing intracellular levels of double-stranded RNA. This in turn stimulates production of type III interferons and hence enhances tumor antigen presentation. Second, CDK4/6 inhibitors markedly suppress the proliferation of regulatory T cells.”

The study found that checkpoint blockades rarely work against cold tumors, most likely because there are not enough T cells to do enough damage to the tumor if the medications succeed in making them attack. Research suggests a possible solution which is to make the tumor “hot.” A hot tumor is surrounded by cells sent out by the immune system— a large enough amount of cells to do actual damage if a checkpoint blockade inspired them to attack the tumor. Some chemotherapies have tendencies to do this, which may help explain why chemotherapy combinations produce so many more responses than immunotherapy alone in patients with breast cancer.

A significant interest has been identified in other strategies to initiate an immune response in breast tumors that can subsequently be reinforced with checkpoint blockade agents. Preclinical experiments have shown that radiation can also attract an immune response. Experience in patients has been limited to date, but that’s about to change. A meta-analysis published in 2017 reported that there were more than 50 ongoing trials designed to evaluate the combination of radiation and some sort of checkpoint inhibitor.⁸

Cryoablation is another strategy investigators are looking at for making cold tumors hot. Research in the lab has demonstrated that the process of injecting tumors with freezing gas damages surviving cancer cells enough to attract a large number of immune cells. A pilot study of this strategy used a single dose of ipilimumab (Yervoy) and/or cryoablation in 19 patients with breast cancer who planned on having mastectomies.⁹

Preoperative cryoablation was given to 7 patients, ipilimumab to 6 patients, and both to the remaining 6 patients. It was noted that the individual treatments proved safe both as monotherapies and in combination. In regard to the effects of the combination, authors wrote, “Potentially favorable intratumoral and systemic immunologic effects were observed with the combination, suggesting the possibility for induced and synergistic antitumor immunity with this strategy.”

Investigators are looking at another experimental option for making cold tumors hot: cancer vaccines. As director of the Breast Immuno-Oncology Program at Dana-Farber/Brigham and Women’s Cancer Center, Mittendorf is currently working with a HER2-derived peptide vaccine. This vaccine stimulates both a direct immune attack against breast cancer while also increasing the efficacy of immune checkpoint blockade agents. Experimental vaccines are being looked at by a number of research teams.

Some investigators believe that the phase III IMpassion130 trial may realistically change treatment strategies in the next year. This study looks at atezolizumab and nab-paclitaxel (Abraxane) with the expectation of reporting preliminary results later this year. The early-stage trial tested the combination against heavily treated TNBC, but IMpassion130 is using the combination as a first-line therapy, expecting a possible change in the standards of care for patients with newly diagnosed TNBC.

“If response in that larger trial matches response in the early-stage trials, it could lead to a change in the therapies we offer patients with metastatic TNBCs,” said Mittendorf.

References:

1. Adams S, Schmid P, Rugo HS, et al. Phase 2 study of pembrolizumab (pembro) monotherapy for previously treated metastatic triple-negative breast cancer (mTNBC): KEYNOTE-086 cohort A.J Clin Oncol35, 2017 (suppl; abstr 1008).. meetinglibrary.asco.org/record/153044/abstract.
2. 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.
3. Adams S, Loi S, Toppmeyer DL, et al. KEYNOTE-086 cohort B: pembrolizumab monotherapy for PD-L1—positive, previously untreated, metastatic triple-negative breast cancer (mTNBC). Abstract presented at: 2017 San Antonio Breast Cancer Symposium; December 5-9, 2017; San Antonio, TX. Abstract PD6-10. 23.
4. Schmid P, Cruz C, Braiteh FS, et al. Atezolizumab in metastatic triplenegative breast cancer: long-term clinical outcomes and biomarker analyses. Abstract presented at: AACR Annual Meeting 2017; April 1-5, 2017; Washington, DC. Abstract 2986. cancerres.aacrjournals.org/content/77/13_Supplement/2986.
5. Encouraging Updated Results from Phase 1b/2 Study Evaluating the Combination of Eribulin Mesylate and Pembrolizumab in Patients with Metastatic Triple-Negative Breast Cancer Presented at the 2017 SABCS [news release]. Woodcliff Lake, NJ: Eisai, PR Newswire; December 8, 2001. https://www.prnewswire.com/news-releases/ encouraging-updated-results-from-phase-1b2-study-evaluating-thecombination-of-eribulin-mesylate-and-pembrolizumab-in-patientswith-metastatic-triple-negative-breast-cancer-presented-at-the2017-sabcs-300568801.html.
6. Domchek SM, Postel-Vinay S, Bang Y-J, et al. An open-label, multitumor, phase II basket study of olaparib and durvalumab (MEDIOLA): Results in germline BRCA-mutated (gBRCAm) HER2-negative metastatic breast cancer (MBC). Presented at: the 2017 San Antonio Breast Cancer Symposium; Dec. 5-9, 2017. Abstract PD6-11.
7. Goel S, DeCristo MJ, Watt AC, et al. CDK4/6 inhibition triggers antitumour immunity.Nature.2017;548(7668):471-475. doi: 10.1038/nature23465.
8. Kang J, Demaria S, Formenti S. Current clinical trials testing the combination of immunotherapy with radiotherapy.J Immunother Cancer.2016;4:51. doi: 10.1186/s40425-016-0156-7.
9. McArthur HL, Diab A, Page DB, et al. A pilot study of preoperative single-dose ipilimumab and/or cryoablation in women with early-stage breast cancer with comprehensive immune profiling.Clin Cancer Res.doi: 10.1158/1078-0432.CCR-16-0190.