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A pair of trials that used checkpoint inhibitors as monotherapy reported lackluster overall response rates in breast cancer.
Elizabeth A. Mittendorf, MD, PhD
Recent immunotherapy trials have produced mixed results in patients with breast cancer. A pair of trials that used checkpoint inhibitors as monotherapy reported lackluster overall response rates (ORRs). Trials that paired immunotherapy with chemotherapy, on the other hand, fared better, and there are promising hints that immunotherapies combined with some targeted agents might also 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 will review the most important data to emerge recently in a presentation entitled “Breast Cancer Immunotherapy Update,” at the Miami Breast Cancer Conference®.
“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.”
Initial analyses of patients with breast cancer enrolled in basket trials of checkpoint blockade monotherapy in many tumor types indicated that such therapy might work in approximately 20% of patients with breast cancer. More recent results from subsequent trials with larger numbers of patients with breast cancer suggest that the true response rate is far lower.
The KEYNOTE-086 study of pembrolizumab (Keytruda) in metastatic triple-negative breast cancers (TNBCs) divided patients into 2 cohorts. In cohort A1 , which consisted of 170 women with previously treated disease, only 1 woman achieved a complete response and only 8 women achieved any sort of response (ORR, 4.7%; 95% CI, 2.3%-9.2%). That rate did not vary significantly for women whose tumors expressed PD-L1 (ORR, 4.8%) and those whose tumors did not (ORR, 4.7%). Such figures were dramatically lower than those in the KEYNOTE-012 basket trial2 , which had reported responses for 5 of 32 patients with heavily pretreated TNBC (ORR, 18.5%) and stable disease in another 7 patients. In cohort B of KEYNOTE-0863, which administered pembrolizumab as first-line therapy to 84 patients whose metastatic TNBC expressed PD-L1, the ORR was 23%.
Results from a monotherapy trial of atezolizumab (Tecentriq)4 were similar, both in actual response rates and in the fact that pretreated patients were far less likely to respond than patients who were treatment naïve. Among 115 women with TNBC, ORR was 10%. High levels of PD-L1 expression (defined as ≥5% positive immune-infiltrating cells) improved that figure, but the real predictor of response was previous treatment. The ORR was 26% among the 19 women whose cancers were treatment naïve (95% CI, 9%-51%) and 7% among the 93 women who had already tried at least 1 other treatment (95% CI, 2%-14%). Those who did respond to treatment tended to enjoy durable responses (median duration, 21.1 months). All responders, but only 11% of nonresponders, were still alive after 2 years. Median survival for the whole patient population was just 9.3 months, roughly normal for untreated patients.
Trials that combine checkpoint blockades with other medications, on the other hand, have produced higher response rates with a combination of pembrolizumab (Keytruda) and eribulin (Halaven)5 produced a 26.4% ORR in 106 patients with metastatic TNBC who took part in the ENHANCE1/KEYNOTE-150 phase Ib/II trial. The ORR, moreover, 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 who responded fared slightly better than treatment-naïve women who responded. Total median overall survival (OS) was 17.7 months (95% CI, 13.7-not estimable).
In immunotherapy and chemotherapy combination trials to date, it’s possible that some responders have responded to chemotherapy alone rather than the combination, but Mittendorf sees plenty of reason to believe that chemotherapy makes checkpoint blockade more effective.
High doses of strong chemotherapies, particularly when administered with steroids, can severely weaken immune systems, but recent research has shown that many chemotherapies have the opposite effect. Indeed, many common chemotherapies actually increase immune response against cancer by altering dying tumor cells in ways that make them visible to the immune system, reducing the ability of tumors to suppress the immune system and stimulating T cells and other effector cells both directly and indirectly. All 3 of these effects, moreover, would seem likely to increase the effectiveness of checkpoint blockades and other immunotherapies.
Other types of medications might enhance the effects of immunotherapies. For example, PARP inhibitors 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 multiply. If DNA degrades enough, the tumor cells die on their own, but a much smaller increase in DNA mutations might be enough to attract a response from the immune system.
That 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)6 . The ORR was 52% (95% CI, 31%-72%) among 25 patients with BRCA-mutated, HER2-negative metastatic breast cancer. Disease control rate (DCR) at 12 weeks was the trial’s primary endpoint. The predetermined measure of success was a DCR of 75%. The actual DCR was 80%. Data for progression-free survival, OS, and duration of response were not yet mature at the time of the analysis.
Another good candidate for use in combination with immunotherapy might be inhibitors of cyclindependent kinases 4 and 6 (CDK4/6). A paper from Shom Goel, PhD, MB, and colleagues published in Nature7 demonstrated that at least 1 such compound increases immunity to breast cancer and other tumor types. “The enhanced antitumor immune response has 2 underpinnings,” the study 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.”
Checkpoint blockades rarely work against cold tumors, most likely because there are not enough T cells nearby to do much damage to the tumor if the medications succeed in making them attack. Research suggests a possible solution: making the tumor “hot.” A hot tumor is surrounded by and riddled with cells sent out by the immune system— enough cells to do real damage if a checkpoint blockade inspired them to attack the tumor. The tendency of some chemotherapies to do this may help explain why chemotherapy combinations produce so many more responses than immunotherapy alone in patients with breast cancer.
There is significant interest in identifying 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
Other investigators are researching another strategy for making cold tumors hot: cryoablation. Work in the lab has shown 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 Investigators gave preoperative cryoablation to 7 patients, ipilimumab to 6 patients, and both to the remaining 6 patients. The investigators noted that the individual treatments proved safe both as monotherapies and in combination. As for the effect of the combination, they 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.”
Cancer vaccines are another experimental strategy for making cold tumors hot. Mittendorf, who is the director of the Breast Immuno-Oncology Program at Dana-Farber/Brigham and Women’s Cancer Center, is working with a HER2-derived peptide vaccine that both stimulates direct immune attack against breast cancer and could increase the efficacy of immune checkpoint blockade agents. Other research teams are working with experimental vaccines.
While many trials investigating these strategies are in the earliest phases, one study that could realistically change treatment strategies in the next year is the phase III IMpassion130 study of atezolizumab and nab-paclitaxel (Abraxane), which could begin reporting some preliminary results later this year. Unlike the early-stage trial, which tested the combination against heavily treated TNBC, IMpassion130 uses it as first-line therapy that could change 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, who is also giving a presentation, titled “Making Cold Tumors Hot.”