Clinical trials continue to demonstrate that combining immunotherapy with chemotherapy and other targeted therapies can improve survival for patients with triple-negative breast cancer, according to results presented at the 21st Annual Lynn Sage Breast Cancer Symposium in Chicago. Nearly 700 physicians and other health professionals attended the symposium, hosted by the Robert H. Lurie Cancer Center of Northwestern University.
“The future is going to be in combination strategies,” said Rita Nanda, MD, Associate Professor of Medicine and Director of the Breast Oncology Program at the University of Chicago, in concluding a review of immunotherapy for breast cancer.1
Rita Nanda, MD
Hope S. Rugo, MD, FASCO
After describing “exciting new treatment approaches to triple-negative breast cancer,” including “new targets, new toxins,” Hope S. Rugo, MD, FASCO, said, “Everything can be combined with immunotherapy, and it might be better.”2 Dr. Rugo is Professor of Medicine and Director of Breast Oncology and Clinical Trials Education at the University of California, San Francisco (UCSF) Helen Diller Family Comprehensive Cancer Center.
Checkpoint Inhibitors in Advanced Breast Cancer
Previous trials have shown “modest response rates with checkpoint inhibitor monotherapy,” Dr. Nanda reported. Response rates in advanced breast cancer range from 2.8% to 8.6% with avelumab and 4.7% to 23.0% with pembrolizumab, and in triple-negative disease specifically, 10% to 26% with atezolizumab. The highest response rates to monotherapy have occurred in patients with triple-negative breast cancer who have not received treatment in the advanced setting and have tumors characterized by high levels of tumor-infiltrating lymphocytes.
“There is a trend toward improvement in overall survival patients with advanced [programmed cell death ligand 1] (PD-L1)-positive triple-negative disease, but it is certainly not a reliable biomarker of who is going to respond to therapy,” Dr. Nanda noted. “There is a stronger correlation with tumor-infiltrating lymphocytes and overall survival in those treated with anti–[programmed cell death protein 1] (PD-1)/PD-L1 therapy alone.”
“What we have learned from the two large monotherapy studies of pembrolizumab and atezolizumab is that the line of therapy matters,” Dr. Nanda said. The response rate “drops off dramatically,” from 26% for first-line atezolizumab to 6.8% for second-line atezolizumab, and from 23% for first-line pembrolizumab to 4.7% for second-line pembrolizumab. “This front-line response rate is comparable to what we see with chemotherapy in this setting. Where immunotherapy is remarkably different from chemotherapy is in the durability of response,” she noted.
“We really are making progress, but not everybody is going to benefit from the checkpoint inhibitors,” Dr. Rugo said. “We know to start them early, but we don’t know who is going to respond to a checkpoint inhibitor.”
Chemotherapy Combinations in Advanced Breast Cancer
The modest response to checkpoint inhibitors has raised interest in looking at combination strategies. The IMpassion130 study3 found that patients with metastatic or inoperable locally advanced PD-L1–positive triple-negative breast cancer who received nab-paclitaxel with atezolizumab had about a 10-month improvement in overall survival compared with those who had chemotherapy alone, Dr. Nanda said. The results cannot be assessed for statistical significance given the statistical design of the trial, and more results are expected as the data mature. Atezolizumab/nab-paclitaxel is currently FDA-approved for PD-L1–positive metastatic triple-negative breast cancer.
Dr. Nanda also described studies testing anti-PD-1/PD-L1 therapy in combination with chemotherapy for triple-negative breast cancer. The TONIC trial assessed no induction therapy or induction therapy with cyclophosphamide, cisplatin, doxorubicin, or radiotherapy followed by durvalumab; it showed the numerically highest response rates with doxorubicin induction therapy. Another small study by Page et al demonstrated promising efficacy for the combination of capecitabine and pembrolizumab.
“Chemotherapy combined with immunotherapy is the new standard of care treatment for PD-L1-positive, triple-negative breast cancer, but we know that a large proportion of patients still do not respond to these therapies, and a number of combination studies are ongoing focusing on strategies to improve response rates to immunotherapy-based treatment,” Dr. Nanda stated.
Checkpoint Inhibitors in the Neoadjuvant Setting
“Standard neoadjuvant chemotherapy with taxane- and anthracycline-based chemotherapy has a pathologic complete response rate of about 35%,” Dr. Nanda said. The I-SPY 2 randomized phase II trial evaluated the checkpoint inhibitor pembrolizumab with a standard taxane followed by anthracycline-based chemotherapy. “One of the arms of this ongoing trial added four cycles of pembrolizumab to the taxane portion of chemotherapy, followed by anthracycline-based chemotherapy alone,” Dr. Nanda reported. “We found this approach was very active for triple-negative disease, and we were also pleasantly surprised to see activity in patients with high-risk, hormone receptor–positive disease,” with a near doubling of pathologic complete response rates in both subtypes.
Building on the success of the I-SPY 2 trial, the KEYNOTE-522 phase III trial randomly assigned patients with early-stage, triple-negative breast cancer to treatment with chemotherapy with pembrolizumab vs placebo. Pembrolizumab was given for the complete duration of chemotherapy and then continued for 27 weeks in the adjuvant setting. Trial results, recently presented at the European Society for Medical Oncology Annual Congress, showed improvement in the pathologic complete response rate from 51% in the control arm to 65% in the pembrolizumab arm, regardless of PD-L1 status—“these results are likely to be practice-changing in the not too distant future,” Dr. Nanda commented.
Trial results also serve as a reminder “that immunotherapy drugs have unique toxicities that we need to monitor, even after patients have completed their therapy, as some of these toxicities can present months after therapy has been completed,” Dr. Nanda said.
“Probably the most important role for platinum is as an anthracycline-sparing [agent] for poor responders,” Dr. Rugo noted. “We would like to get rid of anthracyclines if we could.” Although the KEYNOTE-522 study showed a high pathologic complete response rate, “we have seen higher [response rates] overall, regardless of the setting, when you add platinum to a taxane/anthracycline–based regimen. There is increased toxicity, some reduced delivery of taxane and anthracyclines, depending on the way you use carboplatin,” she said, “and no clear impact on long-term outcome when combined with standard chemotherapy.”
Other studies have been small and used a different regimen or endpoints. “Some countries use carboplatin as their standard,” Dr. Rugo noted. “In the United States, it has been much more variable, and I generally use it with poor responders. But this is going to become a much more acute decision-making issue in the next few months and next year.”
PARP Inhibitors
The poly (ADP-ribose) polymerase (PARP) inhibitor olaparib was tested in both the OlympiAD and the MEDIOLA trials.4,5 “There is some suggestion in the OlympiAD trial that survival differences might be seen in the first-line patients,” Dr. Rugo noted, and then the acquisition of resistance results in less benefit. “You want to try to give it as early as possible, keeping in mind the data we have.”
In the MEDIOLA trial, olaparib monotherapy followed by olaparib plus durvalumab produced an overall response rate of 63% among 30 patients, half with BRCA1, half with BRCA2 mutations. “When you compare that with the OlympiAD randomized phase III data for those patients who got olaparib monotherapy, it was a pretty comparable response rate. So, it doesn’t appear that there was dramatic synergy,” Dr. Nanda said. “But when you look at the duration of response, with PARP inhibitor monotherapy, it was 6.4 months vs 9.2 months” with the combination strategy. “It will be interesting to follow these patients out farther,” she added, “to see if the PARP inhibitor potentially has augmented progression-free survival.”
Although PARP inhibitors have some hematologic and gastrointestinal (GI) toxicities, “most people tolerate them very well,” Dr. Rugo remarked.
The BROCADE 3 trial randomly assigned 513 patients with hormone receptor–positive triple-negative breast cancer to treatment with carboplatin/paclitaxel, with or without veliparib.6 “Veliparib appears to be a little less strong as a PARP inhibitor, and it causes less bone marrow toxicity,” Dr. Rugo said. Progression-free survival, the study’s primary endpoint, was 14.5 months for those who received veliparib vs 12.6 months for those who did not. The difference was greater for time to second disease progression among the patients receiving veliparib—21.3 months vs 17.4 months, with a hazard ratio of 0.76. Progression-free survival rates are “markedly different” at 36 months, 26% with veliparib vs 11% without, Dr. Rugo said. “Maybe the PARP inhibitor added to the chemotherapy is actually changing the microenvironment of the cancer, but certainly something is changing, because the [time to second progression] is even longer than the [time to first progression]. We need more follow-up. Overall survival is still early.”
MEK and AKT Pathways
The MEK pathway is active in triple-negative breast cancer, Dr. Nanda noted, and combining MEK inhibitors with anti–PD-1/PD-L1 agents may improve antigen presentation and block PD-L1–mediated suppression. In the phase II COLET study of the MEK inhibitor cobimetinib with atezolizumab and either paclitaxel or nab-paclitaxel, PD-L1–positive patients had response rates of 44% with the paclitaxel combination vs 33% with nab-paclitaxel.7 The corresponding rates for patients whose disease was not positive for PD-L1 were 11% and 27%, respectively.
Dr. Rugo said that studies looking at MEK inhibitors in triple-negative breast cancer had “some encouraging activity” and urged symposium participants to “stay tuned” for results of trials with MEK inhibitors in combination with other therapies.
Other agents are aimed at the AKT pathway. “Deficient expression of PTEN is common in triple-negative breast cancer and is associated with a higher degree of AKT pathway activation,” Dr. Rugo noted. “Two phase II randomized trials looked at first-line paclitaxel with an AKT inhibitor vs placebo. The two different AKT inhibitors that were used were ipatasertib and capivasertib.”
Although the intent-to-treat data were not especially encouraging, “a small subset of patients had alterations in the PIK3CA/AKT1/PTEN pathway, and there was a suggestion of overall survival benefit in that group of patients,” Dr. Rugo said. These newer agents “do cause GI toxicity with diarrhea as expected but are more tolerable and manageable than the previous generation of AKT inhibitors.”
“Probably the most important role for platinum is as an anthracycline-sparing [agent] for poor responders. We would like to get rid of anthracyclines if we could.”— Hope S. Rugo, MD, FASCO
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Antibody-Drug Conjugates in Triple-Negative and HER2-Positive Disease
Antibody-drug conjugates represent a new class of highly potent anticancer drugs, Dr. Rugo said. “The idea is, you have an antibody that is highly selective for a tumor-associated antigen, one that is not highly expressed on normal, healthy cells. The cytotoxic agent can’t be a toxin that the patients have already received, because it won’t work, and it has to have a big bang for the buck,” she explained. The agent is so toxic that it can’t be administered alone but is just a small amount attached to the antibody. Targeted cell death occurs with internalization and release into the tumor cell.
One antibody-drug conjugate has been approved for breast cancer, trastuzumab emtansine (T-DM1) for HER2-positive disease, and more are in development, Dr. Rugo noted. These agents include sacituzumab govitecan, a novel topoisomerase inhibitor thought to block DNA replication, which contains SN-38, the active metabolite of irinotecan. “Due to the unique cleavable linker, SN-38 is released in tumors both intracellularly and in the tumor microenvironment, allowing for delivery of therapeutic concentrations of the drug in tumors. Sacituzumab-bound tumor cells are killed by intracellular uptake of SN-38; adjacent tumor cells are killed by extracellular release of SN-38,” Dr. Rugo reported.
In a phase I/II trial of 108 patients with refractory triple-negative breast cancer, the confirmed overall response rate with sacituzumab govitecan-hziy was 33.3%, “which is really exciting,” Dr. Rugo commented. “The duration of the response was very good, 7.7 months, and progression-free survival was 5.5 months. The toxicity generally is tolerable, with neutropenia presenting the “biggest challenge.”7
Ladiratuzumab vedotin (SGN-LIV1A) was submitted for accelerated approval based on clinical data, “but the production is quite complex, and there are numerous questions,” Dr. Rugo said. “They are being addressed, and hopefully the drug will receive [U.S. Food and Drug Administration] approval sometime in the first half of next year.” In a phase I study of the drug in 60 patients with heavily pretreated metastatic triple-negative breast cancer, the overall response rate was 25%, and the recommended phase II dose response rate was 34.6%.
“Trastuzumab deruxtecan (DS-8201a/T-DXd) has shown remarkable response rates in patients with HER2-positive disease, as well as in patients with HER2-low disease,” Dr. Rugo said. “The major issue has been with lung disease, including fatalities,” she noted, although monitoring and early intervention can reduce the risk. More commonly occurring adverse events in patients with breast cancer were nausea (79.4%), anorexia (54.1%), and alopecia (46.5%).
“The whole ideas behind T-DXd if you don’t have HER2-positive disease is the bystander effect—the drug leaks out and kills the neighboring cells. So, you don’t need as much HER2 to be expressed,” Dr. Rugo explained. “The clinical activity in HER2-low disease was pretty amazing. Almost all patients responded, and responses appeared to be quite durable.” ■
DISCLOSURE: Dr. Nanda has served on advisory boards for Aduro, AstraZeneca, Athenex, Celgene, Daiichi Sankyo, Genentech, MacroGenics, Merck, Novartis, Pfizer, Puma, and Syndax; a data safety monitoring board for G1 Therapeutics; and has received research funding from AstraZeneca, Celgene, Corcept Therapeutics, Genentech/Roche, Immunomedics, Merck, OBI Pharm, Odonate Therapeutics, Pfizer, and Seattle Genetics. Dr. Rugo has received institutional research funding from Daiichi Sankyo, Eisai, Genentech, Immunomedics, Lilly, MacroGenics, Merck, Novartis, OBI Pharma, Odonate Therapeutics, Pfizer, and Seattle Genetics as well as received travel expenses from Amgen, Mylan, Novartis, OBI Pharma, Pfizer, Puma Biotechnology, Roche/Genentech, and Sanofi.
REFERENCES
1. Nanda R: Immunotherapy for breast cancer: The future is now. 2019 Lynn Sage Breast Cancer Symposium. Presented October 5, 2019.
2. Rugo H: New options for patients with triple negative breast cancer. 2019 Lynn Sage Breast Cancer Symposium. Presented October 5, 2019.
3. Schmid P, Adams S, Rugo HS, et al: Atezolizumab and nab-paclitaxel in advanced triple-negative breast cancer. N Engl J Med 379:2108-2121, 2018.
4. Robson ME, Tung N, Conte P, et al: OlympiAD final overall survival and tolerability results. Ann Oncol 30:558-566, 2019.
5. Domchek S, Postel-Vinay S, Im S, et al: Phase II study of olaparib and durvalumab (MEDIOLA). Ann Oncol 30(suppl 5):v475-v532, 2019.
6. Dieras VC, Han HS, Kaufman H, et al: Phase 3 study of veliparib with carboplatin and paclitaxel in HER2-negative advanced/metastatic gBRCA-associated breast cancer. Ann Oncol 30(suppl 5):v851-v934, 2019.
7. Bardia A, Mayer IA, Vahdat LT, et al: Sacituzumab govitecan-hziy in refractory metastatic triple-negative breast cancer. N Engl J Med 380:741-751, 2019.
