Neoadjuvant pembrolizumab benefits patients with high-risk triple-negative breast cancer
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SAN ANTONIO — The addition of pembrolizumab to neoadjuvant chemotherapy and as adjuvant therapy increased pathologic complete response among patients with high-risk triple-negative breast cancer, according to results of the KEYNOTE-522 trial presented at San Antonio Breast Cancer Symposium.
These included patients with stage IIIa or stage IIIb disease, as well as those with lymph node involvement.
“That is fantastic news for these very high-risk groups who, unfortunately, have a relatively poor prognosis,” Peter Schmid, MD, PhD, FRCP, clinical director of St. Bartholomew Breast Cancer Centre in London and lead of the Centre for Experimental Cancer Medicine at Barts Cancer Institute, told Healio. “We see a substantial benefit, with a difference in pathologic complete response of 20 [percentage points] among node-positive patients and up to 25 [percentage points] in patients with stage III disease. To me, that is a massive result.”
Triple-negative disease is the most aggressive breast cancer subtype. It accounts for about 15% of breast cancer cases and disproportionately affects young women.
Neoadjuvant chemotherapy followed by surgery offers the greatest chance for pathologic complete response.
Taxane- and anthracycline-based chemotherapy induce pathologic complete response rates of approximately 40%, and the addition of platinum agents can increase that rate to about 50%, according to study background. Meta-analyses have shown a strong association between pathologic complete response after neoadjuvant chemotherapy and improved long-term outcomes, including EFS (HR = 0.24) and OS (HR = 0.16).
“There continues to be a significant need for new regimens that can increase the pathologic complete response rate and increase long-term EFS for patients with triple-negative breast cancer,” Schmid said.
In the placebo-controlled KEYNOTE-522 trial — the first phase 3 trial to evaluate immunotherapy for early breast cancer — researchers evaluated the combination of the anti-PD-1 monoclonal antibody pembrolizumab (Keytruda, Merck) and chemotherapy followed by adjuvant pembrolizumab.
The analysis included 1,174 adults with previously untreated, nonmetastatic, centrally confirmed triple-negative breast cancer. All patients had stage T1c N1-2 or T2-4 N0-2 disease.
Researchers assigned 784 patients to 200 mg pembrolizumab every 3 weeks in combination with neoadjuvant chemotherapy (four cycles of paclitaxel and carboplatin, followed by four cycles of doxorubicin or epirubicin plus cyclophosphamide).
The other 390 patients chemotherapy plus placebo.
All patients underwent definitive surgery and received radiation therapy as indicated. After that, depending on randomization, they received adjuvant pembrolizumab or placebo. Adjuvant treatment continued for up to nine cycles, or until disease recurrence or unacceptable toxicity.
Pathologic complete response — defined as ypT0/Tis ypN0, meaning clearance of the cancer from the breast after chemotherapy — and EFS served as dual primary endpoints.
Secondary endpoints included OS, efficacy in the subset of patients with PD-L1-positive disease and additional measurements of pathologic complete response.
Schmid presented results of the definitive pathologic complete response analysis at this year’s European Society for Medical Oncology Congress.
That analysis included 602 evaluable patients and median follow-up of 15.5 months (range, 2.7-25).
Results revealed a statistically significant improvement in pathologic complete response rate with pembrolizumab plus chemotherapy in the entire population (64.8% vs. 51.2%; P = .00055), the subgroup of patients with PD-L1-positive disease (68.9% vs. 54.9%) and the subgroup of those with PD-L1-negative disease (45.3% vs. 30.3%).
In San Antonio, Schmid presented results of the first preplanned interim analysis for EFS. The analysis, also based on 15.5 months of follow-up, included 1,174 patients.
Results showed numerically superior 18-month EFS among patients assigned pembrolizumab (91.3% vs. 85.3%; HR = 0.63; 95% CI, 0.43-0.93). However, the difference did not reach statistical significance based on the precalculated boundary (P = .000051; HR < 0.4).
Schmid also presented pathologic complete response results based on multiple patient characteristics.
An analysis by disease stage showed the benefit with pembrolizumab persisted among patients with stage IIa (73.1% vs. 62.1%), stage IIb (86.2% vs. 48.4%), stage IIIa (66.7% vs. 42.1%) and stage IIIb (48.6% vs. 23.1%) disease.
Researchers observed an improvement in pathologic complete response with the pembrolizumab regimen among patients with node-negative disease (64.9% vs. 58.6%) and node-positive disease (64.8% vs. 44.1%).
“Who would’ve thought we would have achieved a 20 or 25 [percentage point] delta?” Schmid said. “If you had told me that a year ago, I would have said ‘wow.’ I still say ‘wow.’
“Think about what pathologic complete response means from a patient perspective,” Schmid added. “If you have to tell them that, unfortunately, there is still residual cancer left, unfortunately their recurrence risk is pretty high. Being able to give good news to this many more patients makes a huge difference.”
An analysis of pathologic complete response by PD-L1 expression level showed benefits among with pembrolizumab among patients with combined positive scores less than 1 (45.3% vs. 30.3%), 1 or higher (68.9% vs. 54.9%), 10 or higher (77.9% vs. 59.8%) and 20 or higher (81.7% vs. 62.5%).
“Everyone was intrigued by the results we showed at ESMO demonstrating benefit among patients with PD-L1-positive and PD-L1-negative disease,” Schmid told Healio. “We wanted to see if most of that benefit was driven by very inflamed tumors but, actually, you see a consistent benefit across all subsets. This gives us more confidence that what we see in PD-L1-negative tumors is, in fact, real, and PD-L1 staining doesn’t seem to make any difference in the early setting.”
An exploratory analysis showed the pathologic complete response benefit with pembrolizumab also persisted regardless of whether patients received full exposure to chemotherapy (69.7% vs. 55.3%) or less than full exposure (51.1% vs. 35.7%).
“We’re not impacting the delivery of full chemotherapy. We’re adding a checkpoint inhibitor, and that is an important point,” Schmid told Healio. “But if you are unable to give a full dose of chemotherapy because of side effects, optimal response, patient request or other factors, we still see a benefit for those patients from adding pembrolizumab, and that is an encouraging result.”
The pembrolizumab regimen also was associated with a higher rate of patients achieving residual cancer burden scores of 0 or 1.
Immune-mediated adverse event rates continued to appear consistent with known profiles of each regimen, and researchers observed no new safety concerns. The results continue to indicate this is a well-tolerated therapy, Schmid said.
“Our results suggest that adding pembrolizumab to neoadjuvant chemotherapy is beneficial for patients with the most aggressive disease and the highest unmet need,” Schmid said. “I think the results have the potential to be practice-changing.” – by Mark Leiser
Reference:
Schmid P, et al. Abstract GS3-03. Presented at: San Antonio Breast Cancer Symposium; Dec. 10-14, 2019; San Antonio.
Disclosures: Merck Sharp & Dohme sponsored this study. Schmid reports research funding from Astellas, AstraZeneca, Genentech/Roche, Medivation, Novartis and OncoGenex Pharmaceuticals. He also reports honoraria or consultant fees from AstraZeneca, Bayer, Boehringer Ingelheim, Celgene, Eisai, Merck, Novartis, Pfizer, Puma Biotechnology and Roche. Please see the abstract for all other authors’ relevant financial disclosures.
Perspective
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C. Kent Osborne, MD
This study looks very promising and I think it’s going to be practice changing for patients with triple-negative breast cancer. Immunotherapy is still young in breast cancer. It’s not quite as far along as it is in other cancers like melanoma or lung cancer, so we have a ways to go and we have a lot to learn. But we are seeing some promising data that this is going to be a new treatment for our patients. The question is: Can we identify those who will benefit the most? But this is more evidence that immunotherapy will have a role in breast cancer management.
We have been focused so far on checkpoint inhibitors in triple-negative disease, but a number of us think there is a subgroup of ER-positive breast cancers that also may benefit. The trick is to find out which ones they are and what to combine the checkpoint inhibitor with. ER-positive tumors tend to be cold tumors, meaning there are not a lot of tumor-infiltrating lymphocytes in them. But there are new drugs and new techniques that may cause that cold tumor to become a hot tumor, so there are a lot of new things going on that are very intriguing, and we are just in the infancy in understanding immunotherapy in breast cancer.
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Jame Abraham, MD, FACP
The response rate in this trial was pretty impressive. It’s almost like the response rates we see with HER2-targeted agents. In addition, the side effects were manageable, so I think this will definitely change practice. Follow-up for EFS results was short, but if you believe in complete response being a predictor for long-term outcomes, such as OS, it should translate. I think we are beginning to get more questions answered about immunotherapy’s role in breast cancer. We have already seen the benefit of atezolizumab (Tecentriq, Genentech) for patients with PD-L1-positive, metastatic triple-negative breast cancer. KEYNOTE-522 was slightly different because both the PD-L1-positive and PD-L1-negative subgroups benefitted with pembrolizumab. Although much of the data are emerging from triple-negative disease, there are a number of trials looking at HER2-positive and ER-positive disease. Finally, breast cancer is beginning to catch up with other cancer types, so that is great news for our patients.
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Kevin Kalinsky, MD, MS
One of the most intriguing findings from these data is that the delta in pathologic complete response with the addition of pembrolizumab compared with chemotherapy alone is higher among patients with node-positive disease than in the node-negative cohort.We need to consider whether this is a differential effect in terms of the immune-priming phase in the lymph nodes with the addition of checkpoint inhibition.
Researchers also showed a higher pathologic complete response among those with stage III disease than stage II disease in a post-hoc analysis. It is exciting to see improvement in pathologic complete response. It also is exciting to see an early readout of EFS, although this does require additional maturity.
This regimen does not have regulatory approval at this time, but I do think it has the potential to be practice changing for some patients. However, we really need a predictor for checkpoint inhibitor response. PD-1 positivity seems to reflect benefit both with the combination and with chemotherapy alone, so it’s really showing a benefit from neoadjuvant chemotherapy but it’s not showing who benefits from checkpoint inhibition. In the absence of that, the risk-benefit ratio seems to be highest for those with high clinical risk. We need to continue to be aware of long-term toxicities — including potentially permanent toxicities — for those with curable disease.
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