What’s the Current Status of Neoadjuvant Immunotherapy?
For several tumor types, can the successes achieved with immunotherapy in the metastatic and adjuvant settings be replicated in the neoadjuvant setting? An explosion in clinical trials—with more than 300 listed on ClinicalTrials.gov—point to “yes.”
Elizabeth A. Mittendorf, MD, PhD
“The neoadjuvant use of immunotherapy is of great interest now that we’ve had such success in the metastatic setting,” said Elizabeth A. Mittendorf, MD, PhD, the Rob and Karen Hale Distinguished Chair in Surgical Oncology at Brigham and Women’s Hospital, Boston, and Director of the Breast Immuno-Oncology Program.
“We have approved indications in multiple tumor types. Now, we are interested in learning whether we can potentially benefit our early-stage patients by stimulating their immune systems,” she said.
Dr. Mittendorf moderated a session on neoadjuvant immunotherapy at the ASCO-SITC Clinical Immuno-Oncology Symposium.1 She summarized the main messages from the presentations in an interview with The ASCO Post.
Neoadjuvant Immunotherapy in Breast Cancer
“Breast cancer is a tumor type in which neoadjuvant therapy is commonly used, and we know that if a patient with breast cancer has a pathologic complete response, she will have an outstanding prognosis. The question is whether we can improve upon that with immunotherapy,” Dr. Mittendorf said.
The data on this strategy have been mixed, but the target seems valid. Compared with metastatic tumors, primary breast cancers have higher expression of programmed cell death ligand 1 (PD-L1) and have more tumor-infiltrating lymphocytes. Higher levels of PD-L1 and tumor-infiltrating lymphocytes are predictive of benefit with pembrolizumab in the metastatic setting, as described at a session by Sara M. Tolaney, MD, MPH, of Dana-Farber Cancer Institute.
Here are some of the somewhat discordant findings from trials of neoadjuvant therapy incorporating an anti–programmed cell death protein 1 (PD-1)/PD-L1 with standard chemotherapy:
- I-SPY 2: The addition of pembrolizumab almost tripled the rate of pathologic complete response in patients with triple-negative breast cancer—60% vs 20%—and in those with hormone receptor–positive breast cancer—34% vs 13%.2
- KEYNOTE-522: The addition of pembrolizumab increased pathologic complete response rates by approximately 14% and reduced events by 27%.3
- NeoTRIP: The addition of atezolizumab to a nonanthracycline chemotherapy backbone did not improve pathologic complete response rates.4
“As Dr. Tolaney said, we have lots of work to do in breast cancer to identify which patients will benefit most, since many will respond well to chemotherapy alone. Who needs the added toxicity of immunotherapy to get that increase in response?” Dr. Mittendorf asked. “We also want to know whether the choice of chemotherapy backbone matters, whether the timing or sequencing of chemotherapy matters, and whether it’s better to target PD-1 or PD-L1.”
Sara M. Tolaney, MD, MPH
Clinical trials are trying to answer these and other questions, including those pertaining to benefit in the adjuvant setting as well. The phase III SWOG S1418/NRG BR006 trial is evaluating adjuvant pembrolizumab in 1,000 patients with triple-negative breast cancer with residual disease or any positive nodes after standard neoadjuvant chemotherapy. The phase III Italian A-BRAVE trial is evaluating avelumab in 474 patients with high-risk triple-negative breast cancer after completion of curative-intent therapy.
To determine whether benefit extends to patients with estrogen receptor–positive disease, CheckMate 7FL is adding nivolumab to standard neoadjuvant chemotherapy and to adjuvant endocrine treatment as well. KEYNOTE-756 is determining the benefit of adding pembrolizumab to standard neoadjuvant chemotherapy, followed by adjuvant endocrine therapy with or without pembrolizumab.
Can inhibitors of cyclin-dependent kinases 4 and 6 contribute benefit? The randomized phase II CheckMate 7A8 trial is evaluating the addition of nivolumab to palbociclib with anastrozole.
Neoadjuvant Immunotherapy in Melanoma
Jennifer Wargo, MD
The work done in the neoadjuvant (non-immunotherapy) treatment of breast cancer has informed melanoma research, according to a specialist in this area, Jennifer Wargo, MD, of The University of Texas MD Anderson Cancer Center. Preclinical models of melanoma suggest that outcomes are better after neoadjuvant than adjuvant treatment, and encouraging rates of pathologic complete response have been emerging in clinical trials. “Much like what we see in breast cancer, melanoma researchers are seeing that patients who have a pathologic complete response have improved outcomes,” Dr. Mittendorf told The ASCO Post.
Dr. Wargo’s group first studied the use of neoadjuvant targeted therapy in patients with high-risk resectable melanoma with BRAF mutations; the experimental treatment was a BRAF inhibitor plus a MEK inhibitor for 8 weeks, followed by the same in the adjuvant setting.5 Along with a 58% rate of pathologic complete response, improvements were seen in event-free survival (hazard ratio [HR] = 0.016; P < .0001) and distant metastasis–free survival (HR = 0.025; P < .001) with targeted preoperative therapy vs standard-of-care surgery.
This success led to the evaluation of neoadjuvant dual checkpoint blockade (ipilimumab plus nivolumab) in patients with high-risk resectable melanoma, which showed higher response rates and improved recurrence-free survival over nivolumab monotherapy but a high rate of adverse events.6 Correlative studies showed an enrichment of B cells in responders, suggesting they might be important biomarkers for response and could potentially serve as targets.7
“Much like what we see in breast cancer, melanoma researchers are seeing that patients who have a pathologic complete response have improved outcomes.”— Elizabeth A. Mittendorf, MD, PhD
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The International Neoadjuvant Melanoma Consortium was recently formed to foster a better understanding of research findings. Their trial protocols include such strategies as preserving efficacy and reducing toxicity, understanding differences according to gender, and evaluating the need for lymph node dissection in patients with fully resected disease and pathologic complete response. Pooled analyses of cohorts from this consortium has shown that recurrence-free survival can exceed 80% at 3 years and even top 100% for exceptional responders.
Neoadjuvant Immunotherapy in Lung Cancer
Immunotherapy has revolutionalized the treatment of lung cancer in both the metastatic and adjuvant settings. “The question now is whether preoperative immunotherapy can increase the number of patients who could undergo surgery. Perhaps we could even get to the point where we don’t need surgery at all in patients with a very favorable immune response,” Dr. Mittendorf said.
Such possibilities are being widely studied, as more than 50 neoadjuvant immunotherapy trials—many phase III—are accruing in non–small cell lung cancer (NSCLC) alone, according to Patrick Forde, MD, of Johns Hopkins University, who presented the talk on lung cancer.
Patrick Forde, MD
One of the initial studies, coauthored by Dr. Forde, evaluated PD-1 blockade in 20 patients with NSCLC.8 Although there were few pathologic complete responses, nine patients achieved a major pathologic response (< 10% residual tumor) and just one patient experienced disease recurrence (and was successfully re-treated) by 3 years. Long-term, circulating tumor DNA was eliminated in patients with ongoing remission, and responders demonstrated a significant expansion of the top 1% of tumor-resident T-cell clonotypes, potentially driving an antitumor response.
The rate of pathologic complete response to neoadjuvant immunotherapy in NSCLC has averaged 24% in clinical trials, Dr. Forbes determined, further noting that this is higher than the average of 20% seen after treatment with neoadjuvant chemotherapy, with less toxicity. Of note, when nivolumab was added to neoadjuvant chemotherapy, a 74% major pathologic response rate was achieved in early (unpublished) findings from the NADIM II study (ClinicalTrials.gov identifier NCT03838159).
“In lung cancer, we saw a decade of advances from 2010 to 2020 in both targeted therapy and immunotherapy in advanced disease.”— Patrick Forde, MD
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The take-away points made by Dr. Forde are that neoadjuvant immunotherapy (with or without chemotherapy) appears tolerable and drives pathologic regression—an observation being further validated in multiple phase III trials. Current trials comparing neoadjuvant chemoimmunotherapy with chemotherapy alone include CheckMate 816, KEYNOTE-671, and IMpassion030. The AEGEAN study is comparing the anti–PD-L1 agent durvalumab with placebo; Other trials are employing novel designs and incorporating novel agents.
“In lung cancer, we saw a decade of advances from 2010 to 2020 in both targeted therapy and immunotherapy in advanced disease,” Dr. Forde said. “I hope and believe the 2020s will lead us to start to cure earlier-stage patients and prevent relapses.”
DISCLOSURE: Dr. Mittendorf has received honoraria from Physician Education Resource, has served as a consultant or advisor to Merck, Peregrine Pharmaceuticals, Sellas Life Sciences, and TapImmune Inc. Dr. Tolaney has served as a consultant or advisor to AbbVie, AstraZeneca, Bristol-Myers Squibb, Celldex, Eisai, G1 Therapeutics, Genentech, Immunomedics, Lilly, Merck, NanoString Technologies, Nektar, Novartis, Odonate, OncoPep, Paxman, Pfizer, Puma Biotechnology, Sanofi, Seattle Genetics, and Silverback Therapeutics; has received institutional research funding from AstraZeneca, Bristol-Myers Squibb, Cyclacel, Eisai, Exelixis, Genentech/Roche, Immunomedics, Lilly, Merck, NanoString Technologies, Nektar, Novartis, Odonate Therapeutics, and Pfizer; and has been reimbursed for travel, accommodations, or other expenses by AstraZeneca, Celldex, Eisai, Genentech/Roche, Immunomedics, Lilly, Merck, NanoString Technologies, Nektar, Novartis, Pfizer, and Puma Biotechnology. Dr. Wargo has served on the speakers bureau of Imedex, Dava, Omniprex, Illumina, Bristol-Myers Squibb and on the advisory boards of Roche/Genentech, GlaxoSmithKline, Novartis, and AstraZeneca; Dr. Wargo is co-inventor on a patent submitted by MD Anderson to the U.S. Patent and Trademark Office. Dr. Forde has served as a consultant or advisor to AbbVie, AstraZeneca/MedImmune, Bristol-Myers Squibb, and Janssen; and has received institutional research funding from AstraZeneca/MedImmune, Bristol-Myers Squibb, Corvus Pharmaceuticals, Kyowa Hakko Kirin, and Novartis.
1. Mittendorf EA (session moderator): Neoadjuvant trials: Early mobilization of the immune system. Panel discussion. 2020 ASCO-SITC Clinical Immuno-Oncology Symposium. Presented February 8, 2020.
2. Nanda R, Liu MC, Yau C, et al: Pembrolizumab plus standard neoadjuvant therapy for high-risk breast cancer: Results from I-SPY 2. 2017 ASCO Annual Meeting. Abstract 506. Presented June 5, 2017.
3. Schmid P, Park YH, Ferreira M, et al: KEYNOTE-522 study of neoadjuvant pembrolizumab + chemotherapy vs placebo + chemotherapy, followed by adjuvant pembrolizumab vs placebo for early triple-negative breast cancer: Pathologic complete response in key subgroups and by treatment exposure, residual cancer burden, and breast-conserving surgery. 2019 San Antonio Breast Cancer Symposium. Abstract GS3-03. Presented December 12, 2019.
4. Gianni L, Huang CS, Egle D, et al: Pathologic complete response to neoadjuvant treatment with or without atezolizumab in triple negative, early high-risk and locally advanced breast cancer. NeoTRIPaPDL1 Michelangelo randomized study. 2019 San Antonio Breast Cancer Symposium. Abstract GS3-04. Presented December 12, 2019.
5. Amaria RN, Prieto PA, Tetzlaff MT, et al: Neoadjuvant plus adjuvant dabrafenib and trametinib vs standard of care in patients with high-risk, surgically resectable melanoma: A single-centre, open-label, randomized, phase II trial. Lancet Oncol 19:181-193, 2018.
6. Amaria RN, Reddy SM, Tawbi HA, et al: Neoadjuvant immune checkpoint blockade in high-risk resectable melanoma. Nat Med 24:1649-1654, 2018.
7. Helmink BA, Reddy SM, Gao J, et al: B cells and tertiary lymphoid structures promote immunotherapy response. Nature 577:549-555, 2020.
8. Forde PM, Chaft JE, Smith KN, et al: Neoadjuvant PD-1 blockade in resectable lung cancer. N Engl J Med 378:1976-1986, 2018.