Immunotherapy before surgery significantly improves outcomes of patients with melanoma
If cancer exhibits a weakness, exploit it before taking the target away.
That’s what researchers did in a Phase 2, randomized clinical trial showing that adding immunotherapy before surgical removal of stage III-IV melanoma significantly improved event-free survival and produced no more side effects than standard-of-care treatment, which provides immunotherapy only after surgery.
Results of the multicenter trial, led by a team that included UCLA Jonsson Comprehensive Cancer Center researchers, are published in the March 2, 2023 issue of the New England Journal of Medicine.
“This is the first clinical trial demonstrating that neoadjuvant therapy – that given before surgery – is superior to the same therapy given in the adjuvant setting – after surgery,” said Dr. Antoni Ribas, director of the Tumor Immunology Program at UCLA Jonsson Comprehensive Cancer Center, the paper’s senior author. “This is because it is best to turn on the immune system inside the cancer before it is taken out with the surgery.”
The researchers designed the study and treatment regimen on how pembrolizumab – used in this study – and similar drugs, called immune checkpoint inhibitors, are thought to work. The antibody pembrolizumab is a PD-1 inhibitor; it blocks an immune checkpoint that blunts the immune system’s response to cancer. The therapy releases the antitumor immune response – often referred to as “taking the brakes off the immune system” – enabling immune cells already existing at the tumor site to proliferate and attack the cancer cells at that place or anywhere else in the body.
“Based on this understanding, removing the bulk of the tumor, along with the tumor-infiltrating immune cells contained in the surgical specimen, is likely to take away some or even most of the potential antitumor immune cells that would proliferate after PD-1 blockade,” said Ribas, who was chair of the SWOG Cancer Research Network’s melanoma committee when the study was designed and launched. “Our theory has been – and this study confirms it – that starting anti-PD-1 blocking therapy before surgery could activate more antitumor immune cells and improve clinical outcomes compared with the same amount of drug delivered after the surgery.”
As first author Dr. Sapna Patel says, “It’s not just what you give, it’s when you give it.” She is the current chair of the SWOG Cancer Research Network’s melanoma committee and associate professor of Melanoma Medical Oncology at The University of Texas MD Anderson Cancer Center.
The trial included patients with clinically detectable, measurable stage IIIB-IVC melanoma that could be surgically resected. Patients were randomly assigned to one of two groups. Those in the adjuvant therapy group, consisting of 159 patients, were treated with surgery followed by pembrolizumab given every three weeks for a total of 18 infusions. The 154 participants in the neoadjuvant group received three infusions of pembrolizumab before surgery, followed by the remaining 15 infusions after surgery. Therefore, both study groups received the same drug and the same total number of 18 infusions, with the only difference being the timing of surgery.
The researchers found that at two years 72% of patients in the group receiving neoadjuvant pembrolizumab followed by adjuvant pembrolizumab were free of events (inability to get surgery, recurrence of the melanoma or death) compared to 49% of the patients in the adjuvant pembrolizumab alone group.
Dr. Bartosz Chmielowski, clinical professor of medicine in the division of Hematology-Oncology at UCLA and study co-author said the study’s findings could change the way high-risk melanoma is routinely treated.
“The study highlights that the timing of administration of an immune checkpoint inhibitor relative to surgery can have a large effect on patient outcomes, even though the same systemic therapy was given to both study groups,” Chmielowski said. “Our results demonstrate a significant benefit when immunotherapy is started prior to surgery to generate an immune response while the bulk of the cancer and the anti-tumor immune cells remain intact.”
The study, known as S1801, was led by the SWOG Cancer Research Network, supported by the National Cancer Institute and conducted by the National Institutes of Health-funded National Clinical Trials Network. Dr. Chmielowski was UCLA’s principal investigator of the trial. For a complete list of authors, please see the study.
Funding: Research reported in this publication was supported by NIH/NCI grant awards U10CA180888, U10CA180819, U10CA180820, U10CA180821, U10CA180868, UG1CA233329, UG1CA233328, UG1CA233247, UG1CA233180, UG1CA189860, UG1CA233178, UG1CA233160, UG1CA189821, UG1CA233320, UG1CA233331, UG1CA189850, UG1CA233330, UG1CA233234, UG1CA233193, UG1CA189956, UG1CA239767, UG1CA189869, UG1CA180830, P30CA014089, UG1CA239758, P30CA016042, UG1CA189830, P30CA076292, P30CA033572, R35 CA197633 and P01 CA244118; and in part by Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA.
Disclosures and potential conflicts of interest: Disclosure forms provided by the authors are available with the full text of this article at NEJM.org.
Article: Patel SP, Othus M, Chen Y, et al. Neoadjuvant–adjuvant or adjuvant-only pembrolizumab in advanced melanoma. N Engl J Med 2023;388:813-23. DOI: 10.1056/NEJMoa2211437
Article URL (once embargo lifts): https://www.nejm.org/doi/full/10.1056/NEJMoa2211437.
JOURNAL
New England Journal of Medicine
METHOD OF RESEARCH
Randomized controlled/clinical trial
SUBJECT OF RESEARCH
People
ARTICLE TITLE
Neoadjuvant–adjuvant or adjuvant-only pembrolizumab in advanced melanoma.
ARTICLE PUBLICATION DATE
1-Mar-2023
COI STATEMENT
Disclosure forms provided by the authors are available with the full text of this article at NEJM.org
Neoadjuvant pembrolizumab administered before surgery improves outcomes of melanoma patients
Phase 2 clinical trial results show the neoadjuvant-adjuvant therapeutic approach improves event-free survival in high-risk melanoma patients
Peer-Reviewed PublicationTAMPA, Fla. — Outcomes for melanoma patients have vastly improved thanks to new treatment options. However, those with high-risk disease who have their tumors surgically removed still have a substantial chance of relapse. A team of researchers from institutions across the United States, including Moffitt Cancer Center, launched a phase 2 clinical trial evaluating a new treatment option for this patient population. Their results, published in The New England Journal of Medicine, show that treating resectable stage 3 and 4 melanoma patients with the immunotherapy drug pembrolizumab both before and after surgery greatly improves outcomes when compared to pembrolizumab given only after surgery.
Pembrolizumab activates the immune system to target cancer cells for destruction. It is approved to treat many different types of cancer, including melanoma that cannot be surgically removed, or be given as a post-surgery (adjuvant) treatment option. The research team, as part of the Southwest Oncology Group, initiated the phase 2 trial to assess whether pembrolizumab given both before surgery (neoadjuvant) and as adjuvant therapy after surgery could improve outcomes of patients with melanoma that can be surgically removed, compared with the identical number of doses of pembrolizumab given entirely after surgery.
“The dramatic successes we’ve seen with drug treatments for melanoma have led us to use them earlier and earlier in the patient’s course. Neoadjuvant therapy brings the powerful drugs to bear on the tumor even before surgery and has a lot of potential advantages. But many surgeons were reluctant to put off surgery for fear that the tumor would grow or spread and they would miss the opportunity for surgical cure,” said Vernon Sondak, M.D., study co-author and chair of Moffitt’s Department of Cutaneous Oncology.
This trial included 313 patients with resectable stage 3 or 4 melanoma from 90 institutions across the U.S. All patients had tumors that were still present and measurable by CT scans. In other words, they could not have already had all their cancer removed prior to the start of the trial. Patients were randomized into two groups. The first group received pembrolizumab as both neoadjuvant (three doses before surgery) and adjuvant (15 doses after surgery) therapy, while the second group received all 18 doses of pembrolizumab after surgery. With a median follow-up of 14.7 months, the 154 patients in the neoadjuvant-adjuvant group had a significantly longer event-free survival than the 159 patients in the adjuvant only group. The two-year event-free survival rates were 72% in the neoadjuvant-adjuvant group versus 49% in the adjuvant only group. The treatment benefit was observed in all patient subgroups that were analyzed, including groups based on age, sex, performance status and stage of disease. Of particular note, there were fewer postsurgical recurrences in the patients in the neoadjuvant plus adjuvant group.
One concern with neoadjuvant therapy is the potential risk of tumor growth or developing toxicities that would prevent patients from undergoing surgery. In the neoadjuvant-adjuvant group, less than 10% of patients developed progressive disease or toxicities from pembrolizumab neoadjuvant therapy that prevented them from undergoing surgical removal of the tumor. Overall, the rates and types of adverse events were similar between the two treatment groups. The percentage of patients who developed grade 3 or 4 treatment-related adverse events during adjuvant therapy was 12% in the neoadjuvant-adjuvant group and 14% in the adjuvant only group.
“Our trial results shows that the timing of administration of an immune checkpoint inhibitor relative to surgery can have a large effect on patient outcomes. These new landmark data are practice-changing and will impact how clinicians treat patients with advanced melanoma that can be surgically removed. We have been using neoadjuvant therapy extensively for several years now, but these results exceeded even my lofty expectations,” Sondak said. “The next step is to use neoadjuvant therapy to lessen the amount of surgery patients might need and shorten the length of drug treatment they might otherwise require. We’re working on precisely that right now.”
This study was funded by the National Cancer Institute (U10CA180888, U10CA180819, U10CA180820, U0CA180821, U10CA180868, UG1CA233329, UG1CA233328, UG1CA233247, UG1CA233180, UG1CA189860, UG1CA233178, UG1CA233160, UG1CA189821, UG1CA233320, UG1CA233331, UG1CA189850, UG1CA233330, UG1CA233234, UG1CA233193, UG1CA189956, UG1CA239767, UG1CA189869, UG1CA180830, P30CA014089, UG1CA239758, P30CA016042, UG1CA189830, P30CA076292, P30CA033572, R35 CA197633 and P01 CA244118) and Merck Sharp and Dohme.
About Moffitt Cancer Center
Moffitt is dedicated to one lifesaving mission: to contribute to the prevention and cure of cancer. The Tampa-based facility is one of only 53 National Cancer Institute-designated Comprehensive Cancer Centers, a distinction that recognizes Moffitt’s scientific excellence, multidisciplinary research, and robust training and education. Moffitt’s expert nursing staff is recognized by the American Nurses Credentialing Center with Magnet® status, its highest distinction. With more than 7,800 team members, Moffitt has an economic impact in the state of $2.4 billion. For more information, call 1-888-MOFFITT (1-888-663-3488), visit MOFFITT.org, and follow the momentum on Facebook, Twitter, Instagram and YouTube.
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JOURNAL
New England Journal of Medicine
METHOD OF RESEARCH
Randomized controlled/clinical trial
SUBJECT OF RESEARCH
People
ARTICLE TITLE
Neoadjuvant–Adjuvant or Adjuvant-Only Pembrolizumab in Advanced Melanoma
ARTICLE PUBLICATION DATE
2-Mar-2023
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