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These results set a new standard of care in this patient population, the study’s lead author, Christian U. Blank, MD, PhD, reported at the annual meeting of the American Society of Clinical Oncology in Chicago.
Dr. Blank, a hematologist/oncologist from the Netherlands Cancer Institute in Amsterdam, called the result “very special,” noting that the trial included an active comparator, rather than a placebo control.
“When we treat these patients with surgery only, the outcome … is very bad: The 5-year relapse-free survival is only 30% and the overall survival is only 50%. Adjuvant therapy improves relapse-free survival but not overall survival ...Thus, there is an urgent need for these patients for novel therapy approaches,” he said during a press conference at the meeting.
Study Methods and Results
The study included 423 patients with stage III de novo or recurrent pathologically proven resectable melanoma with at least 1 lymph node metastasis. Patients were randomized to either the experimental neoadjuvant arm (n = 212), or the standard treatment control arm (n = 211), which consisted of therapeutic lymph node dissection (TLND) followed by 12 cycles of adjuvant nivolumab (NIVO 480 mg every 4 weeks).
Patients in the experimental arm received two cycles of neoadjuvant ipilimumab (IPI 80 mg every 3 weeks) plus NIVO 240 mg for 3 weeks followed by TLND. Those with a major pathologic response (MPR), defined as less than 10% vital tumor cells in the post-neoadjuvant resection specimen, went straight to follow-up.
Those without an MPR received adjuvant therapy. For patients with BRAF wild-type, this involved 11 cycles of adjuvant NIVO (480 mg every 4 weeks), while BRAF-mutated patients received dabrafenib plus trametinib (150 mg b.i.d./2 mg once a day; 46 weeks).
The study met its primary endpoint — event-free survival (EFS) — at the first interim analysis. After a median follow-up of 9.9 months, the estimated EFS was 83.7% for neoadjuvant immunotherapy versus 57.2% for standard of care, (P less than .0001, hazard ratio [HR] = 0.32).
“When we look into the subgroups, for example BRAF-mutated status or BRAF-wild-type status ... you see for both groups also a highly statistically significant outcome favoring the neoadjuvant therapy with hazard ratios of 0.29 and 0.35,” said Dr. Blank.
In total, 59% of patients in the experimental arm had an MPR needing no further treatment. “This is important, because the patients that achieve a major pathologic response have excellent outcomes, with an EFS of 95%,” said Dr. Blank.
He added that those with a partial response had an EFS of 76%, and among those who had “nonresponse,” the EFS was 57% — the same as that of patients in the control arm.
Toxicities were considered transient and acceptable, with systemic treatment-related grade 3 or 4 events in 29.7% of the neoadjuvant arm and 14.7% of the adjuvant arm.
NADINA is the first neoadjuvant checkpoint inhibitor phase 3 study in melanoma and the first phase 3 trial in oncology testing a checkpoint inhibitor without chemotherapy, noted Dr. Blank.
“At the moment we see only additions of immunotherapy to the chemotherapy neoadjuvant arms, but here you see that we can also treat patients with pure immunotherapy.”
Neoadjuvant Therapy Defined as Standard of Care
When considered along with evidence from the phase 2 SWOG 1801 study (N Engl J Med. 2023;388:813-8), “NADINA defines neoadjuvant therapy as the new standard of care for macroscopic stage III melanoma “which means that all trials currently ongoing need to be amended from adjuvant comparators to neoadjuvant comparators,” he said.
Dr. Blank called the trial a “new template for other malignancies implementing a neoadjuvant immunotherapy regimen followed by a response-driven adjuvant therapy.
“I think we see at the moment only sandwich designs, and this is more sales driven than patient driven, because what we have seen is that if a patient achieves a really deep response, the patient doesn’t need an adjuvant part,” he said.
Commenting during the press conference, Michael Lowe, MD, said the result “confirms and shows for the first time in a phase 3 study that giving immunotherapy before surgery results in superior outcomes to giving immunotherapy only after surgery.”
Dr. Lowe, associate professor in the Division of Surgical Oncology, at Emory University School of Medicine, Atlanta, added that the study “also confirms that giving two immunotherapy drugs before surgery results in excellent responses.”
However, he cautioned that “we cannot make comparisons to trials in which patients only got one immunotherapy. But this study confirms that consistency that patients who receive ipilimumab and nivolumab have superior responses compared to single-agent immunotherapy.”
He noted that all of the patients in the new study had all of their lymph nodes removed and called for doing that to remain the standard of care in terms of surgical approach.
“With short follow-up, it is too early to tell if some patients may have benefited from that adjuvant therapy. However, NADINA confirms that immunotherapy should be given to all patients with advanced melanoma before surgery, when possible, and establishes dual therapy with nivolumab and ipilimumab, as the standard of care in the appropriate patient,” Dr. Lowe said.
EFS Improvement Exceeds Expectations
In an interview, Rodabe N. Amaria, MD, a medical oncologist and professor at The University of Texas MD Anderson Cancer Center in Houston, agreed with Dr. Lowe’s assessment of the findings.
“For years we have been doing neoadjuvant immunotherapy trials, all with favorable results, but all relatively small, with data that was intriguing, but not necessarily definitive,” she said. “I see the data from the NADINA trial as being definitive and true evidence of the many advantages of neoadjuvant immunotherapy for clinical stage 3 melanoma ... This work builds on the data from the SWOG 1801 trial but also exceeds expectations with the 68% improvement in EFS appreciated with the dual combination immunotherapy regimen compared to adjuvant nivolumab.”
Additionally, the approximately 30% grade 3 or higher immune-mediated toxicity is reasonable and in keeping with known data, and this trial demonstrates clearly that neoadjuvant immunotherapy does not increase the rate of surgical complications, she said.
Dr. Amaria also considered that 59% of patients who achieved a major pathologic response were observed in the neoadjuvant setting to be a key finding.
This indicates thats “over half the patients could be spared additional immunotherapy and risk of further immune-mediated toxicities by having only two doses of neoadjuvant immunotherapy, she said.
The results “demonstrate the superiority of a neoadjuvant combination immunotherapy approach for patients with clinical stage III melanoma,” she added.
The study was funded by Bristol Myers-Squibb and the Australian government.
Dr. Blank disclosed ties with Immagene, Signature Oncology, AstraZeneca, Bristol-Myers Squibb, GenMab, GlaxoSmithKline, Lilly, MSD Oncology, Novartis, Pfizer, Pierre Fabre, Roche/Genentech, Third Rock Ventures, 4SC, NanoString Technologies, WO 2021/177822 A1, and Freshfields Bruckhaus Deringer. No other experts reported any relevant disclosures.
These results set a new standard of care in this patient population, the study’s lead author, Christian U. Blank, MD, PhD, reported at the annual meeting of the American Society of Clinical Oncology in Chicago.
Dr. Blank, a hematologist/oncologist from the Netherlands Cancer Institute in Amsterdam, called the result “very special,” noting that the trial included an active comparator, rather than a placebo control.
“When we treat these patients with surgery only, the outcome … is very bad: The 5-year relapse-free survival is only 30% and the overall survival is only 50%. Adjuvant therapy improves relapse-free survival but not overall survival ...Thus, there is an urgent need for these patients for novel therapy approaches,” he said during a press conference at the meeting.
Study Methods and Results
The study included 423 patients with stage III de novo or recurrent pathologically proven resectable melanoma with at least 1 lymph node metastasis. Patients were randomized to either the experimental neoadjuvant arm (n = 212), or the standard treatment control arm (n = 211), which consisted of therapeutic lymph node dissection (TLND) followed by 12 cycles of adjuvant nivolumab (NIVO 480 mg every 4 weeks).
Patients in the experimental arm received two cycles of neoadjuvant ipilimumab (IPI 80 mg every 3 weeks) plus NIVO 240 mg for 3 weeks followed by TLND. Those with a major pathologic response (MPR), defined as less than 10% vital tumor cells in the post-neoadjuvant resection specimen, went straight to follow-up.
Those without an MPR received adjuvant therapy. For patients with BRAF wild-type, this involved 11 cycles of adjuvant NIVO (480 mg every 4 weeks), while BRAF-mutated patients received dabrafenib plus trametinib (150 mg b.i.d./2 mg once a day; 46 weeks).
The study met its primary endpoint — event-free survival (EFS) — at the first interim analysis. After a median follow-up of 9.9 months, the estimated EFS was 83.7% for neoadjuvant immunotherapy versus 57.2% for standard of care, (P less than .0001, hazard ratio [HR] = 0.32).
“When we look into the subgroups, for example BRAF-mutated status or BRAF-wild-type status ... you see for both groups also a highly statistically significant outcome favoring the neoadjuvant therapy with hazard ratios of 0.29 and 0.35,” said Dr. Blank.
In total, 59% of patients in the experimental arm had an MPR needing no further treatment. “This is important, because the patients that achieve a major pathologic response have excellent outcomes, with an EFS of 95%,” said Dr. Blank.
He added that those with a partial response had an EFS of 76%, and among those who had “nonresponse,” the EFS was 57% — the same as that of patients in the control arm.
Toxicities were considered transient and acceptable, with systemic treatment-related grade 3 or 4 events in 29.7% of the neoadjuvant arm and 14.7% of the adjuvant arm.
NADINA is the first neoadjuvant checkpoint inhibitor phase 3 study in melanoma and the first phase 3 trial in oncology testing a checkpoint inhibitor without chemotherapy, noted Dr. Blank.
“At the moment we see only additions of immunotherapy to the chemotherapy neoadjuvant arms, but here you see that we can also treat patients with pure immunotherapy.”
Neoadjuvant Therapy Defined as Standard of Care
When considered along with evidence from the phase 2 SWOG 1801 study (N Engl J Med. 2023;388:813-8), “NADINA defines neoadjuvant therapy as the new standard of care for macroscopic stage III melanoma “which means that all trials currently ongoing need to be amended from adjuvant comparators to neoadjuvant comparators,” he said.
Dr. Blank called the trial a “new template for other malignancies implementing a neoadjuvant immunotherapy regimen followed by a response-driven adjuvant therapy.
“I think we see at the moment only sandwich designs, and this is more sales driven than patient driven, because what we have seen is that if a patient achieves a really deep response, the patient doesn’t need an adjuvant part,” he said.
Commenting during the press conference, Michael Lowe, MD, said the result “confirms and shows for the first time in a phase 3 study that giving immunotherapy before surgery results in superior outcomes to giving immunotherapy only after surgery.”
Dr. Lowe, associate professor in the Division of Surgical Oncology, at Emory University School of Medicine, Atlanta, added that the study “also confirms that giving two immunotherapy drugs before surgery results in excellent responses.”
However, he cautioned that “we cannot make comparisons to trials in which patients only got one immunotherapy. But this study confirms that consistency that patients who receive ipilimumab and nivolumab have superior responses compared to single-agent immunotherapy.”
He noted that all of the patients in the new study had all of their lymph nodes removed and called for doing that to remain the standard of care in terms of surgical approach.
“With short follow-up, it is too early to tell if some patients may have benefited from that adjuvant therapy. However, NADINA confirms that immunotherapy should be given to all patients with advanced melanoma before surgery, when possible, and establishes dual therapy with nivolumab and ipilimumab, as the standard of care in the appropriate patient,” Dr. Lowe said.
EFS Improvement Exceeds Expectations
In an interview, Rodabe N. Amaria, MD, a medical oncologist and professor at The University of Texas MD Anderson Cancer Center in Houston, agreed with Dr. Lowe’s assessment of the findings.
“For years we have been doing neoadjuvant immunotherapy trials, all with favorable results, but all relatively small, with data that was intriguing, but not necessarily definitive,” she said. “I see the data from the NADINA trial as being definitive and true evidence of the many advantages of neoadjuvant immunotherapy for clinical stage 3 melanoma ... This work builds on the data from the SWOG 1801 trial but also exceeds expectations with the 68% improvement in EFS appreciated with the dual combination immunotherapy regimen compared to adjuvant nivolumab.”
Additionally, the approximately 30% grade 3 or higher immune-mediated toxicity is reasonable and in keeping with known data, and this trial demonstrates clearly that neoadjuvant immunotherapy does not increase the rate of surgical complications, she said.
Dr. Amaria also considered that 59% of patients who achieved a major pathologic response were observed in the neoadjuvant setting to be a key finding.
This indicates thats “over half the patients could be spared additional immunotherapy and risk of further immune-mediated toxicities by having only two doses of neoadjuvant immunotherapy, she said.
The results “demonstrate the superiority of a neoadjuvant combination immunotherapy approach for patients with clinical stage III melanoma,” she added.
The study was funded by Bristol Myers-Squibb and the Australian government.
Dr. Blank disclosed ties with Immagene, Signature Oncology, AstraZeneca, Bristol-Myers Squibb, GenMab, GlaxoSmithKline, Lilly, MSD Oncology, Novartis, Pfizer, Pierre Fabre, Roche/Genentech, Third Rock Ventures, 4SC, NanoString Technologies, WO 2021/177822 A1, and Freshfields Bruckhaus Deringer. No other experts reported any relevant disclosures.
These results set a new standard of care in this patient population, the study’s lead author, Christian U. Blank, MD, PhD, reported at the annual meeting of the American Society of Clinical Oncology in Chicago.
Dr. Blank, a hematologist/oncologist from the Netherlands Cancer Institute in Amsterdam, called the result “very special,” noting that the trial included an active comparator, rather than a placebo control.
“When we treat these patients with surgery only, the outcome … is very bad: The 5-year relapse-free survival is only 30% and the overall survival is only 50%. Adjuvant therapy improves relapse-free survival but not overall survival ...Thus, there is an urgent need for these patients for novel therapy approaches,” he said during a press conference at the meeting.
Study Methods and Results
The study included 423 patients with stage III de novo or recurrent pathologically proven resectable melanoma with at least 1 lymph node metastasis. Patients were randomized to either the experimental neoadjuvant arm (n = 212), or the standard treatment control arm (n = 211), which consisted of therapeutic lymph node dissection (TLND) followed by 12 cycles of adjuvant nivolumab (NIVO 480 mg every 4 weeks).
Patients in the experimental arm received two cycles of neoadjuvant ipilimumab (IPI 80 mg every 3 weeks) plus NIVO 240 mg for 3 weeks followed by TLND. Those with a major pathologic response (MPR), defined as less than 10% vital tumor cells in the post-neoadjuvant resection specimen, went straight to follow-up.
Those without an MPR received adjuvant therapy. For patients with BRAF wild-type, this involved 11 cycles of adjuvant NIVO (480 mg every 4 weeks), while BRAF-mutated patients received dabrafenib plus trametinib (150 mg b.i.d./2 mg once a day; 46 weeks).
The study met its primary endpoint — event-free survival (EFS) — at the first interim analysis. After a median follow-up of 9.9 months, the estimated EFS was 83.7% for neoadjuvant immunotherapy versus 57.2% for standard of care, (P less than .0001, hazard ratio [HR] = 0.32).
“When we look into the subgroups, for example BRAF-mutated status or BRAF-wild-type status ... you see for both groups also a highly statistically significant outcome favoring the neoadjuvant therapy with hazard ratios of 0.29 and 0.35,” said Dr. Blank.
In total, 59% of patients in the experimental arm had an MPR needing no further treatment. “This is important, because the patients that achieve a major pathologic response have excellent outcomes, with an EFS of 95%,” said Dr. Blank.
He added that those with a partial response had an EFS of 76%, and among those who had “nonresponse,” the EFS was 57% — the same as that of patients in the control arm.
Toxicities were considered transient and acceptable, with systemic treatment-related grade 3 or 4 events in 29.7% of the neoadjuvant arm and 14.7% of the adjuvant arm.
NADINA is the first neoadjuvant checkpoint inhibitor phase 3 study in melanoma and the first phase 3 trial in oncology testing a checkpoint inhibitor without chemotherapy, noted Dr. Blank.
“At the moment we see only additions of immunotherapy to the chemotherapy neoadjuvant arms, but here you see that we can also treat patients with pure immunotherapy.”
Neoadjuvant Therapy Defined as Standard of Care
When considered along with evidence from the phase 2 SWOG 1801 study (N Engl J Med. 2023;388:813-8), “NADINA defines neoadjuvant therapy as the new standard of care for macroscopic stage III melanoma “which means that all trials currently ongoing need to be amended from adjuvant comparators to neoadjuvant comparators,” he said.
Dr. Blank called the trial a “new template for other malignancies implementing a neoadjuvant immunotherapy regimen followed by a response-driven adjuvant therapy.
“I think we see at the moment only sandwich designs, and this is more sales driven than patient driven, because what we have seen is that if a patient achieves a really deep response, the patient doesn’t need an adjuvant part,” he said.
Commenting during the press conference, Michael Lowe, MD, said the result “confirms and shows for the first time in a phase 3 study that giving immunotherapy before surgery results in superior outcomes to giving immunotherapy only after surgery.”
Dr. Lowe, associate professor in the Division of Surgical Oncology, at Emory University School of Medicine, Atlanta, added that the study “also confirms that giving two immunotherapy drugs before surgery results in excellent responses.”
However, he cautioned that “we cannot make comparisons to trials in which patients only got one immunotherapy. But this study confirms that consistency that patients who receive ipilimumab and nivolumab have superior responses compared to single-agent immunotherapy.”
He noted that all of the patients in the new study had all of their lymph nodes removed and called for doing that to remain the standard of care in terms of surgical approach.
“With short follow-up, it is too early to tell if some patients may have benefited from that adjuvant therapy. However, NADINA confirms that immunotherapy should be given to all patients with advanced melanoma before surgery, when possible, and establishes dual therapy with nivolumab and ipilimumab, as the standard of care in the appropriate patient,” Dr. Lowe said.
EFS Improvement Exceeds Expectations
In an interview, Rodabe N. Amaria, MD, a medical oncologist and professor at The University of Texas MD Anderson Cancer Center in Houston, agreed with Dr. Lowe’s assessment of the findings.
“For years we have been doing neoadjuvant immunotherapy trials, all with favorable results, but all relatively small, with data that was intriguing, but not necessarily definitive,” she said. “I see the data from the NADINA trial as being definitive and true evidence of the many advantages of neoadjuvant immunotherapy for clinical stage 3 melanoma ... This work builds on the data from the SWOG 1801 trial but also exceeds expectations with the 68% improvement in EFS appreciated with the dual combination immunotherapy regimen compared to adjuvant nivolumab.”
Additionally, the approximately 30% grade 3 or higher immune-mediated toxicity is reasonable and in keeping with known data, and this trial demonstrates clearly that neoadjuvant immunotherapy does not increase the rate of surgical complications, she said.
Dr. Amaria also considered that 59% of patients who achieved a major pathologic response were observed in the neoadjuvant setting to be a key finding.
This indicates thats “over half the patients could be spared additional immunotherapy and risk of further immune-mediated toxicities by having only two doses of neoadjuvant immunotherapy, she said.
The results “demonstrate the superiority of a neoadjuvant combination immunotherapy approach for patients with clinical stage III melanoma,” she added.
The study was funded by Bristol Myers-Squibb and the Australian government.
Dr. Blank disclosed ties with Immagene, Signature Oncology, AstraZeneca, Bristol-Myers Squibb, GenMab, GlaxoSmithKline, Lilly, MSD Oncology, Novartis, Pfizer, Pierre Fabre, Roche/Genentech, Third Rock Ventures, 4SC, NanoString Technologies, WO 2021/177822 A1, and Freshfields Bruckhaus Deringer. No other experts reported any relevant disclosures.
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<root generator="drupal.xsl" gversion="1.7"> <header> <fileName>168287</fileName> <TBEID>0C05065F.SIG</TBEID> <TBUniqueIdentifier>MD_0C05065F</TBUniqueIdentifier> <newsOrJournal>News</newsOrJournal> <publisherName>Frontline Medical Communications</publisherName> <storyname/> <articleType>2</articleType> <TBLocation>QC Done-All Pubs</TBLocation> <QCDate>20240604T102823</QCDate> <firstPublished>20240604T103111</firstPublished> <LastPublished>20240604T103111</LastPublished> <pubStatus qcode="stat:"/> <embargoDate/> <killDate/> <CMSDate>20240604T103111</CMSDate> <articleSource>FROM ASCO 2024</articleSource> <facebookInfo/> <meetingNumber>3035-24</meetingNumber> <byline/> <bylineText>KATE JOHNSON</bylineText> <bylineFull>KATE JOHNSON</bylineFull> <bylineTitleText>MDedge News</bylineTitleText> <USOrGlobal/> <wireDocType/> <newsDocType>News</newsDocType> <journalDocType/> <linkLabel/> <pageRange/> <citation/> <quizID/> <indexIssueDate/> <itemClass qcode="ninat:text"/> <provider qcode="provider:imng"> <name>IMNG Medical Media</name> <rightsInfo> <copyrightHolder> <name>Frontline Medical News</name> </copyrightHolder> <copyrightNotice>Copyright (c) 2015 Frontline Medical News, a Frontline Medical Communications Inc. company. All rights reserved. This material may not be published, broadcast, copied, or otherwise reproduced or distributed without the prior written permission of Frontline Medical Communications Inc.</copyrightNotice> </rightsInfo> </provider> <abstract/> <metaDescription>Almost sixty percent of patients with macroscopic stage III melanoma who were randomized to 6 weeks of neoadjuvant immunotherapy needed no further treatment aft</metaDescription> <articlePDF/> <teaserImage/> <teaser>Results of the first phase 3 oncology study to test checkpoint inhibition without chemotherapy were presented at the annual meeting of the American Society of Clinical Oncology.</teaser> <title>Neoadjuvant Checkpoint Inhibition Study Sets New Standard of Care in Melanoma</title> <deck/> <disclaimer/> <AuthorList/> <articleURL/> <doi/> <pubMedID/> <publishXMLStatus/> <publishXMLVersion>1</publishXMLVersion> <useEISSN>0</useEISSN> <urgency/> <pubPubdateYear/> <pubPubdateMonth/> <pubPubdateDay/> <pubVolume/> <pubNumber/> <wireChannels/> <primaryCMSID/> <CMSIDs/> <keywords/> <seeAlsos/> <publications_g> <publicationData> <publicationCode>oncr</publicationCode> <pubIssueName/> <pubArticleType/> <pubTopics/> <pubCategories/> <pubSections/> </publicationData> <publicationData> <publicationCode>skin</publicationCode> <pubIssueName/> <pubArticleType/> <pubTopics/> <pubCategories/> <pubSections/> </publicationData> </publications_g> <publications> <term canonical="true">31</term> <term>13</term> </publications> <sections> <term canonical="true">53</term> <term>27980</term> <term>39313</term> </sections> <topics> <term canonical="true">244</term> <term>270</term> </topics> <links/> </header> <itemSet> <newsItem> <itemMeta> <itemRole>Main</itemRole> <itemClass>text</itemClass> <title>Neoadjuvant Checkpoint Inhibition Study Sets New Standard of Care in Melanoma</title> <deck/> </itemMeta> <itemContent> <p> <span class="tag metaDescription">Almost sixty percent of patients with macroscopic stage III melanoma who were randomized to 6 weeks of neoadjuvant immunotherapy needed no further treatment after therapeutic lymph node dissection in the phase 3 NADINA trial.</span> </p> <p>These results set a new standard of care in this patient population, the study’s lead author, Christian U. Blank, MD, PhD, reported at the annual meeting of the American Society of Clinical Oncology in Chicago.<br/><br/>Dr. Blank, a hematologist/oncologist from the Netherlands Cancer Institute in Amsterdam, called the result “very special,” noting that the trial included an active comparator, rather than a placebo control. <br/><br/>“When we treat these patients with surgery only, the outcome … is very bad: The 5-year relapse-free survival is only 30% and the overall survival is only 50%. Adjuvant therapy improves relapse-free survival but not overall survival ...Thus, there is an urgent need for these patients for novel therapy approaches,” he said during a press conference at the meeting.<br/><br/></p> <h2>Study Methods and Results</h2> <p>The study included 423 patients with stage III de novo or recurrent pathologically proven resectable melanoma with at least 1 lymph node metastasis. Patients were randomized to either the experimental neoadjuvant arm (n = 212), or the standard treatment control arm (n = 211), which consisted of therapeutic lymph node dissection (TLND) followed by 12 cycles of adjuvant nivolumab (NIVO 480 mg every 4 weeks).</p> <p>Patients in the experimental arm received two cycles of neoadjuvant ipilimumab (IPI 80 mg every 3 weeks) plus NIVO 240 mg for 3 weeks followed by TLND. Those with a major pathologic response (MPR), defined as less than 10% vital tumor cells in the post-neoadjuvant resection specimen, went straight to follow-up. <br/><br/>Those without an MPR received adjuvant therapy. For patients with BRAF wild-type, this involved 11 cycles of adjuvant NIVO (480 mg every 4 weeks), while BRAF-mutated patients received dabrafenib plus trametinib (150 mg b.i.d./2 mg once a day; 46 weeks).<br/><br/>The study met its primary endpoint — event-free survival (EFS) — at the first interim analysis. After a median follow-up of 9.9 months, the estimated EFS was 83.7% for neoadjuvant immunotherapy versus 57.2% for standard of care, (<em>P</em> less than .0001, hazard ratio [HR] = 0.32). <br/><br/>“When we look into the subgroups, for example BRAF-mutated status or BRAF-wild-type status ... you see for both groups also a highly statistically significant outcome favoring the neoadjuvant therapy with hazard ratios of 0.29 and 0.35,” said Dr. Blank.<br/><br/>In total, 59% of patients in the experimental arm had an MPR needing no further treatment. “This is important, because the patients that achieve a major pathologic response have excellent outcomes, with an EFS of 95%,” said Dr. Blank.<br/><br/>He added that those with a partial response had an EFS of 76%, and among those who had “nonresponse,” the EFS was 57% — the same as that of patients in the control arm.<br/><br/>Toxicities were considered transient and acceptable, with systemic treatment-related grade 3 or 4 events in 29.7% of the neoadjuvant arm and 14.7% of the adjuvant arm.<br/><br/>NADINA is the first neoadjuvant checkpoint inhibitor phase 3 study in melanoma and the first phase 3 trial in oncology testing a checkpoint inhibitor without chemotherapy, noted Dr. Blank. <br/><br/>“At the moment we see only additions of immunotherapy to the chemotherapy neoadjuvant arms, but here you see that we can also treat patients with pure immunotherapy.”<br/><br/></p> <h2>Neoadjuvant Therapy Defined as Standard of Care</h2> <p>When considered along with evidence from the phase 2 SWOG 1801 study (<span class="Hyperlink"><a href="https://www.nejm.org/doi/full/10.1056/NEJMoa2211437">N Engl J Med. 2023;388:813-8</a></span>), “NADINA defines neoadjuvant therapy as the new standard of care for macroscopic stage III melanoma “which means that all trials currently ongoing need to be amended from adjuvant comparators to neoadjuvant comparators,” he said.</p> <p>Dr. Blank called the trial a “new template for other malignancies implementing a neoadjuvant immunotherapy regimen followed by a response-driven adjuvant therapy.<br/><br/>“I think we see at the moment only sandwich designs, and this is more sales driven than patient driven, because what we have seen is that if a patient achieves a really deep response, the patient doesn’t need an adjuvant part,” he said.<br/><br/>Commenting during the press conference, Michael Lowe, MD, said the result “confirms and shows for the first time in a phase 3 study that giving immunotherapy before surgery results in superior outcomes to giving immunotherapy only after surgery.”<br/><br/>Dr. Lowe, associate professor in the Division of Surgical Oncology, at Emory University School of Medicine, Atlanta, added that the study “also confirms that giving two immunotherapy drugs before surgery results in excellent responses.” <br/><br/>However, he cautioned that “we cannot make comparisons to trials in which patients only got one immunotherapy. But this study confirms that consistency that patients who receive ipilimumab and nivolumab have superior responses compared to single-agent immunotherapy.” <br/><br/>He noted that all of the patients in the new study had all of their lymph nodes removed and called for doing that to remain the standard of care in terms of surgical approach. <br/><br/>“With short follow-up, it is too early to tell if some patients may have benefited from that adjuvant therapy. However, NADINA confirms that immunotherapy should be given to all patients with advanced melanoma before surgery, when possible, and establishes dual therapy with nivolumab and ipilimumab, as the standard of care in the appropriate patient,” Dr. Lowe said.<br/><br/></p> <h2>EFS Improvement Exceeds Expectations</h2> <p>In an interview, Rodabe N. Amaria, MD, a medical oncologist and professor at The University of Texas MD Anderson Cancer Center in Houston, agreed with Dr. Lowe’s assessment of the findings.</p> <p>“For years we have been doing neoadjuvant immunotherapy trials, all with favorable results, but all relatively small, with data that was intriguing, but not necessarily definitive,” she said. “I see the data from the NADINA trial as being definitive and true evidence of the many advantages of neoadjuvant immunotherapy for clinical stage 3 melanoma ... This work builds on the data from the SWOG 1801 trial but also exceeds expectations with the 68% improvement in EFS appreciated with the dual combination immunotherapy regimen compared to adjuvant nivolumab.”<br/><br/>Additionally, the approximately 30% grade 3 or higher immune-mediated toxicity is reasonable and in keeping with known data, and this trial demonstrates clearly that neoadjuvant immunotherapy does not increase the rate of surgical complications, she said.<br/><br/>Dr. Amaria also considered that 59% of patients who achieved a major pathologic response were observed in the neoadjuvant setting to be a key finding. <br/><br/>This indicates thats “over half the patients could be spared additional immunotherapy and risk of further immune-mediated toxicities by having only two doses of neoadjuvant immunotherapy, she said. <br/><br/>The results “demonstrate the superiority of a neoadjuvant combination immunotherapy approach for patients with clinical stage III melanoma,” she added.<br/><br/>The study was funded by Bristol Myers-Squibb and the Australian government.<br/><br/>Dr. Blank disclosed ties with Immagene, Signature Oncology, AstraZeneca, Bristol-Myers Squibb, GenMab, GlaxoSmithKline, Lilly, MSD Oncology, Novartis, Pfizer, Pierre Fabre, Roche/Genentech, Third Rock Ventures, 4SC, NanoString Technologies, WO 2021/177822 A1, and Freshfields Bruckhaus Deringer. No other experts reported any relevant disclosures. </p> </itemContent> </newsItem> <newsItem> <itemMeta> <itemRole>teaser</itemRole> <itemClass>text</itemClass> <title/> <deck/> </itemMeta> <itemContent> </itemContent> </newsItem> </itemSet></root>
FROM ASCO 2024