SPECIALEDITION UPDATE FROM ASCO 2024
From the Desk of Sam Guild, President AIM at Melanoma Foundation
In Plain English: Overview of the 2024 Annual Meeting of the American Society of Clinical Oncology (ASCO)
By Kim Margolin, M.D., FACP, FASCO
Summary of Neoadjuvant Nivolumab and Ipilimumab in Resectable Stage III Melanoma
By Mandi Murph, Director of Medical Education
The Third Annual Evening in Memory of Valerie Guild
FROM THE DESK OF Sam Guild
PRESIDENT | AIM AT MELANOMA FOUNDATION
Thank you for reading our special edition newsletter about the annual meeting of ASCO —the American Society of Clinical Oncology.
Each year in June about 40,000 people from all over the world descend on the city of Chicago and its McCormick Convention Center for the annual ASCO meeting. This meeting brings together all those involved in oncology: medical oncologists, surgical oncologists (general and specialty-focused), radiation oncologists, gynecologic oncologists, physicians in other medical specialties such as supportive care and pain management, oncology nurses, social workers, members of clinical research teams, laboratory investigators, administrators, pharmacists, a wide array of pharmaceutical company employees, and fellows (trainees in the specialties listed above).
The meeting is where results of clinical trials and updates are typically announced, so you might notice that AIM will either send out Breaking News during ASCO or, like this year, summarize the news into a special newsletter after the meeting ends.
One of the highlights this year was the NADINA announcement, and we have an article that explains the NADINA trial and why it matters to patients with melanoma. A second article gives you the rundown of all the other news in melanoma this year, including the updates on TIL therapy and mRNA vaccines in melanoma. Finally, please read the article about AIM at Melanoma’s annual event at ASCO, where the melanoma oncology community gathers each year.
As always, thank you for your support and for being a part of the AIM community, especially this year, our 20th.
SamGuild
IN PLAIN ENGLISH
OVERVIEW OF THE 2024 ANNUAL MEETING OF THE AMERICAN SOCIETY OF CLINICAL ONCOLOGY (ASCO)
BY KIM MARGOLIN, M.D., FACP, FASCO
The American Society of Clinical Oncology or ASCO is a professional organization that hosts a series of meetings about different types of cancers and other professional development opportunities. They also hold a large annual meeting in June every year at which U.S. and foreign oncologists and other oncology-related medical professionals from around the world gather to hear the latest news in their specialties (such as melanoma) and in cancer generally More than 40,000 people, including ASCO members, researchers and those who care for people with cancer, attend this meeting held annually in Chicago.
This year’s ASCO was an exciting meeting that lifted spirits and raised survival curves to new heights in melanoma and several other malignancies. This year was the first year that melanoma appeared on the plenary session (the session that 40,000 people attend in person) since 2015, when we first heard about the highly-active combination of ipilimumab (anti-CTLA-4) and nivolumab (anti-PD-1) for advanced melanoma At that time, four years had passed since the twin breakthroughs of BRAF mutation-targeted therapy and the original immune checkpoint antibody, ipilimumab. Of course, we also know now that immune checkpoint antibodies have caused an explosion in the success of immunotherapy; consequently, the 2018 Nobel Prize in Medicine was awarded to Drs. James Allison and Tasuku Honjo for these discoveries and the resulting therapies
The following pages provide a summary of new developments reported at ASCO in 2024.
Brief points about the NADINA trial, a paradigm shift in the
systemic therapy for melanoma
Now, in 2024, the first randomized, phase III study (NADINA) has demonstrated a major advantage for giving patients with a bulky melanoma mass (usually a large node or cluster of nodes containing melanoma) a brief course of immunotherapy prior to surgical removal The most exciting result was the incredibly high rate of pathologic complete eradication of all living melanoma cells, leading to a long term remission and eliminating the need for further surgery or more systemic treatment Further details of this practicechanging report of the NADINA trial, led by investigators in the Netherlands and Australia, are covered in the accompanying article by Mandi Murph, AIM at Melanoma’s Director of Medical Education.
Tumor-infiltrating lymphocyte therapy—current state of the art
First, we heard updates on tumor-infiltrating lymphocyte (“TIL”) therapy, which was detailed in a recent issue of IPE and recently approved by the FDA for commercial use (that is, no longer requiring the participation in a clinical trial but still having very strict patient selection criteria and operational requirements in order to assure maximum safety and optimal patient outcome). The FDA approval requires that patients first be treated with standard immunotherapy such as pembrolizumab or nivolumabcontaining regimens and, if the melanoma has a BRAF mutation, also to have received one of the targeted therapy regimens against BRAF and MEK (detailed in this IPE article)
Earlier use of TIL cell therapy (before current-day immunotherapy or targeted therapy were available) showed favorable results from the National Cancer Institute (NCI), and a similar trial, in which several institutions collaborated outside of the NCI, was presented at ASCO 2024, where similar favorable results were reported.
The FDA approval of TIL cell therapy is currently an accelerated approval, which means that the data remain preliminary and require confirmation with a randomized trial to get full FDA approval. In order to obtain more data in earlier phases of melanoma and to obtain this full approval by the FDA, the company that produces TIL cells (Iovance) has initiated a trial for patients who have never received treatment for advanced melanoma. Patients will be randomly assigned to receive pembrolizumab with or without TIL cells as their first therapy Patients randomized to pembrolizumab alone who do not go into remission or who go into remission but later relapse may go on to TIL cell therapy for their relapse Thus, the trial could be construed as being a comparison of early TIL versus later TIL rather than TIL versus no TIL.
Tumor-infiltrating lymphocyte (“TIL”) therapy developing better and safer approaches
Among the remaining questions and challenges about TIL cell therapy for melanoma are the possibility of eliminating the initial high-dose chemotherapy and/or reducing or replacing the high-dose interleukin-2 (IL-2) which can be very toxic and require specialized medical management after administration of TIL cells. The purpose of the high-dose interleukin (IL-2) is to act as a T cell growth factor that stimulates the proliferation of the administered TILs as well as activating them to enhance tumor cell killing.
There is now an engineered form of TIL that carries its own T cell growth factor (IL-15) that can be turned on by treating the patient with acetazolamide, a safe oral medication ordinarily used to reduce altitude sickness. The IL-15 is less toxic than IL-2 and may be a solution, but it is still being tested Another form of engineered TIL cell being tested in melanoma and other malignancies uses the CRISPR approach to remove PD-1 from the TIL cells, thus making them better tumor cell killers while avoiding their attack on other tissues of the body. The latter approach is the newest of “personalized” therapies developed to improve the therapeutic index of a particular treatment, representing the relative balance of benefits versus risks or toxicities.
Updates on non-TIL therapies double immune checkpoint blockade targeting LAG-3 and PD-1
Despite the promise of TIL cell therapy, it is complex, potentially dangerous, exorbitantly expensive, and simply not available to a large fraction of the patients who do not benefit from other treatments for advanced melanoma Thus, investigators continue to work on simpler, more widely-available treatments for patients with the most favorable forms of metastatic melanoma those that arise in skin over the trunk, extremities, and head and neck areas who haven’t been fortunate enough to go into remission and stay in remission.
Some of these treatments are also being tested in firstline therapy for patients with the less favorable forms of melanoma that go into remission much less frequently, including those that arise in the palms, soles, fingernails and toenails as well as those that arise in the moist membranes of the body such as the mouth or nose and the anogenital areas
One approved treatment contains two immune checkpoint antibodies, relatlimab and nivolumab in a combined formulation called Opdualag, which can provide a rate of remission about halfway between that of simple nivolumab or pembrolizumab and the more effective but more toxic combination of ipilimumab and nivolumab Similar antibodies from different companies are undergoing testing in several clinical settings, which may eventually define their role in patients with melanoma
Intratumoral immunotherapy using viruses to deliver signals to the immune system
Other treatments are being tested in patients with one or only a few localized, injectable sites of melanoma metastases that can be injected with substances that cause intense inflammation that triggers a strong local immune response The latest of these agents is a genetically-altered form of inactivated Herpes virus similar to the approved agent, TVEC, which has modest antitumor effects at the sites of injected tumors but little activity in distant sites of tumor that have not been injected. Further investigation will demonstrate the possibility that this newer virus, engineered to enhance its ability to alter the immune system’s recognition of tumor cells, is superior to TVEC and whether its antitumor effects will far outweigh any toxicities it may cause. Research also continues on the use of cytokines (molecules that are produced by one type of immune cell and send signals to another kind of immune cell), most recently in engineered forms, to enhance the immune system’s eradication of malignant cells
Development and testing of personalized cancer vaccines for melanoma
Cancer vaccine research began in melanoma but suffered a long series of failed strategies However, beginning in 2024, a complex but rational approach is finally being successfully applied to melanoma therapy At this year’s ASCO, we heard about the updated results of a preliminary study of a personalized melanoma vaccine produced using similar techniques to that of the highly-effective Moderna mRNA vaccine against severe Covid infection.
Melanoma is caused in part by genetic damage from the ultraviolet rays of the sun, which in turn leads to altered mRNA and proteins Fragments of these abnormal proteins can be recognized by immune cells in a way that stimulates killing of the melanoma cells displaying these fragments on their surface Thus, a so-called personalized or patient-specific vaccine can be produced from tiny amounts of patient melanoma tissue that can be obtained from needle biopsies or small surgical biopsies of the melanoma. This form of melanoma vaccine has shown great promise when used as a post-surgical adjuvant regimen in combination with pembrolizumab (one year of therapy), compared with pembrolizumab alone; ongoing studies are designed to validate the promise of this preliminary adjuvant therapy study and to obtain data regarding the power of this form of personalized cancer vaccine for patients with recurrent melanoma
Bispecificorbifunctionalstructuresin treatmentofmelanoma
Melanoma will not be the first disease in which to witness successful engineering of therapeutic molecules to make structures that can be used to link two important elements together for enhanced tumor killing. However, melanoma may well be one of the next few diseases where this approach can be applied successfully
The newest molecule to be ready for testing is created from the linkage of the antigen PRAME with an activating antibody that binds to and stimulates CD3, an important signaling molecule on killer T cells The result of this linkage of structure with function and tumor location is to bring a T lymphocyte into contact with an antigen that it would not normally recognize and to enhance its likelihood of attacking tumor cells expressing that antigen. Such approaches have already shown activity in other tumor types: a form of leukemia that is highly lethal is now treated routinely by the FDA-approved double-function drug blinatumomab, and the uveal form of melanoma, which is highly resistant to other forms of immunotherapy, appears to be controlled for prolonged periods by another FDA-approved double-function drug (tebentafusp) that links the melanoma antigen gp-100 with the anti-CD3 stimulating antibody described above.
This year’s ASCO was an exciting meeting that lifted spirits and raised survival curves to new heights in melanoma and several other malignancies.
All told, 2024 is turning out to be a banner year for big therapeutic advances in melanoma. With the explosive growth of knowledge about how melanoma is wired and how its surrounding immune environment can be understood and manipulated, the possibilities are now realistic for eradicating much more of the suffering and death from this disease in the foreseeable future
Dr Margolin is a Medical Director of the SJCI Melanoma Program, St John’s Cancer Institute. She worked at City of Hope for 30 years and also held faculty positions at the Seattle Cancer Care Alliance/University of Washington and at Stanford University. Among her academic achievements were long-term leadership of the Cytokine Working Group, leadership involvement in the Cancer Immunotherapy Trials Network, participation in the Southwest Oncology Group’s Melanoma Committee, and many positions in the American Society of Clinical Oncology and the Society for Immunotherapy of Cancer. Dr. Margolin has reviewed grants for many cancer-related nonprofit organizations and governmental agencies She has also served as a member of the Oncology Drugs Advisory Committee to the FDA, the American Board of Internal Medicine’s Medical Oncology certification committee, and the Scientific Advisory Committee of the European Organization for the Research and Treatment of Cancer.
Dr Margolin collaborates with AIM at Melanoma to write our In Plain English articles to provide timely updates on new developments for patients, caregivers, and other individuals with an interest in medical advances in melanoma
KIM MARGOLIN, M.D., FACP, FASCO
ASCO2024
ADVANCESINMELANOMAANDRELATEDCANCERS
In collaboration with Save Your Skin Foundation, we are excited to share this post-ASCO webinar. Dr. Omid Hamid, MD, the Chief of Research in Immuno-Oncology at The Angeles Clinic and Research Institute, provides insights and updates from ASCO 2024, with a special focus on melanoma, non-melanoma skin cancers, and ocular/uveal melanoma.
Our partner in Canada, Save Your Skin Foundation, is a charitable entity committed to increasing awareness and offering support to individuals impacted by skin cancer.
SUMMARYOFNEOADJUVANT NIVOLUMABANDIPILIMUMAB INRESECTABLESTAGEIII MELANOMA
ByMandiMurph,Directorof MedicalEducation,AIMatMelanoma
Treatment may be changing for patients with Stage III melanoma Recent clinical trial results show improved outcomes when ipilimumab plus nivolumab is given to Stage III patients with melanoma before the melanoma is removed by surgery. Giving drugs before surgery would be a major change to the order of treatment for this patient population.
Usually, patients with resectable (meaning it can be removed with surgery) Stage III melanoma begin treatment by receiving surgery to remove lymph nodes that contain melanoma. Following their surgery, many are treated with immunotherapy that is given every three, four, or six weeks for up to a year. Much of cancer is treated in this way – surgery before drug therapy. This is referred to as “adjuvant therapy.”
However, a Phase 3 clinical trial (NADINA) published in The New England Journal of Medicine and detailed in the plenary session at the 2024 ASCO meeting showed that patients with Stage III melanoma who received two rounds of ipilimumab plus nivolumab before surgery did better than those who first underwent surgery and then received 12 cycles of nivolumab These results have the potential to reverse the order of melanoma treatment for Stage III patients
Receiving the combination immunotherapy treatment before surgery led to an event-free survival of 83 7% The group receiving 12 cycles of nivolumab after surgery had an event-free survival of 57.2%. Event-free survival was defined as the time of randomization to the occurrence of progression to unresectable (meaning it cannot be removed by surgery) melanoma before surgery, disease recurrence (meaning the return of the melanoma), or death due to melanoma or due to treatment.
Changing the regimen to two cycles of the combination immunotherapy first, followed by surgery, increased event-free survival and reduced the risk of melanoma recurrence by 27% within the first 12 months. Also, 47.2% of the patients had a pathological complete response, meaning no tumor was detected by the pathologist when the remaining mass was surgically removed and examined under the microscope. These results confirm earlier Phase 1 and 2 studies, which showed similar outcomes.
Clinicians think combination immunotherapy before surgery works better because it generates a stronger immune response. They believe that the presence of the melanoma tumor is involved in inducing a more diverse and powerful response among immune cells than can be obtained with only microscopic circulating tumor cells, such as in the setting of postoperative treatment with immunotherapy Additionally, ipilimumab may broaden the immune response (make it recognize and kill a wider variety of melanoma cells) and is known to improve the effectiveness of nivolumab
Patients in the study had resectable, macroscopic (can be felt or can be seen without a microscope) lymph nodes, arising from Stage III cutaneous or acral melanoma or melanoma of an unknown origin The patients also had at least one lymph node with melanoma and a maximum of three other sites of metastases.
The study had limitations. Patients receiving ipilimumab plus nivolumab before surgery experienced higher rates of serious complications (36.3%) compared to other patients (23.6%). Clinicians say this emphasized the need to identify which patients will do better on one of these sequences rather than the other. Much of today’s cancer immunotherapy research is directed toward ways to identify the best match between patients and treatment so that the balance of benefit and risk may be optimized when choosing the best therapy. Summary of Neoadjuvant Nivolumab and Ipilimumab in Resectable Stage III Melanoma June 3, 2024
ThirdAnnual Evening in Memory of Val Guild
At the 2024 ASCO, the melanoma scientific community once again gathered for a special event The Third Annual Evening in Memory of Valerie Guild a fundraiser for AIM and a great evening for melanoma
Organized by the Melanoma Committees U S and worldwide (such as SWOG, ECOG, and EORTC; these are the cooperative groups that meet regularly, run clinical trials, assess data, etc ), this year’s event brought together over 160 of the world’s melanoma oncologists, researchers, KOLs (Key Opinion Leaders), pharmaceutical company leads, and others who work in melanoma
After a day full of formal conference sessions, the social atmosphere was welcomed. Old friends chatted and new friends were made. In addition to the standard food and drink, there was a special wine tasting of Napa Valley wines and several key speakers Dr Christian Blank, who gave the plenary talk at ASCO, spoke for a few minutes about the NADINA trial
Drs. Georgina Long and Toni Ribas talked about the future of melanoma treatment. And the highlight was a patient named David Harlan, who spoke alongside his doctor, Allison Betof Warner, about his TIL treatment David was “Patient #1” the first patient to receive TIL treatment after the FDA approved it for melanoma in February, 2024
Please view the picture gallery of the event here.
The party is a tribute to Val Guild, who founded AIM and who was melanoma’s patient advocate extraordinaire. The money raised at this event helps fund the research and patient projects to which Val devoted her life after her daughter’s passing from melanoma.
The Featured Sponsors for this year’s event were Bristol Myers Squibb, Castle Biosciences, Pfizer, and Regeneron; the Collaborating Sponsors were Iovance and Merck; and the Contributing Sponsors were Immunocore and Replimune. AIM at Melanoma thanks these generous sponsors and the Melanoma Committees U.S and worldwide for their support.
Val Guild Founder AIM at Melanoma Foundation
