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Immune checkpoint inhibitors (ICIs) have revolutionized cancer care over the past decade. These drugs can result in robust and durable remissions in melanoma and other cancer types. Despite continual advancements, including combinatorial ICI regimens designed to improve response rates and survival outcomes in patients with advanced melanoma, these drugs have 2 main problems: A large percentage of patients do not respond to ICI treatment and excessive activation of the immune system can lead to significant complications (termed immune-related adverse effects [irAEs]), which can involve almost any organ in the body.

Many biomarkers cannot predict which patients will respond and/or develop a complication from ICIs, as they often fail to fully capture the complexity of the tumor response during treatment. Tissue biopsy–based biomarkers require invasive procedures, and peripheral blood biomarkers cannot account for spatial information of tumors. Neither can account for immune response in multiple organs simultaneously, which can overlook early signs of tumor progression and severe irAEs.

Noninvasive assessment of ICI response both spatially and temporally makes imaging an ideal tool. However, the optimal timing to evaluate ICI response is unclear. Current standard practice is to repeat imaging approximately 3 months after initial treatment. Earlier response assessment with a standard CT scan is often interpreted with caution, as there is no consensus or analytic framework to differentiate between pseudoprogression—where disease response occurs after an initial increase in tumor burden during treatment with ICI—and true disease progression. Although rates of pseudoprogression are unclear for combinatorial ICI therapy, they have been reported in up to 10% of patients treated with ICI monotherapy.

Progressive disease (PD) during early initial response assessment may still be predictive of survival outcomes in patients with advanced-stage melanoma treated with dual-agent ICI therapy. We previously published a study evaluating patients with advanced melanoma treated with the combination of ipilimumab (Yervoy) plus nivolumab (Opdivo) and evaluated radiographic (CT or MRI) response after 1 and/or 2 doses of therapy. We found that achieving a clinical benefit response vs PD per RECIST 1.1 after 2 doses was predictive of progression-free survival (PFS; HR, 0.09; 95% CI, 0.05-0.16; 

 < .001) and overall survival (OS; HR, 0.07; 95% CI, 0.03-0.14; 

 .001) benefit. Furthermore, in a subset of patients who underwent radiographic response assessment after 1 dose of ipilimumab plus nivolumab, early response was also predictive of PFS (HR, 0.16; 95% CI, 0.08-0.33; 

 < .001) and OS (HR, 0.12; 95% CI, 0.05-0.32; 

As neoadjuvant ICI therapy enters the treatment landscape for resectable melanoma, imaging assessment will be increasingly important in evaluating tumor responses before surgery. Conventional CT and MRI imaging methods may be insufficient to characterize outcomes. Discordance between radiographic and pathologic responses has been observed.

Several studies have investigated the utility of 18F-fluorodeoxyglucose (18F-FDG) PET/CT imaging in early detection of response to targeted and chemotherapeutic agents in a variety of tumor types. Functional imaging information from 18F-FDG PET can complement data from anatomic imaging studies from CT and MRI. The role of 18F-FDG PET/CT in the early detection of ICI response continues to be an area of ongoing exploration. In one study, melanoma response by 18F-FDG PET/CT at 3 to 4 weeks after starting ICI monotherapy was shown to be indicative of future best response.

In the phase 3 CheckMate 067 trial (NCT01844505), 59% of patients treated with standard-dose ipilimumab plus nivolumab experienced grade 3 to 4 treatment-related AEs.

The effects of these irAEs can have significant financial burdens and impacts on quality of life. Costs associated with managing grade 3 to 4 irAEs can be up to approximately $47,000 per effect.

To date, there are no validated biomarkers to predict the onset or severity of irAEs.Comprehensive spatiotemporal information from 18F-FDG PET/CT can not only allow for assessment and monitoring of treatment efficacy but may also provide predictive information for ICI-induced toxicities. In one of our studies, we found that organ-specific 18F-FDG uptake cutoff values in the bowel, lung, and thyroid can be predictive of developing irAEs in patients with melanoma treated with ICIs before clinical symptoms appear.

Early assessment of treatment response can lead to actionable changes without compromising long-term clinical outcomes. A response-adapted treatment strategy is adopted in the management of advanced classic Hodgkin lymphoma, where early interval FDG PET/CT is often performed after 2 cycles of chemotherapy to guide the appropriateness of treatment deescalation to help minimize treatment-associated toxicities.

Given the unacceptably high rates of severe irAEs in patients with melanoma treated with combinatorial ICIs, efforts to mitigate these AEs with a risk-adapted treatment strategy warrant similar exploration. In the phase 2 ADAPT-IT study (NCT03122522), adaptive dosing of nivolumab plus ipilimumab based on early radiographic assessment displayed comparable response and toxicity rates compared with historical data for conventional administration of the combination in patients with advanced melanoma. Patients received 2 doses of nivolumab plus ipilimumab followed by repeat imaging at week 6. Patients with early favorable antitumor effect (FATE) were transitioned to nivolumab monotherapy, and those without FATE received the remaining 2 induction doses of nivolumab plus ipilimumab followed by nivolumab monotherapy, per standard of care. Although the results of the study are promising for a novel treatment strategy in melanoma management, a larger validation study is warranted. The study also raises the consideration of exploring response assessment after 1 dose of combination ICI.

We have an ongoing pilot study at the University of Wisconsin evaluating the role of 18F-FDG PET/CT and circulating tumor DNA assessment after 1 cycle of combinatorial ICI (nivolumab/relatlimab [Opdualag] or ipilimumab/nivolumab) in patients with advanced stage melanoma. The goals of the study are to accurately predict clinical efficacy (best response and survival) and identify the subclinical onset of irAEs with an early interval 18F-FDG PET/CT 3 to 4 weeks after starting treatment. We anticipate that the results of our study will one day provide clinicians with actionable, quantitative, and clinically relevant decision-making data to optimally balance ICI benefits and risks, potentially improve clinical outcomes, reduce toxicities, and decrease health care costs for many patients.

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Articles

 Functional imaging information from 18F-FDG PET can complement data from anatomic imaging studies from CT and MRI to predict response to ICI therapy.

18F-FDG PET/CT May Serve as Early Interval Response Assessment Tool in Patients Receiving Combinatorial ICI Therapy

Taking part in community outreach and engagement conversations centered around key matters affecting National Cancer Institute (NCI)-designated cancer centers, such as Cancer Center Support Grants (CCSGs) and catchment, are crucial for community outreach offices, according to Kiara Ellis, MSW.

“[Working in community outreach], we serve as a key bridge in developing best practices that will be impactful,” Ellis said. “There are centers that do a lot of work with their patient population—how do we approach [them] about clinical trials? How do we share information about these complicated cancers? What is it they want to know? It’s the outreach offices that drive that work. Sometimes they can be underutilized or not tapped [into] for that expertise in all settings, but being able to bring relationships to the cancer centers anchors the center in their community. Without that component and great support for that component, it doesn’t give the cancer center the legs it needs to be interactive in its community.”

Bringing the members of different NCI-designated cancer center community outreach and engagement (COE) offices together serves to further extend an office’s impact in the community it serves. The Cancer Center Community Impact Forum (CCCIF), a national meeting of COE professionals in the US, has highlighted matters that are essential to a COE office since its formation in 2019. The 2023 CCCIF brought up several key topics such as catchment and CCSGs and gave community outreach professionals the opportunity to see how peers are engaging their community to extend the reach of the cancer center.

Ellis, the director of community outreach and engagement at the Masonic Cancer Center, University of Minnesota, in Minneapolis, is a founder of the conference, which was created to feel tactical and practical for staff in the cancer centers. “[Topics we discuss with colleagues include] how to build our community engagement boards, showcasing successful offices that got high marks in their CCSG,” Ellis said. “Who are those champions, and how did they highlight the wins that their office had in their CCSG to get that high score? We talk about catchment and connection with our clinical partners, [as well as] marketing and communications and the role that plays in lifting up the community outreach work that we do.”

The 5-year CCSG has proven to be instrumental for institutions, with the UCSF Helen Diller Family Comprehensive Cancer Center noting that the grant is a major source of federal funding for their center, equaling approximately $7 million in total costs per year.

 Yale Cancer Center also reported that the CCSG provides the resources and infrastructure to aid in the coordination of 6 of the center’s interdisciplinary research programs that range from basic laboratory research to clinical investigations.

“[Catchment is] one of those huge and powerful topics because I don’t know that all our outreach staff and faculty are as immersed in geospatial mapping and that data piece [of it]. Catchment informs our work,” Ellis said.

The catchment area of the Masonic Cancer Center encompasses the entire state of Minnesota, and cancer is the state’s leading cause of death. Masonic noted that meeting diverse communities is essential, as Minnesota has the largest Somali American population in the US, the largest urban population of Hmong people in the world, and 11 federally recognized American Indian tribes.

“The work we’ve done has been bringing awareness to our community partners about this amazing resource. [MCC is] a hidden gem in the Twin Cities; you don’t have to go far for great care, and you don’t have to go far if you’re interested or thinking about clinical research or being involved in it. We’re right in your city. There are ways you can engage with us, and meeting [the] community where they’re at is one of the biggest ways we’ve gone about doing it,” Ellis said.

Additionally, a recent catchment analysis conducted in Delaware characterized the geographic distribution of mammography sites and Breast Imaging Centers of Excellence. The study, which was published in 

, identified census tract–level correlates of access and additional areas that could serve as mammography sites per breast cancer screening guidelines.

For each standard deviation increase in the number of Black women in a census tract, the catchment analysis determined there were 89% (95% CI, 60%-98%) fewer Breast Imaging Centers of Excellence and 68% (95% CI, 38%-85%) fewer mammography units. Additionally, more rural counties comprised 41% of Delaware’s population; however, only 22% of the Breast Imaging Centers of Excellence were in rural counties. The study authors concluded that using catchment and location-allocation analytic tools may aid in reducing breast cancer disparities and selecting new locations for mammography facilities.

Delving Into How Colleagues Bring Care to The Community

One of the preconference activities at the 2023 CCCIF meeting included a community tour. “This year at Sylvester [Comprehensive Cancer Center] in Miami during our social event, we got to see their ‘Game Changer’ mobile unit and how they’re doing screening in the community,” Ellis said. “They brought the unit [to the community], their staff was there, and we got to talk to them and ask questions focused on that example.”

Sylvester Comprehensive Cancer Center’s three 40-ft Game Changer vehicles have been bringing free cancer screenings to neighborhoods in South Florida since 2018, which was made possible by support from community organizations and philanthropic donors. Multilingual health care professionals from Sylvester travel to local libraries, businesses, or community events such as health fairs where they offer screening for HIV and prostate, colorectal, gastric, and head/neck cancers.

In the first 7 months of 2023, Sylvester reported that they screened more than 300 adults, identified 33 positive results, and referred all those with positive results for follow-up care.

“One of the bigger impacts from this conference is that connection to NCI, how decisions are made, and [what] future planning is happening for various areas. Community outreach—in any space, not just cancer centers—sometimes is a topic that can be glossed over,” Ellis said. “The way that our groups have come together has shown us how essential these offices are and how supporting that infrastructure can push forward and make a large impact in the communities we serve, which is our goal.”

Moreover, at the 2022 CCCIF meeting, Simona Kwon, DrPH, MPH, an associate professor in the Department of Population Health, director of the section for health equity, and vice chair for diversity, equity, and inclusion in the Department of Population Health at NYU Langone Health Perlmutter Cancer Center, served as a panelist who discussed innovative methods of COE. A method of community engagement employed by Kwon and colleagues at Perlmutter Cancer Center in New York includes the Stamp Out Cancer Brooklyn initiative, which engages local communities on cancer prevention, early detection, care, and survivorship topics. Stamp Out Cancer and the Brooklyn Public Library hold 4-part virtual workshops once a month encompassing a variety of cancer awareness topics.

Ellis explained that the CCCIF began after the Masonic Cancer Center hosted the Cancer Center Administrators Forum in 2019, which focused on administrative leadership in NCI-designated centers and those seeking NCI designation.

 After the event, she realized she had never met any other COE leaders. Ellis then connected with Julie HT Dang, PhD, MPH, an assistant adjunct professor in the Department of Public Health Sciences and the executive director in the Office of Community Outreach and Engagement at UC Davis Comprehensive Cancer Center, to begin planning the CCCIF. Discussions at the American Society of Preventive Oncology annual meetings also inspired the creation of the location-rotating CCCIF meeting, as COE was discussed frequently.

“[Community outreach for cancer centers] is vital,” Ellis said. “Research in a laboratory or even behind the scenes can only go so far. It advances the scientific community and the way the medical community approaches treatment and support, but it’s the outreach office that is the wheels on the bus. [The outreach office] brings knowledge into the community, listens and relates to community voices, and brings that information back to the cancer centers.”

Understanding the CCSG. University of California San Francisco. Accessed December 19, 2023. bit.ly/47m8kQx

The Cancer Center Support Grant (CCSG/P30). Yale Cancer Center. Accessed December 19, 2023. bit.ly/3RPsSMv

About community outreach and engagement. University of Minnesota. Accessed December 19, 2023. bit.ly/3TrqrRD

Webster JL, Goldstein ND, Rowland JP, Tuite CM, Siegel SD. A catchment and location-allocation analysis of mammography access in Delaware, US: implications for disparities in geographic access to breast cancer screening. 

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Sylvester’s Game Changer vehicles bring free cancer screenings to underserved South Florida communities. News release. Newswise. August 23, 2023. Accessed December 19, 2023. bit.ly/48HW5Pl

Community outreach & engagement core. NYU Langone Health. Accessed December 19, 2023. bit.ly/41rlxpL

Stamp out cancer: how can we do it? Brooklyn Public Library. Accessed December 19, 2023. bit.ly/476kgWb

Leader AE, Brandt HM, Briant KJ, et al. Community outreach and engagement at U.S. cancer centers: notes from the third Cancer Center Community Impact Forum. 

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CCAF Cancer Center Administrators Forum. Cancer Center Administrators Forum. Accessed December 19, 2023. bit.ly/3trI2OQ

Kiara Ellis, MSW, details community outreach and engagement conversations centered around key matters affecting NCI-designated cancer centers.

Outreach and Engagement: Colleagues Come Together to Improve Community Care 

Concepts that originated from basic research have kept the hematology field on its toes as they turn into significant advancements, and promising new therapies to treat malignancies and graft-vshost disease (GVHD) continue to emerge. The high-precision cell therapy Orca-T is one that has surfaced in clinical trials for patients who received allogeneic hematopoietic stem cell transplant (HSCT), as is axatilimab, which stood out at the 2023 American Society of Hematology (ASH) Annual Meeting & Exposition as a potential future option for patients with GVHD. 

“It’s extraordinary to see the breadth of scientific inquiry and how that is now impacting patients,” Robert S. Negrin, MD, vice president of ASH and a professor of medicine at Stanford University in California, said in an interview with OncologyLive. “My own research endeavors are interesting. Some of the work that we did in murine models 20 years ago, we’ve [just] published the first papers on.” 

Negrin explained that he’s excited about further development of gene therapy applications. When considering all that has been learned about sickle cell disease—ranging from etiology to the discovery that enhancing fetal hemoglobin can help correct it—the therapies developed from these concepts are nothing short of amazing to Negrin. “It is incredible stuff,” he said. 

Exciting endeavors investigators are exploring include those focused on the treatment of patients with GVHD. Because chronic GVHD significantly impacts quality of life and is a main cause of late morbidity in approximately 30% to 50% of patients, there is a need for well-tolerated, efficacious treatments. Data on the CSF-1R targeted investigational monoclonal antibody axatilimab presented at 2023 ASH demonstrated promise as patients receiving the agent at 0.3 mg/kg every 2 weeks had durable and rapid responses.

Findings from the phase 2 AGAVE-201 trial (NCT04710576) revealed that patients experienced an overall response rate of 74% (95% CI, 63%-83%) in the 0.3 mg/ kg every 2 weeks cohort (n = 80), 67% (95% CI, 55%-77%) at 1.0 mg/kg every 2 weeks (n = 81), and 50% (95% CI, 39%-61%) in the 3.0-mg/ kg every-4-weeks cohort (n = 80). Additionally, 60% (95% CI, 43%-74%) of patients maintained a response for at least 12 months in the 0.3-mg/kg cohort.

“Axatilimab is a new drug to treat chronic GVHD that’s being developed. It came from basic research to now clinical application, and hopefully a drug approval [will occur]. We will see how we use cellular-based therapeutics to improve outcomes for our patients who are undergoing transplant— [that] is an area of extraordinary growth with lots of activity right now,” Negrin said. 

Findings from the safety population of the 0.3-mg/kg cohort (n = 79) revealed that the most common any-grade adverse events (AEs) associated with axatilimab treatment were fatigue (22.8%), headache (19.0%), and COVID- 19 (16.5%), and 17.7% of patients experienced at least 1 grade 3 or higher AE. One patient in the 0.3-mg/kg cohort, 7 patients in the 1.0-mg/kg cohort, and 6 patients in the 3.0-mg/kg cohort (n = 79) died from an AE. Notably, rates of periorbital edema were 2.5% vs 23.5% vs 29.1%, respectively. The rates of laboratory abnormalities were also lower in the 0.3-mg/kg arm, and the most common events included increased levels of aspartate aminotransferase (13.9%), lactate dehydrogenase (13.9%), alanine aminotransferase (12.7%), creatine phosphokinase (11.4%), lipase (11.4%), and amylase (3.8%).

“Our field is extraordinarily rich,” Negrin said of the findings presented at 2023 ASH. “What’s most extraordinary to me is that it’s no longer just the laboratory-based scientists and the clinicians working in parallel universes—now these 2 worlds have come together in truly profound ways.” 

High-Precision Cell Therapy Gains Traction

Orca-T has also sparked promise with previous data from a phase 1/2 trial (NCT01660607) demonstrating that the high-precision cell therapy produced a 100% overall survival rate in 8 patients with hematologic malignancies who received an allogeneic HSCT with 7/8 nonpermissive human leukocyte antigen mismatched donors.

“This concept of using a ‘precision graft’ instead of just isolating cells from the donor, but now purifying different cell populations that may bring out some of the positive impacts of an allogeneic transplant, [can] limit some of the challenges like GVHD and perhaps improve immune recovery,” Negrin said.

Investigators who presented data at 2023 ASH on Orca-T noted that there’s an opportunity to improve clinical outcomes from allogeneic HSCT; as current transplants are an uncontrolled mix of more than 50 cell types typically administered together in a single infusion, cellular selection may allow for greater benefit.

Orca-T therapy has 3 separate components: hematopoietic stem cells infused on day 0, highly purified regulatory T cells given in a separate infusion on day 0, and conventional T cells infused on day plus 2 (Figure). 

Presenting author Caspian Oliai, MD, MS, medical director of the UCLA Bone Marrow Transplantation Stem Cell Processing Center at UCLA Health in Los Angeles, California, said, “This separation allows for the regulatory T cells to travel to the solid organs first so that by the time the conventional T cells arrive, an immune barrier is in place that can potentially mitigate GVHD while maintaining an optimal graft vs leukemia effect through natural immune reconstitution. This has been demonstrated preclinically.”

Negrin noted, “To me, this Orca-T trial represents a combined effort to try to move these concepts forward from promising preclinical studies to initial studies in patients and now, finally, a phase 3 registration trial. I hope the trial is successful, but it represents a little bit more than just the success of that individual product. [It represents] this cooperative reliance of academia and pharmaceutical companies that is critical to move concepts forward to the success and benefit of our patients.” 

The phase 3 Precision-T trial (NCT05316701) is currently enrolling approximately 174 patients with advanced hematologic malignancies undergoing allogeneic HSCT to receive Orca-T or standard-of-care allogeneic graft.

Negrin Looks to Leave a Global Mark on ASH 

With the conclusion of 2023 ASH, Negrin has assumed his 1-year role as vice president; his terms as president-elect and president will follow. A member of ASH since 1998, Negrin was the chief of the Division of Blood and Marrow Transplantation at Stanford University from 2000 to 2020 and was founding editor in chief of the peer-reviewed journal Blood Advances from 2016 to 2021.

“I’ve been involved with ASH for several decades now so I’m excited and incredibly honored to be able to take on a leadership role,” Negrin said. “I’m particularly interested in ASH’s international role. How do we more effectively utilize the success that ASH has achieved in being the leading voice in the field of hematology to impact our more global community? How do we utilize the science that is being developed to [usher in] new therapies and do whatever we can to make sure they’re available to our patients, especially those in greatest need and who are most vulnerable? That’s an area that we have a lot of work to do in.” 

One of several ASH programs designed for hematologists practicing outside of the US, Mexico, and Canada is the Translational Research Training in Hematology joint program with the European Hematology Association; the yearlong training and mentoring experience is for junior researchers.

Additionally, regarding research in the transplant field, Negrin noted he’s interested in ways to “solve or make inroads on challenges and extend transplant into other areas. There’s a lot of work being done, for example, to treat [diseases] other than hematologic malignancies such as autoimmune disorders or induction of solid organ tolerance as we learn how to manage the complications of transplant,” Negrin said. 

He noted that funding is an area he also hopes to home in on during these next few years with ASH. “The funding environment that we’re in is still very challenging not only for academic researchers but also for investment in a lot of these concepts,” Negrin noted. 

"I’ve seen several companies that have very successful ideas [and are] not able to find funding, so I hope that we’ll be able to advocate for improved financial support, not only for academia but also for the development of these concepts,” he said. “Ultimately, how do we export them to our patients? How do we meet the patients in greatest need from the most challenging environments, both in our country and abroad? How do we provide these benefits to those individuals as well? [These] are areas that are incredibly important and areas that I hope to work on in my roles in the ASH leadership.”

Wolff D, Cutler C, Lee SJ, et al. Safety and efficacy of axatilimab at 3 different doses in patients with chronic graft-versus-host disease (AGAVE-201). Blood. 2023;142(suppl 1):1. doi:10.1182/blood-2023-186963 

Pavlova A, Lowsky R, Muffly LS, et al. Orca-T, a high-precision cell therapy, for the treatment of hematologic malignancies in patients with 7/8 mismatch donors. Presented at: 2023 Transplantation & Cellular Therapy Meetings of ASTCT and CIBMTR; February 15-19, 2023; Orlando, FL. Abstract 30. 

Oliai CH, Pantin JM, Hoeg RT, et al. Optimizing outcomes with myeloablative conditioning in older patients: efficacy and safety of precision engineered Orca-T in patients > 55 years old with hematologic malignancies. Blood. 2023;142(suppl 1):230. doi:10.1182/blood-2023-186749 

Precision-T: a randomized phase III study of Orca-T in recipients undergoing allogeneic transplantation for hematologic malignancies (Orca-T). ClinicalTrials.gov. Updated September 26, 2023. Accessed December 20, 2023. bit.ly/3RFmGFQ 

New leadership elected to the American Society of Hematology. News release. American Society of Hematology. October 26, 2023. Accessed December 20, 2023. bit.ly/3RRcafN 

Robert Negrin. Stanford Medicine CAP Profiles. Stanford Medicine. Accessed December 20, 2023. bit.ly/48pp6Px 

Global initiatives. American Society of Hematology. Accessed December 20, 2023. bit.ly/3GTNHjA

The field of hematology is experiencing significant advancements as promising new therapies for malignancies and GVHD continue to emerge. 

Vice President of ASH Will Focus on Gene Therapies, ASH’s Global Impact

 Peer Exchange, expert oncologists reviewed long-term and preliminary data from key clinical trials in the field of melanoma that could add clarity to treatment standards and lead to improved patient care. During their discussion, the panelists paid particular attention to therapies for patients with 

-mutated disease and brain metastases. Findings were primarily presented during the European Society for Medical Oncology (ESMO) Congress 2023, which took place from October 20 to 24, 2023, in Madrid, Spain.

The panel began the discussion by emphasizing the importance of consistent genetic testing for patients with advanced melanoma, including immunohistochemistry and standardized next-generation sequencing, to identify patients who could be good candidates for a given therapy. Then they dove into updates from clinical trials in the field presented during ESMO 2023, first examining therapies for patients with 

"[BRAF] testing is helpful because psychologically when the patient first gets diagnosed, it's devastating and they're wondering what options they have," 

 said. "Even if you don't use that piece of data right away, it colors your interaction with them and what you can offer that patient in terms of [treatment] options."

In the phase 2/3 RELATIVITY-047 trial (NCT03470922), investigators evaluated the combination of the anti-LAG-3 antibody relatlimab and the anti-PD-1 antibody nivolumab (Opdualag) compared with nivolumab (Opdivo) monotherapy in patients with previously untreated, unresectable, or metastatic melanoma. Previously published findings from RELATIVITY-047 showed that, at a median follow-up of 25.3 months, nivolumab plus relatlimab continued to display a benefit over nivolumab monotherapy; the median progression- free survival (PFS) was 10.2 months vs 4.6 months, respectively (HR, 0.81; 95% CI, 0.67- 0.97), and the median overall survival (OS) was not yet reached (NR) vs 33.2 months, respectively (HR, 0.82; 95% CI, 0.67-1.02).

In March 2022, the FDA approved the combination of nivolumab and relatlimab for the treatment of adult and pediatric patients 12 years or older with unresectable or metastatic melanoma. The regulatory decision was supported by findings from RELATIVITY-047.

To further define the clinical characteristics of relatlimab plus nivolumab, investigators performed subgroup analyses, from which findings with 2 years of follow-up were presented during ESMO 2023. Data showed that the combination offered a PFS benefit over nivolumab monotherapy in subgroups of patients with baseline liver lesions (HR, 0.81; 95% CI, 0.53- 1.23) as well as those with baseline lung lesions (HR, 0.77; 95% CI, 0.57-1.05). Additionally, the combination also provided an OS benefit over nivolumab monotherapy in these groups, with respective HRs of 0.62 (95% CI, 0.37-1.03) and 0.72 (95% CI, 0.50-1.04). The central nervous system (CNS) metastasis-free survival in patients without CNS lesions at baseline also favored the combination arm (HR, 0.66; 95% CI, 0.34-1.27).

Study authors concluded that relatlimab plus nivolumab provided an efficacy benefit over nivolumab monotherapy in patients with advanced melanoma regardless of number of baseline disease sites or the presence of baseline liver or lung lesions. They also noted that the combination displayed early signals of CNS activity and a manageable safety profile with a favorable risk to benefit ratio.

“When I meet a frontline patient and I’m planning to do immune therapy, I first think, ‘Can I give you full-dose ipilimumab [Yervoy] plus nivolumab?’ If not, then certainly nivolumab plus relatlimab is my mainstay, as opposed to single-agent PD-1 [therapy],” 

, said. “Since the approval of relatlimab, I have given select patients singleagent– PD-1 [therapy]. What we saw in the RELATIVITY-047 study was that the toxicity [with nivolumab plus relatlimab] was very similar to anti–PD-1 monotherapy, but double the PFS, so I do like that option for some patients. [However], based on the long-term data [from the phase 3 CheckMate 067 trial] that we have with ipilimumab plus nivolumab, that’s still my go-to.”

“The patient has to decide, and we owe it to them to portray the toxicity as fully as we can,” 

, added. “[The key is] the detailed presentation of the toxicities of the two regimens [and choosing between] the maturity of the data for ipilimumab plus nivolumab vs the hope, but still early status for the relatlimab plus nivolumab trial data, and then it’s [the patient’s] decision. [However], ipilimumab plus nivolumab is the default; at this point in time I believe that is the gold standard.”

Ipilimumab with or without nivolumab was evaluated in patients with PD-1/L1 blockade refractory metastatic melanoma in the phase 2 S1616 study (NCT03033576). The study enrolled patients with metastatic melanoma who had received frontline anti-PD-1/L1 inhibition and experienced disease progression (n = 92). Patients were randomly assigned 3:1 to receive nivolumab plus ipilimumab or ipilimumab monotherapy. The primary end point was PFS; secondary end points included objective response rate (ORR), OS, and safety.

Updated findings from the study showed that treatment with the combination resulted in a significant improvement in PFS compared with ipilimumab (HR, 0.63; 90% CI, 0.41-0.97, 1-sided 

 = .04). Additionally, the ORR was 28% (90% CI, 19%-38%) vs 9% (90% CI, 2%-25%), in the nivolumab plus ipilimumab vs the ipilimumab arm, respectively (1-sided 

 = .05). Investigators concluded that primary resistance to PD-1 blockade could be reversed in some patients with the combination of CTLA-4 and PD-1 blockade, although the change in intratumoral CD8 T-cell density had not reached significance.

Another study that evaluated a combination approach in patients with locally advanced, unresectable, or metastatic melanoma was the phase 3 COLUMBUS trial (NCT01909453). The study enrolled patients with 

 V6000E/ K-mutated disease who were treatment naive or had progressed following frontline immunotherapy, had an ECOG performance status of 1 or less, and had received no prior therapy with a BRAF and/or MEK inhibitor. COLUMBUS evaluated the combination of the BRAF inhibitor encorafenib (Braftovi) plus the MEK inhibitor binimetinib (Mektovi) vs encorafenib or vemurafenib (Zelboraf). The primary end point was PFS; secondary end points included ORR, OS, and safety.

Findings from the 7-year update of COLUMBUS presented during ESMO 2023 demonstrated that patients in the combination (n = 192), vemurafenib (n = 191), and encorafenib (n = 194) arms experienced 7-year PFS rates of 21.2% (95% CI, 14.7%-28.4%), 6.4% (95% CI, 2.1%-14%), and 15.8% (95% CI, 9.3%- 23.8%), respectively, with the combination offering a PFS benefit over both vemurafenib (HR, 0.51; 95% CI, 0.39-0.66) and encorafenib (HR, 0.77; 95% CI, 0.60-0.99). Additionally, encorafenib plus binimetinib conferred a significant OS benefit vs vemurafenib (HR, 0.67; 95% CI, 0.53-0.84) and a slight benefit over encorafenib (HR, 0.93; 95% CI, 0.73-1.18; 

Investigators concluded that encorafenib plus binimetinib displayed long-term, sustained efficacy with more than 20% of patients free of progression. The combination also displayed a safety profile consistent with that previously reported of the agents with no new safety signals.

Moreover, study authors also shared findings from the phase 2 REDUCTOR trial (EudraCT2013-002616-28) during ESMO 2023. REDUCTOR examined the clinical utility of neoadjuvant cytoreductive BRAF/MEK inhibition with dabrafenib (Tafinlar) plus trametinib (Mekinist) to allow for complete surgical resection in patients with previously unresectable, locally advanced 

-mutated melanoma. Previous findings from the study showed that major pathologic responses were observed in 50% of patients who received the combination and underwent surgery (n = 18).

Results from the long-term survival follow-up of REDUCTOR presented during the conference showed that, at a median follow-up of 80.9 months (IQR, 38.6-89.7), the median relapse-free survival was 15.4 months (95% CI, 8.89-not reached [NR]) in patients who received the combination and underwent surgery (n = 18). Additionally, the median PFS was 12.4 months (95% CI, 8.68-NR); the median OS was NR, but the 1-, 3-, and 5-year OS rates were 100%, 85% (95% CI, 70.7%-100%), and 75% (95% CI, 58.2%-96.6%), respectively.

“In those patients who relapse with resectable, regional disease we have a second gun loaded in our holster [following recurrence] because we have PD-1–[directed] interventions that are highly effective,” Kirkland said. “The modality of circulating tumor DNA tracking is something that we will use more and more in those scenarios. Also, in [terms of] monitoring the patient with BRAF/MEK treatment, we will probably learn more about this in the next few years, which will allow us to intelligently approach this going forward.”

“That’s going to be a big question: response in the metastatic setting with prior exposure to these agents in the adjuvant setting. We don’t have formal data on this exactly, but I would hope that the longer gap in between the adjuvant and the metastatic treatment can keep the patient sensitized to another course of what they’ve had,” 

The panel transitioned the conversation to discuss treatment options for patients with melanoma brain metastases. Melanoma is among the solid tumors most likely to lead to brain metastases; greater than 25% of patients have metastatic disease at the point of diagnosis and more than 15% have brain metastases. Notably, 75% of patients with melanoma have been found to die with brain metastases, according to autopsy reports. Brain metastases in melanoma are also associated with worse outcomes and, despite treatment advances, there is no optimal treatment available to manage melanoma-related brain metastases.

During ESMO 2023, investigators presented findings from the 7-year follow-up analysis of the phase 3 NIBIT-M2 trial (NCT02460068), which enrolled patients with metastatic melanoma with active and untreated asymptomatic brain metastases; patients were not allowed to have received prior systemic therapy for advanced disease. The study randomly assigned patients 1:1:1 to receive fotemustine (arm A; n = 23), ipilimumab plus fotemustine (arm B; n = 26), or ipilimumab plus nivolumab (arm C; n = 27). The primary end point was OS; secondary end points included PFS, intracranial and global immune-related (ir) ORR, and safety.

At the May 1, 2023, data cutoff, at a median follow-up of 67 months (IQR, 42-79), the median OS in arms A, B, and C was 8.5 months (95% CI, 4.8-12.2) vs 9.1 months (95% CI, 4.3-20.4) vs 29.2 months (95% CI, 12.9-65.1), respectively. The 5-year OS rates were 10%, 10%, and 43%, respectively; notably, 43% of patients remained alive in arm C at 7 years. The median PFS was 3.0 months (95% CI, 2.3-3.6) vs 3.5 months (95% CI, 1.2-5.9) vs 8.7 months (95% CI, 5.7-17.6), respectively.

Notably, patients who received ipilimumab plus nivolumab experienced a significant benefit in terms of intracranial irORR; the rates were 0% vs 19.2% vs 44.4% in arms A, B, and C, respectively. Additionally, the ir disease control rates (DCRs) were 21.7% vs 34.6% vs 55.5%, respectively. In terms of global response, the irORRs were 0% vs 23.1% vs 44.4%, respectively. The global response irDCRs were 17.4% vs 30.8% vs 55.5%, respectively.

“If a patient has truly asymptomatic disease and has a BRAF mutation, you’re in this fortunate situation where you have a lot of options,” 

, said. “You have 3 generations of BRAF/MEK inhibitors, and you have fulldose ipilimumab at 3 mg with nivolumab at 1 mg. We’ve never compared the head-to-head activity of one group of drugs vs another, [but] we feel comfortable with the immunotherapy responses and the durability. [Data from] the NIBIT-M2 study showed that those asymptomatic patients are doing quite well in the long run. Immunotherapy [with ipilimumab plus nivolumab] remains our go-to for them, and we hope that that becomes a long-[term] treatment and that they get the benefit of that treatment- free interval.“

Finally, in the phase 2 SECOMBIT trial (NCT02631447) study authors compared a targeted approach with encorafenib plus binimetinib (arm A) with the immunotherapy combination of ipilimumab plus nivolumab (arm B), and evaluated a third arm in patients who received encorafenib plus binimetinib with a preplanned switch to ipilimumab plus nivolumab at 8 weeks then back to encorafenib plus binimetinib after progression. Patients in arm A switched to the arm B regimen following progression and vice versa. The primary end point was OS; secondary end points included PFS, ORR, and safety.

At the May 31, 2023, data cutoff, at a median follow-up of 56 months (IQR, 48-63), findings presented during ESMO 2023 demonstrated that the 5-year OS rates in arms A (n = 69), B (n = 69), and C (n = 68) were 45% vs 52% vs 57%, respectively. An exploratory analysis showed that patients in both arms B (HR, 0.75; 95% CI, 0.46-1.22; 

 = .25) and arm C (HR, 0.71; 95% CI, 0.43-1.16; 

 = .17) experienced an OS benefit vs those in arm A.

The 5-year PFS rates in arms A, B, and C were 27% vs 50% vs 50%, respectively. Data from an exploratory analysis showed that both arms B (HR, 0.61; 95% CI, 0.39-0.94; 

 = .03) and arm C (HR, 0.58; 95% CI, 0.37-0.90; 

 = .02) achieved a significant PFS benefit over arm A.

The authors concluded that, although the study was limited by its phase 2 nature and small patient population, patients treated in arm A were at a higher risk of developing brain metastases than those in arms B and C. The study is ongoing to evaluate long-term outcomes and additional biomarkers, they noted.

Long GV, Hodi FS, Lipson EJ, et al. Nivolumab (NIVO) plus relatlimab (RELA) vs NIVO in previously untreated metastatic or unresectable melanoma: 2-year subgroup analyses from RELATIVITY-047. 

. 2023;34(suppl 2):S664-S665. doi:10.1016/j.annonc.2023.09.2237

FDA approves Opdualag for unresectable or metastatic melanoma. News release. FDA. Updated March 21, 2022. Accessed December 19, 2023. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-opdualag-unresectable-or-metastatic-melanoma

VanderWalde A, Bellasea SL, Kendra KL, et al. Ipilimumab with or without nivolumab in PD-1 or PD-L1 blockade refractory metastatic melanoma: a randomized phase 2 trial. 

. 2023;29(9):2278-2285. doi:10.1038/s41591-023- 02498-y

Schadendorf D, Dummer R, Flaherty KT, et al. COLUMBUS 7-year update: a randomized, open-label, phase III trial of encorafenib (enco) + binimetinib (bini) vs vemurafenib (vemu) or enco in patients (pts) with BRAF V600–mutant melanoma. 

. 2023;34(suppl 2):S670-S671. doi:10.1016/j.annonc.2023.09.2247

Burgers FH, Blankenstein S, Rohaan M, et al. Long-term survival follow-up from the REDUCTOR trial: neoadjuvant cytoreductive treatment with BRAF/MEK inhibition of prior unresectable regionally advanced melanoma to allow complete surgical resection. 

. 2023;34(suppl 2):S662. doi:10.1016/j. annonc.2023.09.2233

Wilson TG, Winter H, Taylor H, Herbert C. Treating brain metastases in melanoma: what is the optimal CNS-directed and systemic management? 

Di Giacomo AM, Sileni VC, Del Vecchio M, et al. Nivolumab plus ipilimumab in melanoma patients with asymptomatic brain metastases: 7-year outcomes and quality of life from the multicenter phase III NIBIT-M2 trial. 

. 2023;34(suppl 2):S653-S654. doi:10.1016/j.annonc.2023.09.2218

Ascierto PA, Mandala M, Fercucci PF, et al. Brain metastases and survival evaluation in the SECOMBIT trial. Ann Oncol. 2023;34(suppl 2):S651-S700. doi:10.1016/annonc/ annonc1329

Oncologists reviewed data from clinical trials in the field of melanoma that could add clarity to treatment standards and lead to improved patient care. 

Data From ESMO 2023 Further Define Treatment Paradigm in Advanced Melanoma

It is appreciated that all areas of medicine employ a set of standard terminologies designed to serve as critical components of an effective communication strategy. For example, there is a template for documenting a medical history, physical findings, laboratory evaluations, and conclusions based on those observations as well as formats for follow-up of abnormalities. Specific specialties will modify and expand sections based on unique aspects of the care provided.

In the past this language was principally shared by members of the medical and scientific establishment or more exclusive specialty communities, but in recent years the public and individual patients have become increasingly involved in discussions related to the interpretation of terms employed in the clinical practice of medicine. For example, it is increasingly routine for patients to have almost immediate access through a private electronic portal to all data within their medical records, even at times before their own physicians have had the opportunity to review a new report.

Although it is perhaps reasonable to suggest that most of the terminologies employed by the clinical community, whether long-standing or relatively recently introduced, are as general concepts not overly difficult for the non-expert to understand, the absence of clearly articulated definitions as well as the lack of transparency related to how outcomes are interpreted and utilized within a particular category may raise legitimate concerns.

The concept of “quality of life” routinely discussed within the oncology arena serves as a good illustration of the issue being highlighted here. Surely there will be little if any debate among treating physicians, patients, their families, payers, or regulators regarding the relevance of the quality of life being experienced by a patient with cancer. A specific anxiety will be the potential impact of a proposed therapeutic on this critical factor for both the overall population who might be considered to receive such therapy as well as any individual patient.

However, this universal agreement may dissipate or even completely disappear when one begins to inquire about the details of the concept of quality of life. For example, who decides if a measured “negative” impact of a given therapeutic (eg, short- or longer-term fatigue or interference with activities of daily living) in a clinical trial is greater that the potential “positive” effects (eg, prolong time to symptomatic or measurable disease progression) such that regulatory approval for noninvestigative use will be denied or that third-party payment (eg, private or government insurer) will not be provided?

Stated more directly: What role should individual patients play in the interpretation of quality-of-life data as relates to their own care vs that of study investigators in reviewing quality-of-life data obtained in a clinical trial or (as noted above) regulators or payers?

A second, and in the opinion of this commentator, more problematic expression that continues to permeate the medical literature is that of “complementary and alternative medicine” (CAM). Space does not permit a detailed critique of the unfortunate continued misleading representation by some of the widespread use by patients with cancer of a large variety of strategies designed to favorably impact their quality of life following the diagnosis of cancer. Such approaches include spiritual endeavors, behavioral modifications, physical maneuvers (eg, acupuncture) and herbal medications, among many other tactics.

The field of integrative medicine is increasingly characterized by the conduct of clinical trials, including well-designed phase 3 randomized studies, from recognized academic institutions and published in highly regarded peer-reviewed medical journals.

 Yet despite published data refuting such conclusions,

 we continue to see publications that somehow feel justified to lump together complementary/integrative care efforts with so-called alternative (or refusal of conventional care) approaches suggesting that the compilation of strategies negatively impacts clinical outcomes (including survival).

Is it not time to simply eliminate the term CAM from our clinical vocabulary, since there is absolutely nothing inherently “alternative” about ongoing approaches within the sphere of integrative oncology designed to improve the quality of life for patients during their cancer journey? Continuing to employ this completely outdated term is potentially terribly misleading if not actually harmful.

The final category of terminology requiring extensive thought and reorganization is the concept of cancer staging.

 To be clear, there should be no debate regarding the clinical utility of this fundamental process.

However, the management of solid tumors has evolved substantially over the past several decades from a rather straightforward approach (eg, surgery followed by local radiation, or possibly 1 course of moderately/minimally helpful systemic antineoplastic therapy in the presence of disease recurrence or metastatic disease at diagnosis) to the delivery of an intricate and wide array of beneficial therapeutics. This major change in management has resulted in an increasing number of cancers being appropriately considered as “chronic illnesses.”

Simply stated, the current universally employed cancer staging system does not adequately capture the complexity of frequently multiyear management of many cancers. For example, what does it mean and what are the therapeutic and future survival implications associated with stating a patient is about to receive “first-line,” “second-line,” or “third-line” treatment of metastatic or recurrent disease, or is embarking on “maintenance therapy”? How does the oncology community evaluate the impact of intermittent systemic vs prolonged daily oral therapy on clinical outcomes (survival and quality of life)?

The current cancer staging system and standards for suggested or mandated data collection to help inform the future development of optimal approaches to disease management are (to be brutally blunt) woefully inadequate.

And as a last point to emphasize the constraints of the current approach to cancer staging, one must acknowledge the limitations of survival data related to stage. Again, at a time when the treatment of solid tumors was relatively simple, defining the opportunity for survival based on stage at diagnosis was objectively meaningful. But what is the anticipated survival of a population of individuals whose disease progresses at some point after initial treatment but who respond impressively well to a second-line approach vs individuals who achieve only a more minor (or no) response?

Or consider this question: If a newly diagnosed patient with a metastatic cancer projected to have a population-based 10% chance of 5-year survival remains disease-free after 3 years of observation (with or without ongoing treatment) and asks her/his physician what is the likelihood he/she will experience an additional 5 years of survival (conditional survival analysis), how should the physician respond?

 And this is a highly meaningful inquiry to which we should be able to provide an answer.

Is it time for the oncology community to begin to address these issues?

Maurie Markman, MD, is president of Medicine & Science at Cancer Treatment Centers of America, a part of City of Hope.

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Yang Y, Li X, Chen G, et al. Traditional Chinese medicine compound (Tongxinluo) and clinical outcomes of patients with acute myocardial infarction: the CTS-AMI randomized clinical trial. 

. 2023;330(16):1534-1545. doi:10.1001/jama.2023.19524

Epstein AS, Liou KT, Romero SAD, et al. Acupuncture vs massage for pain in patients living with advanced cancer: the IMPACT randomized clinical trial. 

. 2023;6(11):e2342482. doi:10.1001/jamanetworkopen.2023.42482

Wells JC, Sidhu A, Ding K, et al. Complementary medicine use amongst patients with metastatic cancer enrolled in phase III clinical trials. 

. 2022;27(3):e286-e293. doi.10.1093/oncolo/oyac020

Johnson SB, Park HS, Gross CP, Yu JB. Complementary medicine, refusal of conventional cancer therapy, and survival among patients with curable cancers. 

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Hutten RJ, Weil CR, King AJ, et al. Multi-institutional analysis of cancer patient exposure, perceptions and trust in information sources regarding complementary and alternative medicine. 

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Green FL, Sobin LH. The staging of cancer: a retrospective and prospective appraisal. 

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Jung SH, Lee HY, Chow SC. Statistical methods for conditional survival analysis. 

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The absence of clearly articulated definitions and transparency related to how clinical trial outcomes are interpreted and utilized raise concerns.

Vol. 25 No. 2 | Oncology Live®

18F-FDG PET/CT May Serve as Early Interval Response Assessment Tool in Patients Receiving Combinatorial ICI Therapy

Outreach and Engagement: Colleagues Come Together to Improve Community Care

Vice President of ASH Will Focus on Gene Therapies, ASH’s Global Impact

Data From ESMO 2023 Further Define Treatment Paradigm in Advanced Melanoma

Outdated Terminology in Oncology: Is It Finally Time to Reassess?