Twelve years after key research into immune checkpoint inhibitor therapy first made a splash at the American Society of Clinical Oncology Annual Meeting, evidence continues to mount that supports the durability of these agents in a range of cancers.
Twelve years after key research into immune checkpoint inhibitor (ICI) therapy first made a splash at the American Society of Clinical Oncology (ASCO) Annual Meeting, evidence continues to mount that supports the durability of these agents in a range of cancers. However, questions persist about patients’ goals for their care and optimal approaches to chronic toxicities.
Immuno-oncology (IO) takeaways from ASCO 2022 included long-term follow-up data for dual ICI therapy with ipilimumab (Yervoy) and nivolumab (Opdivo) in melanoma and non–small cell lung cancer (NSCLC).1,2 Against this backdrop, a panel of experts parsed the implications of long-term disease control through ICI therapy. Although ICI therapy has made a significant impact on outcomes for subsets of patients in multiple tumor types, questions linger about what constitutes long-term survival and about how best to manage toxicities.3
“One of the things that you have to [do] when you’ve got so many good agents coming on board— some more mature, some less mature—is to look beyond overall survival [OS],” Stephanie L. Goff, MD, said during the panel discussion. “You have to look at toxicity, you have to look at tolerability, you have to look at quality of life, you have to look at cost. Until you have a lot of options, those things are a little bit less important.”
Goff, an associate research physician in the surgery branch of the Center for Cancer Research at the National Cancer Institute, noted that OS remains the goal of therapy but that “once you’ve gotten into a range where you’re seeing major improvements, that’s where you factor in all the other pieces.”
ICI milestones have been a feature of ASCO meetings since 2010, when investigators first reported an improvement in OS for patients with metastatic melanoma treated with ipilimumab, a CTLA-4 inhibitor.4 Two years later, early data showing the potential for inhibiting the PD-1/ PD-L1 immune checkpoint in several tumor types stirred excitement.5,6
Since those findings, the FDA has approved ICI therapies for 22 cancer types.7 The use of these agents has been expanding not only in the proportion of regimens including an ICI but also in the migration of ICIs from second- to f irst-line settings, according to a realworld analysis from UnitedHealthcare and Optum Health Solutions presented at ASCO 2022.8
The study included 20,992 eligible patients with 9 cancer types who initiated treatment with chemotherapy and/or an FDA-approved ICI from 2018 through 2020. In all, approximately 33% received ICIs during the study period, including 18% in the front line and 14% in the second line. By 2020, frontline use of ICI therapy had increased across cancer types, particularly in patients with melanoma (rising to 95%), renal cell carcinoma (RCC; 81%), and NSCLC (42%).8
At ASCO 2022, F. Stephen Hodi Jr, MD, a 2019 Giants of Cancer Care® award winner in the melanoma and other skin cancers category, and colleagues presented findings from the phase 3 CheckMate 067 trial (NCT01844505) in which 945 patients with previously untreated unresectable or metastatic melanoma were randomly assigned to receive the PD-1 inhibitor nivolumab plus ipilimumab, nivolumab plus placebo, or ipilimumab plus placebo.1
After a minimum follow-up of 7.5 years, dual therapy with nivolumab and ipilimumab demonstrated a median OS of 72.1 months (95% CI, 38.2-not reached) compared with 36.9 months (95% CI, 28.2-58.7) for nivolumab alone and 19.9 months (95% CI, 16.8-24.6) for ipilimumab alone. Those outcomes translated into a reduction in risk for the ICI combination of 16% vs nivolumab alone (HR, 0.84; 95% CI, 0.68-1.04) and 47% vs ipilimumab alone (HR, 0.53; 95% CI, 0.44-0.65). The percentage of patients alive at 7.5 years was 48% with the combination, 42% with nivolumab alone, and 22% for ipilimumab alone (Table).1
The dual ICI regimen also hit other benchmarks. “Median melanoma-specific survival is still not reached for patients treated with nivolumab plus ipilimumab,” said Hodi, who is director of the melanoma center and the center for immune-oncology and the Sharon Crowley Martin Chair in Melanoma at Dana-Farber Cancer Institute in Boston, Massachusetts. “Patients treated with nivolumab plus ipilimumab were less likely to receive subsequent systemic therapy or received it later than those treated with nivolumab alone or ipilimumab alone.”
The findings presented at ASCO 2022 were similar to the 6.5-year follow-up data that Jedd D. Wolchok, MD, PhD, FASCO, and colleagues reported in the Journal of Clinical Oncology in January 2022. The results for CheckMate 067 represent the longest follow-up data from a phase 3 trial in melanoma involving PD-1–directed therapy, the authors noted. The outcomes reached in the study contrast sharply with the pre-ICI era, when the standard median OS for advanced melanoma was 8 months and the 5-year OS rate was 10%.9
At ASCO 2022, Wolchok was honored with the 2022 David A. Karnofsky Memorial Award and Lecture in recognition of his many contributions to the field of immunotherapy. Wolchok, a 2014 Giants of Cancer Care® award winner in the melanoma category, is the Lloyd J. Old/ Virginia and Daniel K. Ludwig Chair in Clinical Investigation, director of the Parker Institute for Cancer Immunotherapy, and associate director of the Ludwig Center for Cancer Immunotherapy at Memorial Sloan Kettering Cancer Center in New York, New York.
During his award lecture, Wolchok noted the progress that has been made in melanoma during the past 12 years. Turning his attention to CheckMate 067, he said the long-term follow-up period enabled investigators to analyze melanoma-specific survival and the toxicity impact of the dual ICI regimen.10
“It was very comforting to see that the melanoma-specific survival was even a little bit higher than the overall survival for all of the groups,” Wolchok said.
At the same time, the frequency of grade 3 or 4 adverse effects was nearly 60% with the ICI doublet vs 24% with nivolumab monotherapy, Wolchok noted. The adverse effects with combination therapy were “not different in quality than the adverse [effects] that we saw with monotherapy, but [they were] certainly different in quantity—more patients having adverse effects, more patients having multiple adverse effects. However, the strategies that the community of investigators developed to manage the toxicities of monotherapy were really the cornerstone of how we were able to deliver this type of therapy safely,” he said.
Wolchok said patients’ response to ICI therapy in melanoma and other cancers depends on their baseline immune profile. “The more mutations the tumor has, the more potential neoantigens are shown to the immune system, and the more likely it is that there is a baseline immune response that can then be disinhibited with the use of checkpoint blockade,” he said. “Although this may occur and result in regression in antigen spreading, and this can lead to durable disease control, this only happens in some patients. . . We may be faced with the challenge of supplementing the immune repertoire with engineered T cells or ex vivo expanded tumor-infiltrating lymphocytes.”
During ASCO 2022, investigators presented 5-year updates for the combination of nivolumab plus ipilimumab in the first-line treatment of patients with metastatic NSCLC from part 1 of the Checkmate 227 trial (NCT02477826). The data mark the longest reported follow-up from any phase 3 trial evaluating an IO/IO combination in this population, lead investigator Julie R. Brahmer, MD, MSc, said.2
After a minimum follow-up of 61.3 months, patients who received nivolumab plus ipilimumab (n = 396) experienced a durable survival benefit compared with platinum-doublet chemotherapy (n = 397) regardless of PD-L1 expression level. The combination also was more effective than outcomes among participants who received nivolumab monotherapy (n = 396), although a formal comparison was not conducted.2 In participants with PD-L1 expression of 1% or greater, the median OS was 17.1 months for patients who received the combination vs 14.9 months with chemotherapy (HR, 0.77; 95% CI, 0.66-0.91) and 15.7 months with nivolumab alone. The 5-year OS rate was 24% with the combination, 17% with nivolumab alone, and 14% with chemotherapy. The median duration of response with the combination was 24.5 months (95% CI, 15.5-33.9) compared with 15.5 months (95% CI, 12.5-20.8) with nivolumab alone, and 6.7 months (95% CI, 5.6-7.6) with chemotherapy.2
“A plateau of the nivolumab and ipilimumab curve is evident by 3 years and is maintained at 5 years,” said Brahmer, director of the thoracic oncology program, professor of oncology, and the Marilyn Meyerhoff Professor in Thoracic Oncology at Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins in Baltimore, Maryland. “It is important to note when considering these data that patients had been off IO-based treatment for at least 3 years per protocol, and the durability of responses is still maintained.”
ICIs have transformed therapy for patients with advanced melanoma and made a significant impact in NSCLC and RCC, participants in the ASCO 2022 panel noted. However, improvements in median OS have not lifted 5-year OS in patients with metastatic colorectal cancer (CRC) at diagnosis.3
For NSCLC, panelist Hossein Borghaei, DO, MS, illustrated the progress that has been made by comparing findings from 2 studies reported nearly 20 years apart. Borghaei is the Gloria and Edmund M. Dunn Chair in Thoracic Oncology, chief of the Division of Thoracic Medical Oncology, and a professor in the Department of Hematology/Oncology at Fox Chase Cancer in Philadelphia, Pennsylvania.
In 2002, Borghaei noted, a study of 4 chemotherapy doublets for patients with advanced disease showed that none of the regimens offered a significant advantage over the others; the overall 2-year survival rate was 11%.11
In July 2021, however, investigators reported results from the phase 3 KEYNOTE-024 trial (NCT02142738) in which pembrolizumab (Keytruda), a PD-1 inhibitor, was tested against platinum-based chemotherapy in patients with previously untreated stage IV NSCLC with a PD-L1 tumor proportion score of at least 50%. In the 5-year follow-up analysis, the median OS was 26.3 months (95% CI, 18.3-40.4) in patients who received pembrolizumab vs 13.4 months (95% CI, 9.4-18.3) for chemotherapy. The 5-year OS rates were 31.9% vs 16.3%, respectively.12
The findings represent the first 5-year follow-up for any phase 3 frontline immunotherapy trial in NSCLC, Reck et al said in detailing the data in the Journal of Clinical Oncology.12 “I want to emphasize this is a single checkpoint inhibitor compared [with] platinum doublet, and you see the wonderful 5-year overall survival data that we’ve been able to achieve,” Borghaei said. “Now is this adequate? Is this where we are? And should we be happy? Of course not. There are a lot of efforts underway to improve in all of that. But I do want to emphasize that we have come a long way in lung cancer. We’ve made a lot of progress.”
In melanoma, the progress has been dramatic, Goff noted, discussing 6.5-year data from CheckMate 067 that was updated at ASCO 2022.1,9 “Rather than those survival curves going down to 0, which is what we always saw in the era of chemotherapy, that plateau has just gone up and up and up,” she said.
In RCC, the combination of ipilimumab plus nivolumab maintained its efficacy vs sunitinib malate (Sutent) as first-line therapy for patients with advanced disease in the phase 3 CheckMate 214 trial (NCT02231749). After a minimum 42 months’ follow-up, the median OS in patients with intermediate/poor risk RCC was 47.0 months (95% CI, 35.6-not estimable) with the IO combination vs 26.6 months (95% CI, 22.1-33.5) with sunitinib (HR, 0.66; 95% CI, 0.55-0.80; P < .0001). The OS rate was 52% vs 39%, respectively.13
“You can see how that plateau, that flattening of the curve, is getting higher and higher with the combination of nivolumab and ipilimumab,” Goff said. “So I think the benefit of what we’re all talking about here, long-term survival, is that we’re moving that survival curve up off the x-axis and getting it higher and higher. But until we get it up into the 90%, 100% range, we all know we’ve got a lot of work to do.”
In CRC, however, the introduction of new treatment strategies including ICIs has not resulted in a notable improvement in 5-year OS, Goff said. She noted that by the mid-2000s, median OS improved with the development of 3-drug chemotherapy regimens or targeted therapy plus chemotherapy. Nevertheless, 5-year OS has improved only slightly since then, including with the introduction of ICI therapies for patients with mismatch repair–deficient or microsatellite instability–high metastatic or unresectable CRC.3
“While there has been a slight uptick [in 5-year OS], it’s still below 20%,” Goff said. “So we’ve got a lot of room for improvement in colorectal cancer.”
Although 5 years is often considered long-term follow-up for clinical trial purposes, doctors and patients might have a different view of what constitutes durability.
Martin H. Voss, MD, who served as moderator of the panel and is clinical director of the genitourinary medical oncology service at Memorial Sloan Kettering Cancer Center, polled attendees at the session about their views on survival. Of the 13 respondents, 7 defined the benchmark as 5 years (53.8%), 5 said 10 years or longer (38.5%), 1 said 2 years (7.7%), and no one said 1 year.
Voss then cited results from a poll of 117 patients with metastatic RCC with exposure to systemic therapy. Nearly 50 respondents defined long-term survival as more than 5 years and 40 patients said more than 10 years. The poll was conducted in June 2022 via social media platforms by the Kidney Cancer Research Alliance (KCCure), an advocacy group.3
“Most patients in this group replied more than 5 years, lots more than 10,” Voss said. “Very few would define a year or even 6 months as longterm survival.” The patient poll matched up with the answers from the ASCO audience, Voss noted.
In another survey, KCCure asked patients with metastatic RCC receiving systemic therapy and their caregivers about their treatment priorities. Of 411 respondents, 67% were patients and 33% were caregivers (Figure14).
In response to a question about what they considered the most important outcome of their treatment, 58.8% chose complete response (CR), followed by tumor control (10.2%), low risk of toxicity (5.7%), the chance to discontinue therapy (3.7%), and cost (2.9%).14
“I thought it was just interesting to highlight how patients feel about goals of their systemic therapy for metastatic disease as they embark on the treatment course with their doctors,” Voss said in citing the survey findings. “By far most relevant to a patient, as you would imagine early on, is elimination of radiographic-evident disease. So achieving a CR counts more than duration of disease, counts more than successful treatment of symptoms.”