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Following the February 2024 FDA accelerated approval of the first cellular therapy for patients with melanoma, the tumor-derived autologous T-cell immunotherapy lifileucel (Amtagvi), investigators are hoping to build on this and other recent gains by developing additional novel therapies for these patients who often experience resistance to other available treatments.

“Novel agents may be helpful in overcoming primary resistance, and that still [represents] a significant proportion of our patients—40% to 50% don’t respond to initial checkpoint inhibitor therapy,” Omid Hamid, MD, director of the Melanoma Program at Cedars Sinai in Los Angeles, California, said in an interview with OncologyLive. “Novel combinations may help overcome that [resistance]. We know that because [data on] our tumor-infiltrating lymphocyte [TIL] therapies in initial trials have shown that most patients [who] responded were initially enrolled [with] primary resistance [following] progression on checkpoint [inhibitors].” 

The February regulatory decision by the FDA earned lifileucel an indication for the treatment of adult patients with unresectable or metastatic melanoma previously treated with a PD-1 blocking antibody, and if BRAF V600 positive, a BRAF inhibitor with or without a MEK inhibitor. The approval was supported by findings from the phase 2 C-144-01 study (NCT02360579). The trial enrolled patients with unresectable or metastatic melanoma who previously received at least 1 systemic therapy, including a PD-1 blocking antibody, as well as a BRAF inhibitor alone or in combination with a MEK inhibitor if they had BRAF V600–mutated disease.

At the time of the approval, efficacy-evaluable patients who received the recommended dose range of 7.5 x 109 to 72 x 109 viable cells (n = 73) achieved an objective response rate (ORR) of 31.5% (95% CI, 21.1%-43.4%), including a complete response (CR) rate of 4.1%. Notably, the median duration of response (DOR) was not reached (NR; 95% CI, 4.1 months-NR). Patients experienced a DOR of at least 6, 9, or 12 months at rates of 56.5%, 47.8%, and 43.5%, respectively.

Additional findings from C-144-01 published in the Journal for ImmunoTherapy of Cancer demonstrated that patients who received lifileucel who underwent at least 4 prior lines of therapy (n = 54) achieved an ORR of 29.6% (95% CI, 18.0%-43.6%). Patients who were treated with a previous anti–CTLA-4 agent (n = 125), those who received prior anti–PD-1 plus anti–CTLA-4 combination therapy (n = 82), and those who were primary refractory to anti–PD-(L)1 treatment (n = 83) achieved ORRs of 32.8% (95% CI, 24.7%- 41.8%), 26.8% (95% CI, 17.6%-37.8%), and 31.3% (95% CI, 21.6%-42.4%), respectively.

NOVEL THERAPIES AND COMBINATIONS MOVE THROUGH THE DEVELOPMENT PIPELINE IN MELANOMA 

In light of the success of lifileucel monotherapy in patients with heavily pretreated melanoma, investigators are evaluating the agent in combination with pembrolizumab (Keytruda) for the frontline treatment of patients with advanced melanoma in the phase 2 IOV-COM-202 study (NCT03645928).

During the 2024 American Society of Clinical Oncology Annual Meeting, investigators presented findings from cohort 1A (n = 23) of IOV-COM-202, which enrolled patients with immune checkpoint inhibitor–naive melanoma; prior treatment with a BRAF/MEK inhibitor was permitted if a patient had BRAF-mutated disease. Response-evaluable patients achieved an ORR of 65.2% (95% CI, 42.7%-83.6%), with a CR rate of 30.4%. At a median follow-up of 21.7 months, the median DOR was NR (95% CI, 16.8-NR). The 6- and 12-month DOR rates were 73.3% and 53.3%, respectively. At the data cutoff, 66.7% of responders remained on the study with an ongoing response. These findings led to the initiation of the phase 3 TILVANCE-301 trial (NCT05727904), which is examining lifileucel plus pembrolizumab vs pembrolizumab monotherapy in patients with treatment-naive advanced melanoma. The coprimary end points of the global, randomized study are ORR per RECIST 1.1 by blinded independent review committee (BICR) assessment and BICRassessed PFS per RECIST 1.1. Overall survival is the key secondary end point, with other secondary end points including DOR, event-free survival, and safety.

Other novel agents under investigation in melanoma include IBI363, which is being examined in a phase 1 trial (NCT05460767) study which enrolled patients with melanoma and other solid tumors.

 “IBI363 is a PD-1, IL-2α bispecific antibody. “We’ve always known that being able to utilize combinations of immunotherapy in separate classes may be helpful in [these] patients, and initial signals of efficacy with this drug post PD-1 [inhibitor] failure have shown good disease control rates [DCRs] and ORRs,” Hamid explained. 

Findings from the first-in-human trial presented during the 2024 European Society for Medical Oncology Virtual Plenary meeting showed that patients with melanoma who received prior treatment with an immuno-oncology (IO) agent (n = 37) achieved an ORR of 29.7% (95% CI, 15.9%-47.0%), including a 2.7% CR rate. The DCR was 73.0% (95% CI, 55.9%-86.2%). Most patients (73.0%) received at least 2 prior lines of therapy, and the median duration of prior IO treatment was 5.8 months. 

These data supported the FDA’s September 2024 decision to grant fast track designation to IBI363 monotherapy for the treatment of patients with unresectable locally advanced or metastatic melanoma, excluding choroidal melanoma, who experienced disease progression following at least 1 prior line of systemic treatment, including a PD-(L)1 inhibitor.

“There is a huge unmet medical need for these types of drugs which have shown activity in [the] second line,” Hamid said. “Although we have novel options that have been approved in the second line, including TIL therapy, the real issue is that they’re not available for everyone. There are patients who don’t have the [necessary] performance status and would need something available off the shelf.” 

Hamid also highlighted the personalized cancer vaccine mRNA-4157 (V940), which is being investigated in combination with pembrolizumab in the phase 2b KEYNOTE-942 trial (NCT03897881). KEYNOTE-942 enrolled patients with completely resected stage IIIB to IV melanoma and randomly assigned them 2:1 to receive mRNA-4157 plus pembrolizumab (n = 107) or pembrolizumab monotherapy (n = 50). The primary end point was recurrence-free survival (RFS); secondary end points included distant metastasis-free survival, safety, and tolerability.

Data from KEYNOTE-942 published in The Lancet demonstrated that at a median follow-up of 23 months (IQR, 17-30) in the combination group and 24 months (IQR, 21-31) in the monotherapy group, patients achieved an 18-month RFS rate of 79% (95% CI, 69.0%-85.6%) vs 62% (95% CI, 46.9%- 74.3%), respectively. Treatment with V940 plus pembrolizumab led to a 44% reduction in the risk of disease recurrence or death compared with pembrolizumab alone (HR, 0.561; 95% CI, 0.309- 1.017; 2-sided 

“The major randomized phase 3 [V940-001] trial [NCT05933577] of mRNA-4157 in the adjuvant setting—from stage IIB all the way to stage IV resected [melanoma]—has fully accrued [patients and is examining the agent] plus pembrolizumab vs pembrolizumab,” Hamid said. “The data [with V940] are extremely compelling and hopefully we’ll get some more of that information in the year to come.” 

INVESTIGATORS GATHER TO SHARE FURTHER UPDATES ACROSS MELANOMA AND CUTANEOUS MALIGNANCIES 

On February 8, 2025, Physicians’ Education Resource, LLC, will host the 21st Annual International Symposium on Melanoma and Other Cutaneous Malignancies®. The virtual conference will be cochaired by Hamid and Sapna Patel, MD, of the University of Colorado Cancer Center in Aurora. During the meeting, Hamid and Patel will present a session titled “Novel Mechanisms in Melanoma and Beyond: Emerging Agents in Nonmelanoma Skin Cancer [NMSC].” They will also be leading multiple panel discussions and question and answer sessions throughout the day engaging leading investigators in the field of melanoma and cutaneous malignancies.

“[Our presentation] will include up-to-date data on what’s available for NMSCs [as well as] other pathways to explore, and initial data for these patients,” Hamid said. “We’ve made these headways in melanoma itself, [and] we’ve seen that a lot of them translate into NMSCs, [including] squamous, basal, and Merkel cell [cancers]. A lot of these patients are rarely seen and there are questions that ensue. For example, a significant proportion of these cutaneous squamous cell carcinomas are [present] in immune-suppressed patients where immunotherapy may not be the right answer. There are [also] questions about how to move forward with Merkel cell [carcinoma], either initially or post progression on PD-1–[directed] therapies.” 

There will also be sessions detailing frontline immunotherapy considerations in melanoma, targeted therapies in melanoma, and TIL therapies, among other exciting topics.

“This is a didactic-heavy meeting where each topic has 5 to 10 minutes of slides. [There will be] case presentations and experts from around the world discussing how they take care of patients, what they see the future [of treatment] being, and how it could relate to clinical care,” Hamid said.

Articles

The FDA's accelerated approval of lifileucel, a tumor-derived autologous T-cell immunotherapy, marks a significant advancement in melanoma treatment, particularly for patients resistant to existing therapies. Lifileucel demonstrated promising efficacy in heavily pretreated patients, leading to further exploration in combination with pembrolizumab. Novel agents like IBI363 and personalized cancer vaccines such as mRNA-4157 are also under investigation, showing potential in overcoming resistance. The upcoming International Symposium on Melanoma will discuss these advancements and explore emerging therapies for melanoma and other cutaneous malignancies.

Omid Hamid, MD, discusses recent advances in the melanoma treatment landscape and highlights the 21st Annual International Symposium on Melanoma and Other Cutaneous Malignancies®.

Novel Therapies and Combinations Augment Melanoma Treatment Arsenal

In recent years, combination regimens have reshaped the hepatocellular carcinoma (HCC) treatment landscape, offering options to better personalize frontline treatments. Specifically, single tremelimumab (Imjudo) and regular-interval durvalumab (Imfinzi; STRIDE) is the most recent regimen to gain FDA approval in treatment-naive HCC, with other combination regimens showing promise as they progress through the development pipeline.

“In liver cancer, 20 years ago we were still giving [only] chemotherapy; now we have targeted therapy, immunotherapy, and combinations of different modalities,” 

, said. “Now, we [are discussing treatment] sequencing because we have so many different agents. I foresee liver cancer being one of the cancers with the best prognosis and a higher cure population. This is our dream and is a goal that we need to move toward.”

During the 2024 European Society for Medical Oncology (ESMO) Congress in Barcelona, Spain, 

 with leading experts in the field of HCC. The panelists discussed how new data presented during the meeting could be used to optimize treatment in the frontline setting, touching on updates from the phase 3 HIMALAYA (NCT03298451), LEAP-012 (NCT04246177), EMERALD-1 (NCT03778957), and IMbrave050 (NCT04102098) trials. They also discussed findings from the phase 4 STELLAR study (NCT04763408) and looked ahead to the future of HCC treatment.

New Data With Combination Regimens Emerge in Frontline HCC

A regimen that has moved to the forefront of the first-line treatment landscape of unresectable HCC in recent years is STRIDE. In October 2022, STRIDE was approved by the FDA for the treatment of adult patients with unresectable HCC based on data from HIMALAYA. HIMALAYA was an open-label, multicenter study for patients who had no prior systemic treatment for HCC and were randomly assigned 1:1 to receive STRIDE, durvalumab monotherapy, or sorafenib (Nexavar) monotherapy.

Findings from the 5-year overall survival (OS) update of HIMALAYA presented during the 2024 ESMO Congress demonstrated that patients who were treated with the STRIDE regimen (n = 393) achieved a median OS of 16.43 months (95% CI, 14.16-19.58) compared with 13.77 months (95% CI, 12.25-16.13) among patients treated with sorafenib (HR, 0.76; 95% CI, 0.65- 0.89; 2-sided 

 = .0008). STRIDE also produced superior OS rates vs sorafenib, respectively, at 18 months (48.7% vs 41.5%), 24 months (40.5% vs 32.6%), 36 months (30.7% vs 19.9%), 48 months (25.2% vs 15.1%), and 60 months (19.6% vs 9.4%). Study authors noted that these data had the longest follow-up to date in phase 3 studies of treatments for unresectable HCC.

“Where in the Child-Pugh B [score range you] can give doublets vs a single [agent] is subjective at the moment,” 

, commented. ”I worry about giving a doublet either [when a patient’s] liver function is not great, [due to their] performance status, or other worries. It has become a minority of patients who get single-agent IO [immuno-oncology], but it still does exist in my practice.”

Another combination regimen, lenvatinib (Lenvima) plus pembrolizumab (Keytruda) and transarterial chemoembolization (TACE), is under investigation in LEAP-012. The coprimary end points of the study are OS and progression-free survival (PFS). TACE is considered the standard of care for patients with intermediate-stage HCC, and lenvatinib monotherapy is an FDA-approved option for the first-line treatment of patients with unresectable HCC.

Data from LEAP-012 presented during the 2024 ESMO Congress showed that patients who received lenvatinib, pembrolizumab, and TACE (n = 237) achieved a median PFS of 14.6 months (95% CI, 12.6- 16.7) vs 10.0 months (95% CI, 8.1-12.2) among patients who received dual placebo with TACE (HR, 0.66; 95% CI, 0.51-0.84; 

 = .0002). The 12-month PFS rates were 62.2% vs 43.4%, respectively, and the 18-month rates were 39.1% vs 27.9%,respectively. The addition of lenvatinib and pembrolizumab to TACE also led to an OS benefit (HR, 0.80; 95% CI, 0.57-1.11; 

 = .0867). The 12-month OS rates were 89.0% vs 83.1%, respectively, and the 24-month rates were 74.6% vs 68.6%, respectively.

“[These findings] go to the question of, ‘should we be using the combination strategy up front or waiting until a later time to introduce systemic therapy following initial liver-directed therapy?’” 

, said. “I believe toxicity matters here. In terms of grade 3 or higher treatment-related adverse effects [AEs], in the combination arm, it was [approximately] 71% and in the TACE alone arm, it was approximately 31%, so essentially a doubling of toxicity. Some of those toxicities are easier to manage but we have to see more data. What wasn’t presented were the quality- of-life [QOL] data, and those can potentially help us determine whether this up-front combination strategy is the way to go going forward.”

“I was excited with the results of LEAP-012 because they solidify some of the current direction in the community about not waiting until the patient develops metastatic disease or progression [to use a regimen such as this]. I believe we are going to see more and more IO/tyrosine kinase inhibitor [TKI] combinations in different lines of treatment,” 

The EMERALD-1 study is also evaluating a TACEbased regimen in frontline unresectable HCC, combining it with durvalumab with or without bevacizumab (Avastin) in patients who are eligible for embolization. The primary end point of the study is PFS by blinded independent central review per RECIST 1.1; OS and QOL represent key secondary end points.

Findings from EMERALD-1 presented during the 2024 American Society of Clinical Oncology Gastrointestinal Cancers Symposium revealed that patients who received TACE with durvalumab and bevacizumab (n = 204) achieved a median PFS of 15.0 months (95% CI, 11.1-18.9) compared with 8.2 months (95% CI, 6.9-11.1) among patients treated with TACE alone (HR, 0.77; 95% CI, 0.61-0.98; log-rank 

 = .032), meeting the study’s primary end point. Additionally, the objective response rates (ORRs) were 43.6% vs 29.6%, respectively, (OR, 1.87; 95% CI, 1.24- 2.84), including respective complete response (CR) rates of 3.0% vs 2.5%.

Then, during the 2024 ESMO Congress, investigators presented findings from an analysis of EMERALD-1 that examined outcomes with TACE plus durvalumab with or without bevacizumab by baseline tumor burden. Investigators stratified patients using the up-to-7 criterion, which was defined as the sum of the number of tumors and their size in cm. Data from the analysis showed that the addition of durvalumab and bevacizumab to TACE improved PFS regardless of tumor burden; there was a significant PFS benefit in both the up-to-7 criterion (HR, 0.72; 95% CI, 0.51-1.03) and beyond the up-to-7 criterion (HR, 0.79; 95% CI, 0.57-1.09) subgroups.

“We checked the efficacy outcome—PFS within up-to-7 criteria—and the PFS HR was very similar to the PFS of [those with] beyond up-to-7 criteria, [as was] the time to progression,” 

, who was a coauthor of the analysis, noted. “Even though the tumor burden is very high, beyond the up-to-7 criteria, durvalumab plus bevacizumab and TACE showed better efficacy compared with TACE alone.”

The final study the panelists discussed in the frontline setting was IMbrave050, which examined the combination of atezolizumab (Tecentriq) and bevacizumab vs active surveillance in patients with resected or ablated high-risk HCC. The primary end point of the study was recurrence-free survival (RFS); secondary end points included OS and safety.

Updated findings from IMbrave050 presented during the 2024 ESMO Congress showed that the initial RFS benefit that was previously observed with atezolizumab plus bevacizumab did not persist with additional follow-up. At a median follow-up of 35.1 months, the median RFS in the investigational arm (n = 334) was 33.2 months (24.3-not estimable [NE]) vs 36.0 months (95% CI, 22.7-NE) in the active surveillance arm (n = 334; HR, 0.90; 95% CI, 0.72-1.12). OS data were immature at the time of the presentation, with both arms having a median OS of NE (95% CI, NE-NE; HR, 1.26; 95% CI, 0.85-1.87; 

“One of the challenges is defining high-risk [disease],” 

, said. “We’re seeing a [median] RFS of [approximately] 3 years in a control arm. That’s not the estimate we would assume with this study population. That relates somewhat to the statistical assumptions in this population, which we’re still learning about. But, at this point, there’s no reason to offer patients adjuvant treatment after surgery outside of a clinical trial.”

Real-World Data Inform Future HCC Research Directions

The panelists concluded their session by discussing real-world findings in HCC and highlighted what could become the latest FDA-approved regimen in frontline HCC: nivolumab (Opdivo) plus ipilimumab (Yervoy). “[In terms of] the knowledge gaps that have resulted from the rapid accumulation of new drugs and studies in the management of our patients with unresectable liver cancer, real-world evidence is supplementing some of those gaps,” Finn said.

The real-world STELLAR trial was an open-label, observational study that enrolled patients with advanced or unresectable HCC who received lenvatinib or sorafenib according to local prescribing practices. The study enrolled patients in Australia, Europe, and the US. The primary end point was to further elucidate the hepatotoxicity and overall safety profile of lenvatinib.

“The purpose of [this study] was to evaluate the tolerance and effectiveness of the therapy in [additional], less restricted populations, which may be different from the clinical trial populations,” Chan added.

Findings from STELLAR presented during the 2024 ESMO Congress showed that, at a median follow-up of 9.5 months (95% CI, 8.3-11.4) among patients who received lenvatinib (n = 149), the median OS was 16.3 months (95% CI, 11.8-NE). Comparatively, at a median follow-up of 7.4 months (95% CI, 6.5-8.5), the median OS was 13.6 months (95% CI, 8.4-NE) in the sorafenib group (n = 93). Lenvatinib also offered a benefit vs sorafenib regarding 6-month (83.9% vs 79.2%) and 12-month (59.2% vs 54.3%) OS rates.

In terms of safety, no new signals were identified with lenvatinib, and AEs were able to be managed via standard clinical practice. Any-grade treatment-emergent AEs (TEAEs) occurred at a rate of 79.9% vs 81.7% in the lenvatinib and sorafenib arms, respectively; patients in both arms experienced treatmentrelated TEAEs (58.4% vs 66.7%), grade 3 or higher TEAEs (40.3% vs 37.6%), grade 3 or higher treatment- related TEAEs (20.8% vs 18.3%), serious TEAEs (30.2% vs 31.2%), and fatal serious TEAEs (9.4% vs 4.3%).

Any-grade hepatotoxicity occurred in 22.8% of patients who received lenvatinib compared with 33.3% of patients treated with sorafenib. Grade 3 or higher hepatotoxicity was reported at rates of 8.1% vs 15.1%, respectively. Other common any-grade TEAEs occurring in both arms included decreased appetite (24.8% vs 23.7%), fatigue (21.5% vs 21.5%), and diarrhea (19.5% vs 28.0%).

“In terms of the tolerance and the AE profile, they’re very similar to what we have observed from previous clinical trials,” Chan said. “Although we are using more immunotherapy nowadays, TKIs are still used frequently for those patients who are not eligible for immunotherapy or don’t have access to immunotherapy. Sometimes [we also use TKIs] for patients who have failed immunotherapy. I consider this study to be potentially impactful and meaningful for our practice.”

The panelists concluded their discussion by providing their view of updated findings from the phase 3 CheckMate 9DW trial (NCT04039607), which is comparing nivolumab plus ipilimumab vs standard-of-care lenvatinib or sorafenib in frontline unresectable HCC. The primary end point of the study is OS; secondary end points include ORR and duration of response (DOR).

At a median follow-up of 35.2 months (range, 26.8-48.9), the median OS in the combination arm (n = 335) was 23.7 months (95% CI, 18.8-29.4) vs 20.6 months (95% CI, 17.5-22.5) in the lenvatinib/ sorafenib arm (n = 333; HR, 0.79; 95% CI, 0.65- 0.96; 

 =.018). The 24-month OS rates were 49% vs 39%, respectively, and the 36-month OS rates were 38% vs 24%, respectively. The ORR in the combination arm was 36% (95% CI, 31%-42%), with a CR rate of 7%, vs 13% (95% CI, 10%-17%), with a 2% CR rate, in the control arm (

 < .0001). The median DOR was 30.4 months (95% CI, 21.2-NE) vs 12.9 months (95% CI, 10.2-31.2), respectively.

Based on data from CheckMate 9DW, the FDA accepted the supplemental biologics license application seeking the approval of nivolumab plus ipilimumab in frontline unresectable HCC in August 2024. The Prescription Drug User Fee Act goal date is April 21, 2025.

 The regimen previously earned accelerated approval from the FDA in March 2020 for the treatment of patients with HCC who were previously treated with sorafenib; the regulatory decision was supported by findings from the phase 1/2 CheckMate 040 trial (NCT01658878).

“[I believe this regimen] will be approved by the FDA, European Medicines Agency, and the Pharmaceuticals and Medical Devices Agency [of Japan],” Kudo said. “An important point is that in patients who [went on to receive] second-line treatment, the PFS and PFS2 were much longer than in the control arm. That is a very good message, if the [patient received] nivolumab/ipilimumab, the second-line treatment will be better.”

FDA approves tremelimumab in combination with durvalumab for unresectable hepatocellular carcinoma. FDA. Updated October 24, 2022. Accessed October 23, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-tremelimumab-combination-durvalumab-unresectable-hepatocellular-carcinoma

Rimassa L, Chan SL, Sangro B, et al. Five-year overall survival (OS) and OS by tumour response measures from the phase III HIMALAYA study of tremelimumab plus durvalumab in unresectable hepatocellular carcinoma (uHCC). Ann Oncol. 2024;35(suppl 2):S656. doi:10.1016/j.annonc.2024.08.1007

Llovet J, Finn RS, Ren Z, et al. Transarterial chemoembolization (TACE) with or without lenvatinib (len) + pembrolizumab (pembro) for intermediate-stage hepatocellular carcinoma (HCC): phase III LEAP-012 study. 

 2024;35(suppl 2):S1229. doi:10.1016/j.annonc.2024.08.2277

FDA approves lenvatinib for unresectable hepatocellular carcinoma. FDA. August 16, 2018. Accessed October 24, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-lenvatinib-unresectable-hepatocellular-carcinoma

Lencioni R, Kudo M, Erinjeri J, et al. EMERALD-1: a phase 3, randomized, placebo-controlled study of transarterial chemoembolization combined with durvalumab with or without bevacizumab in participants with unresectable hepatocellular carcinoma eligible for embolization. 

. 2024;42(suppl 3):LBA432. doi:10.1200/JCO.2024.42.3_suppl.LBA432

Kudo M, Lencioni R, Erinjeri JP, et al. Outcomes by baseline tumour burden in EMERALD-1: a phase III, randomised, placebo (PBO)-controlled study of durvalumab (D) ± bevacizumab (B) with transarterial chemoembolisation (TACE) in participants (pts) with embolisation-eligible unresectable hepatocellular carcinoma (uHCC). 

. 2024;35(suppl 2):S658-S659. doi:10.1016/j.annonc.2024.08.1010

Yopp A, Kudo M, Chen M, et al. Updated efficacy and safety data from IMbrave050: phase III study of adjuvant atezolizumab (atezo) + bevacizumab (bev) vs active surveillance in patients (pts) with resected or ablated high-risk hepatocellular carcinoma (HCC). 

. 2024;35(suppl 2):S1230. doi:10.1016/j. annonc.2024.08.2279

Peck Radosavljevic M, Abdelgafur AM, Granito A, et al. Lenvatinib (L) and sorafenib (S) in patients (pts) with advanced or unresectable hepatocellular carcinoma (uHCC): an international, multicenter, phase IV study (STELLAR). 

. 2024;35(suppl 2):S664. doi:10.1016/j.annonc.2024.08.1024

Decaens T, Yau T, Kudo M, et al. Nivolumab (NIVO) plus ipilimumab (IPI) vs lenvatinib (LEN) or sorafenib (SOR) as firstline (1L) treatment for unresectable hepatocellular carcinoma (uHCC): expanded analyses from CheckMate 9DW. 

. 2024;35(suppl 2):S657. doi:10.1016/j.annonc.2024.08.1025

Bristol Myers Squibb receives US Food and Drug Administration sBLA acceptance for first-line treatment of unresectable hepatocellular carcinoma. News release. Bristol Myers Squibb. August 21, 2024. Accessed October 25, 2024. https://news.bms.com/news/details/2024/Bristol-Myers-Squibb-Receives-U.S.-Food-and-Drug-Administration-sBLA-Acceptance-for-First-Line-Treatment-of-Unresectable-Hepatocellular-Carcinoma/default.aspx

FDA grants accelerated approval to nivolumab and ipilimumab combination for hepatocellular carcinoma. FDA. Updated March 11, 2020. Accessed October 25, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-nivolumab-and-ipilimumab-combination-hepatocellular-carcinoma

Recent advancements in hepatocellular carcinoma (HCC) treatment have been driven by combination regimens, notably the STRIDE regimen, which has shown improved overall survival compared to sorafenib. The LEAP-012 and EMERALD-1 trials have demonstrated promising results with combination therapies involving lenvatinib, pembrolizumab, and durvalumab. The IMbrave050 study, however, did not sustain its initial recurrence-free survival benefit. Real-world data from the STELLAR trial support the safety and efficacy of lenvatinib. The CheckMate 9DW trial suggests potential FDA approval for nivolumab plus ipilimumab in frontline unresectable HCC.

In a Peer Exchange, HCC experts discussed how new data from the HIMALAYA, LEAP-012, EMERALD-1, and IMbrave050 trials could be used to optimize treatment.

Combination Regimens Make Their Mark in Frontline HCC

This commentary poses the following question: Is it time to end or at least vigorously challenge the continued rhetoric and associated claims that seek to deny the clinical benefit of regulatory agency–approved antineoplastic pharmaceutical agents due to the absence of a documented statistically significant improvement in overall survival (OS) in a randomized clinical trial?

Before proceeding, it is important to be clear that academics (and others) can certainly elect to analyze any issue they feel appropriate surrounding the regulatory review process, including multiple components of the conduct of clinical studies as well as the statistical analysis employed to make judgments related to approval for commercial sale. This includes specific decisions regarding drug labeling. Further, they have every right (as do all individual citizens or organizations) to criticize or support the final determinations of the FDA. 

Finally, there is no intent in the following discussion to defend in any manner dysfunctional pharmaceutical/ biotech industry antineoplastic drug pricing policies, maneuvers to extend exclusive patents, or reported efforts to delay generic or biosimilar marketplace competition when legally permitted. In fact, while various reasons may be suggested as to why high-impact medical journals persist in the publication of manuscripts that fundamentally reject oncology drug regulatory decisions based on so-called surrogate end points (such as progression-free survival [PFS]), it is the opinion of this commentator that perhaps interest in this topic has more to do with the continued staggering rise in costs associated with newly approved drugs rather than the specific end point employed by the FDA in its review process.

What follows are arguments that specifically deal with the question of antineoplastic drug 

, again recognizing the increasingly intense societal debate regarding the cost associated with these agents.

Although it is appropriately recognized that regulatory agencies require clear definitions, objective metrics, and consistency when making decisions, there is a fundamental question within the oncology sphere as to 

 and what process should be employed to determine 

As currently suggested in regulatory guidelines, there is no reason to challenge the opinion that patients would agree that both improving survival and enhancing quality of life (QOL) are meaningful goals of antineoplastic therapeutics. However, what is unclear is why some have concluded that prolonging the time to ultimate disease progression following the delivery of an antineoplastic agent in a therapeutic trial is not evidence of clinical benefit. Stated more directly: Should it be the regulators or academic pundits who decide if improved PFS is a relevant indication for treatment with a particular agent, or should it be patients themselves who make this determination?

If one asks the question of objective metrics to permit regulatory approval, OS is surely simple to measure, but what about QOL? Who should define this complex parameter for patients? Is there a single global metric agreeable to all that will declare QOL to be better, worse, or unchanged? Surely, the answer to this question is no. And to emphasize this concern, is it relevant to inquire just how many antineoplastic agents have been approved to date for commercial sale based solely on demonstrating an improvement in QOL in an oncology randomized trial?

Returning to the question of OS as a primary study end point, there will certainly be no ambiguity regarding the objectivity of the data (date of study entry to date of death). However, as has been previously noted by this commentator, as cancer becomes a more 

 with patients with advanced cancer living for extended periods of time (increasingly measured in years, rather than months) following the finish of a specific therapeutic trial, is it rational to routinely consider the multiple potential life-events as being a result of the agent(s) administered in the completed study?

Unfortunately, the reality of cancer care today is that the numerous compounding factors that might influence a patient’s ultimate survival may seriously interfere with the OS metric as a meaningful approach to evaluating the clinical utility of trial-based antineoplastic therapeutics. For example, randomized studies may permit crossover from the control arm to the experimental regimen at the time of disease progression or the investigated drug (or a comparably active agent) may be able to be administered when a patient goes off-study.

Further, with increasingly extended survival, patients may receive multiple agents, some producing a favorable effect on the disease process while others may have no influence, or possibly even a negative effect due to excessive toxicity. Based on the pattern of disease recurrence or progression, individual patients may receive palliative local radiation or surgical interventions that may significantly prolong their survival.

One must add that in the era of molecularly targeted therapeutics, an increasing percentage of patients may benefit from options based on a next-generation sequencing test that reveals unique findings (eg, < 5% of individuals with a particular tumor type), resulting in the delivery of a novel therapeutic and a favorable survival impact.

All the above factors may influence OS independently of any effect from the outcome of the strategy employed in the prior clinical trial.

Into this mix, one must add the impact of common comorbidities (eg, cardiac, renal, hepatic, pulmonary, metabolic, neurologic) on a patient’s ultimate survival unrelated to study drug-related adverse effects, especially with the observed increasing time intervals from the completion of a clinical trial until an individual’s death.

The rather profound alteration in the relationship between trial-measured PFS and OS was pointedly highlighted in an important publication that examined outcomes in metastatic malignant melanoma early in the targeted therapeutic era vs a time when such agents were more widely available as an option after a patient had completed a clinical trial. In the earlier era, at the time of disease progression when there were essentially no effective commercially available drugs (or relevant trial crossovers to active agents), the analysis revealed study-measured PFS was highly correlated with OS (correlation coefficient 0.96).

 However, at the later time point, the correlation was substantially reduced (correlation coefficient 0.55), indicating the impact of subsequent lines of active treatment (commercially available drugs or trial crossover).

Finally, it is critical to acknowledge there is no intent here to suggest that it is not possible for a new/novel antineoplastic agent to demonstrate a statistically significant improvement in OS in a well-designed, appropriately powered, randomized phase 3 trial. However, the failure to accomplish this aim in most oncology settings today unequivocally does not justify the conclusion that there is an absence of clinical benefit.

Maurie Markman, MD, is president of Medicine & Science at City of Hope Atlanta, Chicago, and Phoenix.

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Is it time to end the rhetoric that denies the benefit of antineoplastic pharmaceutical agents due to the absence of an OS improvement in a clinical trial?

Vol. 25 No. 16 | Oncology Live®

Novel Therapies and Combinations Augment Melanoma Treatment Arsenal

Combination Regimens Make Their Mark in Frontline HCC

The Ongoing Debate: Progression-Free vs Overall Survival as the Primary Study Outcome in Therapeutic Cancer Trials