The New Horizon in Melanoma

Jeffrey Weber, MD, PhD

Early in this decade, Jeffrey S. Weber, MD, PhD, saw how well nivolumab (Opdivo) performed against advanced melanoma and recognized a good thing. He had a hunch the PD-1 inhibitor would reduce relapse rates by stimulating immune response against any cancer cells that escaped the surgeon’s knife.

Weber urged the drug’s developer, BristolMyers Squibb (BMS), to launch a trial of nivolumab in the adjuvant setting for patients with newly resected stage III or IV melanoma, but BMS officials were skeptical. They thought the drug was unlikely to work in the absence of a tumor microenvironment and were unwilling to fund trials.

In most cases, such a refusal would have prevented investigation, but Weber, a 2016 Giants of Cancer Care^® award winner, thought the chance to significantly lower relapse rates justified an independent pilot study. He secured the funding, the pilot took place, and the results led BMS to launch the CheckMate 238 trial (NCT02388906) of adjuvant immunotherapy with nivolumab versus ipilimumab (Yervoy) in patients with resected advanced melanoma.¹ The trial was positive and earned nivolumab an FDA approval in this setting in 2017. Adjuvant treatment with nivolumab or the PD-1 inhibitor pembrolizumab (Keytruda) is now a standard of care (SOC) in patients with newly resected stage III or IV melanoma.

“It took a huge amount of effort to make that pilot happen. I really didn’t buy their reasoning for why adjuvant treatment wouldn’t work, so I just stuck with it,” said Weber, the deputy director of the Laura and Isaac Perlmutter Cancer Center at NYU Langone Health in New York, New York. “The historic rate of relapse for resected stage III melanoma was over 60%. Adjuvant treatment [with a PD-1 inhibitor] cuts that down to about 40%. That’s a big diminution, and it applies to a big patient population. There have to be 20,000 patients with stage III melanoma in the United States each year.”

The effort that helped usher in the adjuvant use of PD-1 inhibitors may be Weber’s greatest achievement as a researcher so far, but he has been investigating melanoma treatment for decades, which is why he was selected to cochair the 16th Annual International Symposium on Melanoma and Other Cutaneous Malignancies^® February 8, 2020, at the InterContinental New York Times Square in New York City.

“Dr Weber is an outstanding physicianscientist who has pioneered the development of immunotherapies for patients with melanoma and other cancers for the last several decades,” said Steven A. Rosenberg, MD, PhD, chief of the National Cancer Institute’s Surgery Branch in Bethesda, Maryland.

The conference, hosted by Physicians Education Resource^®, LLC (PER^®), will provide a concise and complete update on new investigations and updated standards for physicians who treat skin cancers. Key topics include best practices for using immune checkpoint inhibitors (ICIs) and other immunotherapeutic agents alone or in combination; emerging investigation into other therapeutic targets, such as activity related to LAG3; and strategies for mitigating adverse events (AEs) arising from ICIs and targeted treatments. Speakers include many eminent researchers, such as Weber and Omid Hamid, MD, director of the Melanoma Center and Phase I Immuno-Oncology at The Angeles Clinic and Research Institute in Los Angeles, California. Hamid also serves as a cochair of the symposium.

Immunotherapy Combinations are Introduced

The combination of nivolumab and the CTLA-4 inhibitor ipilimumab is the only treatment for metastatic melanoma for which median overall survival (OS) has not been reached at 5 years, according to CheckMate 067—trial investigators.

Most recently, the CheckMate 067 trial established the existence of an impressive 60-month plateau for patient groups that received regimens containing nivolumab. Long-term survival figures compared ipilimumab monotherapy with both nivolumab monotherapy and ipilimumab plus nivolumab. At a minimum follow-up of 5 years, median overall survival (OS) was 19.9 months (26%) in the ipilimumab monotherapy group, 36.9 months (44%) in the nivolumab-alone group, and not yet reached (52%) in the ipilimumab-plus-nivolumab group (Figure).² This represented a huge bump up from historically dismal 5-year survival rates among patients with metastatic melanoma.

“Those survival data should make ipilimumab plus nivolumab [ipi-nivo] the presumptive treatment for pretty much any patient without some contraindication, and even for patients with targetable mutations,” Weber said. “If you look at the median survival, for patients who start out with targeted therapy, it’s between 25 and 33 months. If you look at the median survival of frontline ipi-nivo, it’s more than 5 years. You tell me what you want: median survival of 25 to 33 months [with targeted therapy] or median survival of more than 5 years? Some patients choose otherwise, but I’d accept the increased toxicity and go for the longer survival.”

Figure. Survival and TRAEs for Nivolumab + Ipilimumab at 5-Year Mark

Weber has witnessed many patients with no treatment options die within months; to him, a treatment that keeps half of all patients alive more than 5 years seems nearly miraculous. However, serious toxicity drawbacks with the combination of ipilimumab and nivolumab spurred a number of phase III trials designed to investigate alternatives. The high cost of treatment may be a problem that trials cannot solve. The price tag for a year of nivolumab and ipilimumab is astronomical—over $250,000³—and novel therapies that demonstrate improved survival could cost more.

Some Novel Regimens Falter in Phase III Trials

However, many experts hope that experimental combinations will produce fewer AEs and work at least as well as ipilimumab and nivolumab, especially in patients who never respond or stop responding to this combination.

“There are certainly a lot of people looking for new drugs to combine with PD-1 blockade that wouldn’t significantly increase the toxicity. You might not have to use ipi-nivo, which, frankly, can be a pretty toxic combination,” Weber said. “We’ve had some pretty interesting early-stage results from several combinations, but the few late-stage trials so far have been total failures.”

The first of those trials was reported at the 2018 American Society of Clinical Oncology (ASCO) Annual Meeting. A total of 706 patients in the phase III ECHO-301/KEYNOTE-252 study were randomized evenly to pembrolizumab with either placebo or the IDO1 enzyme inhibitor epacadostat. After a median follow-up of 12.4 months, median progression-free survival (PFS) was 4.7 months with the combination and 4.9 months with pembrolizumab alone. These findings were consistent across PD-L1 and BRAF mutation subgroups.⁴

The phase III trial was launched in part because the combination of pembrolizumab and epacadostat produced an objective response rate (ORR) of 55% in a phase I/II trial.⁵ However, in the larger trial, ORRs in the combination group and the pembrolizumab and placebo group were 34.2% versus 31.5%, respectively.

Grade 3/4 treatment-related AEs (TRAEs) occurred in 21.8% of patients who received the combination and 17.0% of those who received pembrolizumab monotherapy. In CheckMate 067, by contrast, 59% of all patients who received ipilimumab and nivolumab experienced grade 3/4 TRAEs.⁶

Another combination, the PD-L1 inhibitor atezolizumab (Tecentriq) and the MEK inhibitor cobimetinib (Cotellic), failed to meet the primary end point of the phase III IMspire170 trial (NCT03273153) to show improved PFS over pembrolizumab monotherapy in patients with previously untreated BRAF V600 wild-type melanoma. Genentech, which manufactures atezolizumab and is sponsoring the trial, announced that it will present the findings at an upcoming medical meeting.

“It is depressing that both of the most recent phase III trials have apparently produced negative results. We don’t know how the atezolizumab combination fared because they haven’t published details— maybe there’s something to salvage—but the pembro [and epacadostat] trial was the most negative trial I’ve seen in a long time,” Weber said. “Having a couple major failures in a row gets me thinking back to the part in the book of Genesis about the 7 years of feasts followed by the 7 years of famine. We definitely had 7 years of feasts between 2010 and 2017. I hope we haven’t started 7 years of famine.”

Weber worries that more negative results are a very real possibility because he believes several ongoing phase III trials of anti—PD-1/ PD-L1 antibodies plus novel treatments have been launched with modest supporting evidence from earlier trials.

The MASTERKEY-265/KEYNOTE-034 trial (NCT02263508),⁷ which is assessing pembrolizumab and talimogene laherparepvec (Imlygic; T-VEC) in advanced, unresectable melanoma, expanded straight from a stage phase Ib trial to a phase III trial. The phase I portion of the trial included 21 patients who were treated with the combination. The ORR was 62%, with a complete response (CR) rate of 33%.⁸

Those results triggered the phase III portion, which will randomize roughly 700 patients with advanced melanoma to pembrolizumab and placebo or T-VEC, a type 1 herpes simplex virus genetically modified to break down cancer cells without harming normal cells. The FDA approved T-VEC in 2015 as monotherapy for the local treatment of unresectable, subcutaneous, and nodal lesions in patients with melanoma that recurs after initial surgery.

The phase III ILLUMINATE 301 trial (NCT03445533) is a relatively large study that sits on a foundation of results from a small patient population.⁹ ILLUMINATE-301 is comparing ipilimumab with and without tilsotolimod (IMO-2125) in patients with anti—PD-1 refractory advanced melanoma. Ipilimumab monotherapy is a common treatment for this population, but the response rate is roughly 13%.

Tilsotolimod is a toll-like receptor 9 (TLR9) agonist that could improve response to ipilimumab by activating innate and adaptive immune responses. A preliminary analysis from a phase II study of the combination reported an ORR of 47% (n = 15), and 3 patients exhibited stable disease.10 The phase III trial will randomize 454 patients between ipilimumab monotherapy and ipilimumab plus tilsotolimod.

Novel Agents Look Promising

ILLUMINATE 301 is not the only phase III trial testing a TLR inhibitor with an ICI in patients with melanoma, and a number of early-stage trials have produced promising results. For example, in patients with PD-1 inhibitor—refractory advanced melanoma, a combination of pembrolizumab and the TLR9 inhibitor CMP-001 produced an ORR of 22.5% among 40 patients dosed weekly and 7.7% among 13 patients treated every 3 weeks.¹¹

Also, in patients naïve to anti—PD-1/PD-L1 treatment with unresectable melanoma, the combination of pembrolizumab and another TLR9 agonist, SD-101, produced an ORR of 76% (including 8 CRs and 26 PRs) among 45 participants treated with 2-mg intratumoral SD-101 and 49% (including 4 CRs and 16 PRs) among 41 patients treated with an 8-mg dose.¹²

Another phase III trial (NCT03635983) of nivolumab with or without bempegaldesleukin (NKTR-214)¹³ is under way in 764 patients with previously untreated unresectable or metastatic melanoma. Bempegaldesleukin is an investigational CD122-preferential interleukin-2 pathway agonist that increases the activity of some immune T cells and some natural killer cells. The phase III trial isn’t scheduled to be completed until 2025, but the combination might not have to wait that long for FDA approval.

The agency gave the combination a breakthrough therapy designation based on results from the phase I/II Pivot-02 trial, which were presented orally at the 2019 ASCO Annual Meeting. Some 53% of patients with metastatic melanoma and 48% with metastatic urothelial carcinoma who received the bempegaldesleukin and nivolumab combination responded to the treatment, including those whose tumor surroundings were deemed least favorable, patients with low levels of PD-L1 expression and T cells.¹⁴ The phase III trial of nivolumab and bempegaldesleukin is also assessing the efficacy of a triplet that includes ipilimumab.

Another ongoing phase III study combines the MEK inhibitor cobimetinib and the BRAF inhibitor vemurafenib (Zelboraf) with either placebo or atezolizumab in 513 patients with previously untreated BRAF V600 mutation—positive metastatic or unresectable locally advanced melanoma.¹⁵ A phase Ib trial published in June reported that the triple therapy had an ORR of 71.8% (95% CI, 55.1%-85.0%). The estimated median duration of response was 17.4 months (95% CI, 10.6-25.3 months). After 29.9 months of follow-up, 39.3% of patients were still responding.¹⁶

Weber said he is nervous that, although positive, these trial outcomes could be misleading, chance occurrences. “My concern is a lot of [the ongoing phase III trials] were embarked upon without an adequate phase II randomized experience, so there is a risk, and the risk is that these may not be positive trials. And that’s going to hurt the field,” said Weber, who, before taking his current position at Perlmutter Cancer Center, was chief of medical oncology at the University of Southern California in Los Angeles and then the director of the Donald A. Adam Comprehensive Melanoma Research Center at Moffitt Cancer Center in Tampa, Florida.

“The phase III trial of IMO-2125 was embarked upon with the advantage of having treated 26 patients,” Weber said. “That’s a very aggressive drug development pathway. The worst-case scenario is [that] none of them are positive, and that would be horrible. The best-case scenario is [that] all of them are positive, and then we’ll have a wealth of options and can avoid the highly toxic ipi-nivo combination.”

Treatments Move to the Adjuvant Setting

Until recently, the only approved adjuvant treatment for high-risk melanoma was interferon, which confers a significant but small benefit that by 1 meta-analysis amounted to a 3.0% increase in 5-year OS.¹⁷ The FDA added ipilimumab to the list of approved adjuvant treatments in 2015, after a 1:1 randomized study in 951 patients found a 5-year OS of 65.4% among those who received ipilimumab and 54.4% among those who received placebo.¹⁸

Thanks to Weber’s efforts to test nivolumab’s efficacy in the adjuvant setting, that drug was added to the list of FDA-approved options in 2017. The Checkmate 238 trial leading to the approval compared nivolumab not with placebo but with the ipilimumab treatment that already proved to have significant benefits. Still, the PD-1 inhibitor proved itself far more effective than the CTLA-4 inhibitor. Initial analysis showed that the 12-month rate of recurrence free survival (RFS) was 70.5% among nivolumab patients and 60.8% among ipilimumab patients, and grade 3 or 4 TRAEs were 14.4% in the nivolumab group and 45.9% in the ipilimumab group.¹⁹ In October, investigators updated those results, showing 3-year RFS rates of 58% in nivolumab patients and 45% in ipilimumab patients.²⁰

The FDA approved pembrolizumab for the same indication in 2019, based on results from the KEYNOTE-054 study. Among 1019 patients randomized between pembrolizumab and placebo, the 12-month RFS rate was 75.4% in the pembrolizumab arm and 61.0% in the placebo arm. In the subgroup of 853 patients with PD-L1—positive tumors, the 12-month RFS rate was 77.1% in the pembrolizumab arm and 62.6% in the placebo arm.²¹

The recent series of adjuvant treatment approvals includes 1 regimen that uses targeted therapies rather than ICIs: dabrafenib (Tafinlar) plus trametinib (Mekinist) in stage III BRAF-mutated melanoma. The approval was based on findings from the phase III Combi-AD trial, in which the 3-year RFS rate was 58% with dabrafenib and trametinib compared with 39% with placebo.²²

The combination of ipilimumab and nivolumab was approved for treatment of V600 wild-type, unresectable or metastatic melanoma in 2015, but the combination has not been approved for adjuvant therapy in patients with stage III melanoma. However, promising findings have emerged.

A study conducted at Moffitt Cancer Center included 40 patients with stage IIIc or IV melanoma. After a median follow-up of 2.9 years, median RFS survival had yet to be reached, and 3-year RFS rates were 70% among the 20 patients who received 1 mg/kg of nivolumab plus 3 mg/kg of ipilimumab every 3 weeks for 4 doses, followed by maintenance, and 75% among those (n = 20) who received 3 mg/kg of nivolumab plus 1 mg/kg of ipilimumab every 3 weeks for 4 doses, followed by maintenance.

Unfortunately, the trial investigators reported that the combination seemed even more toxic in the adjuvant setting than the metastatic setting: Roughly 80% of all patients experienced grade 3/4 TRAEs.²³

Investigators on a 3-arm trial of adjuvant nivolumab plus ipilimumab versus nivolumab monotherapy versus placebo also reported positive results during a presentation at the 2019 European Society for Medical Oncology. In early f indings from the phase II IMMUNED study, adjuvant treatment for patients with high-risk stage IV disease demonstrated a 2-year RFS rate of 70% in the combination arm (n = 55) versus 42% for those who received nivolumab alone (n = 56; HR, 0.40; 95% CI, 0.22-0.73) and 14% for placebo (n = 51; HR, 0.23; 95% CI, 0.13-0.41). Grade 3/4 TRAEs occurred in 27% of patients who received nivolumab monotherapy and 71% of those who received the combination.²⁴

“This looks phenomenal, and these are the patients with the worst outcomes. It’s fantastic, looks very good. It’s better than any of the other immunotherapy arms looking at 1-year and 2-year [data],” Weber said during a presentation at the 37th Annual CFS^®: Chemotherapy Foundation Symposium. The 2-year data here look as good as the 1-year data for pembrolizumab or nivolumab alone if you were looking at stage III disease, but this is stage IV,” said Weber. “These data are very promising.”

In an interview, Weber elaborated on the potential for this combination in the advanced setting. “There are some pilot trial data to suggest that using the ipi-nivo combo as adjuvant treatment in stage III or IV patients is more effective [than any approved adjuvant treatment] at preventing relapse, though it’s obviously toxic,” he said.

“That’s being tested with the [phase III] CheckMate 915 trial that compares adjuvant ipi-nivo with nivo alone. That trial had accrued all its patients as of last year, and we’ll probably need to wait another year to see any information at all,” said Weber, adding that neoadjuvant treatments, whether used by themselves or in addition to adjuvant treatments, might also prove more effective than today’s approved adjuvant treatments. “There is an ECOG trial that is testing pembrolizumab—neoadjuvant and adjuvant versus adjuvant alone.”

A number of small trials indicate that neoadjuvant treatment may work even better than adjuvant therapy for at least some patients with melanoma. For example, a phase Ib trial of neoadjuvant pembrolizumab in stage IIIb/c and IV melanoma showed a 2-year disease-free survival rate of 63% and a 2-year OS rate of 93%. A single dose of pembrolizumab produced a complete or major pathological response in 8 of 27 patients.²⁵

A small study of neoadjuvant dabrafenib and trametinib had similarly promising results. Investigators presented results in May 2019 for 19 patients with BRAF-mutated, unresectable, locally advanced stage III or oligometastatic stage IV melanoma who underwent 8 weeks of treatment. Of these, 2 patients showed progressive disease and did not proceed to surgery. Resection was possible after neoadjuvant treatment in 17 of the 18 (94%) remaining patients. Median RFS was 9 months in patients undergoing surgery.²⁶

References

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