The addition of T-VEC (T-VEC; Imlygic), a herpes simplex virus 1-based oncolytic virus, to CTLA-4 inhibitor ipilimumab (Yervoy) improves the objective response rate (ORR) in patients with unresected stage IIIb to IV melanoma, according to findings presented at the 7th European Post-Chicago Melanoma/Skin Cancer Meeting.

T-VEC was the first approved oncolytic virus therapy in Europe, the United States, and Australia, and its efficacy was previously demonstrated in a phase III trial comprising patients with advanced unresectable melanoma.

In a phase II open-label study, 198 patients with unresected stage IIIb to IV melanoma and measurable/injectable tumor(s) were randomized in a 1:1 ratio to T-VEC plus ipilimumab (n = 98) or ipilimumab alone (n = 100). T-VEC was administered from week 1 and ipilimumab was administered at 3 mg/kg intravenously every 3 weeks for 4 cycles starting from week 6 in the combination arm and from week 1 in the monotherapy arm.

Prior treatment was allowed but was not a prerequisite for study entry. The primary endpoint was ORR, according to immune-related response criteria. At the start of the study, 54% of patients had stage IIIb to IVM1a disease, 46% had stage IVM1b/c disease and baseline characteristics were similar between treatment arms.

After a median follow-up period of 68 and 58 weeks in the combination and monotherapy arms, respectively, T-VEC plus ipilimumab resulted in a doubling of the ORR, compared with ipilimumab alone (38.7% vs 18.0; odds ratio [OR], 2.9; 95% CI, 1.5-5.5; 

More patients experienced a complete or partial response in the combination arm (13.3% and 25.5%, respectively) than patients who were receiving ipilimumab alone (7.0% and 11.0%, respectively). Significantly more patients had disease control (complete or partial response plus stable disease) in the T-VEC plus ipilimumab arm versus the ipilimumab-alone arm (58.2% vs 42.0%; OR, 1.9; 95% CI, 1.1-3.4; 

Improvement in ORR in the combination arm was observed across all subgroups analyzed, aside from patients with elevated lactate dehydrogenase, as well as for all disease substages. In patients with stage IIIb/c-IVM1a disease, ORR was 44.0% in the T-VEC plus ipilimumab arm and 19.3% in the ipilimumab-alone arm (OR, 3.3; 95% CI, 1.4-7.8; 

 = .007). The difference in ORR was no longer significant in patients with more advanced disease, with ORRs of 33.3% and 16.3% being reported, respectively (OR, 2.6; 0.9-7.0; 

In addition, over a third of patients (35.5%) in the combination arm experienced a reduction from baseline of at least 50% in total visceral tumor area versus 13.6% of patients in the ipilimumab-alone arm, supporting the improved systemic effect of the combination therapy. “Hopefully, this will translate into improved overall survival, which we will see in a future evaluation,” said presenter Claus Garbe, MD, of the University of Tuebingen, Germany. As of the presentation, 89% and 83% of responding patients in the T-VEC plus ipilimumab and ipilimumab-alone arms, respectively, remained in response.

Median progression-free survival was nonsignificantly longer in the T-VEC plus ipilimumab arm, compared with ipilimumab alone (8.2 vs 6.4 months; hazard ratio [HR], 0.83; 95% CI, 0.56-1.23; 

Ninety-five patients were evaluable for safety in each arm. The combination of T-VEC plus ipilimumab was tolerable and no unexpected adverse events (AEs) occurred. The most frequently reported AEs were fatigue (59% vs 42% of patients in the T-VEC plus ipilimumab and ipilimumab-alone arms, respectively), chills (53% vs 3%), and diarrhea (42% vs 35%). Grade 3 or higher AEs considered related to treatment occurred in 28% of T-VEC plus ipilimumab recipients and 18% of patients receiving ipilimumab alone. Three deaths occurred in the combination therapy arm, none of which were considered related to treatment (progressive disease and myocardial infarction; n = 2 and n = 1, respectively).

“What will be very important is to see the results of the MASTERKEY-265 study, which is a combination of pembrolizumab [Keytruda] plus T-VEC because we have to try to get immune responses in first-line treatment by combining as many treatment approaches as possible,” said Garbe. “So, I am still hoping that T-VEC will add something to that. We will probably not bring ipilimumab plus T-VEC into clinical practice but the main question will be whether we can combine it with PD-1 inhibitors or with both—with PD-1 plus CTLA-4 inhibitors in a triplet combination. And, if T-VEC can improve the outcome in our metastasized patients we will undoubtedly use it.”

Chesney J, Puzanov, Ross M, et al. Combination of talimogene laherparepvec and ipilimumab versus ipilimumab alone in unresected stage IIIB-IV melanoma: primary results from a randomized (1:1), open-label phase 2 study. Presented at: 7th European Post-Chicago Melanoma/Skin Cancer Meeting; June 29-30, 2017; Munich, Germany.

Articles

The addition of T-VEC (T-VEC; Imlygic), a herpes simplex virus 1-based oncolytic virus, to CTLA-4 inhibitor ipilimumab (Yervoy) improves the objective response rate in patients with unresected stage IIIb to IV melanoma.

Positive Results from First Randomized Study Assessing T-VEC/Ipilimumab Combo in Advanced Melanoma

Pembrolizumab (Keytruda) provides a long-term survival benefit in both ipilimumab-naïve and ipilimumab-treated patients with advanced melanoma, according to 4-year overall survival (OS) data from KEYNOTE-001 presented at the 7th European Post-Chicago Melanoma/Skin Cancer Meeting.

At 4 years, 37.3% of patients in the overall study population were still alive and median overall survival (OS) was 23.8 months (95% CI, 20.2-30.4). In ipilimumab-naïve and ipilimumab-treated patients, median OS was 29.1 months (95% CI, 22.8-39.0) and 20.2 months (95% CI, 17.8-27.1), respectively; estimated 4-year OS rates were 41.7% and 32.7%, respectively.

OS rate at 4 years was 48% in treatment-naïve patients, and the median OS duration was 41.2 months (range, 27.2-not reached). The tail of the Kaplan-Meier OS curves implied a long-term benefit for a certain fraction of pembrolizumab-treated patients.

“After this long follow-up we show that pembrolizumab continues to demonstrate a favorable tolerability and safety profile,” Caroline Robert, MD, from the Gustave-Roussy and Paris-Sud University, said during her presentation. “The CRs [complete responses] are durable, even after this additional 6 months of follow-up. Median time to obtain complete response is a little bit more than 1 year, 91% are ongoing and the median duration of response has not been reached.”

In the phase 1b multicohort KEYNOTE-001 trial, patients received 2 mg/kg or 10 mg/kg pembrolizumab every 3 weeks, or 10 mg/kg every 2 weeks until disease progression, unacceptable toxicity, or investigator decision to withdraw the patient from the trial.

Median age of the patients was 61 years (range, 18-94), 62% were male, and 68% had an ECOG status of 0. The patient population had very advanced melanoma: 78% had stage M1c disease and 38% had elevated lactate dehydrogenase at baseline. Eight percent had stable brain metastases.

More than half of patients (52%) had received prior ipilimumab and 24% were treatment-naïve. Roughly a third had received 1 line of therapy, 27% had received 2 lines of therapy, and 17% had received 3 or more lines of therapy. One-third of patients (33%) had received prior chemotherapy, and 17% had previously received a BRAF inhibitor with or without a MEK inhibitor.

At the data cutoff date of September 1, 2016, the median follow-up period was 43.3 months (range, 36.0-57.1). Investigators recorded 388 deaths (59.2%), an increase of 30 patients from the 3-year analysis. Median duration of pembrolizumab treatment was 5.6 months (range, 0.03-55.2), and 238 (36.3%) patients remained on pembrolizumab for longer than 12 months. At the time of data cutoff, 104 (15.9%) patients were either still receiving pembrolizumab (n = 47) or had discontinued treatment due to experiencing complete response (n = 57).

The disease control and CR rates remained the same at 4 years when compared with the 3-year analysis, with a slight increase in the overall response rate at 4 years (34% vs 33%). Overall, 105 (16%) patients had a CR. Of those, 13% remained on pembrolizumab, 23% discontinued pembrolizumab due to adverse events (AEs), progressive disease or other reasons, and 64% stopped pembrolizumab to undergo observation.

In the complete responders who stopped pembrolizumab to undergo observation, median time to CR was 13 months (range, 3-36), and 91% of these responses were ongoing at the time of this analysis. Median CR duration has not yet been reached. Four (6%) of these patients experienced progressive disease, all of whom received further pembrolizumab treatment. Three of these patients continued to have progressive disease and one patient receiving second-line pembrolizumab had a partial response.

Compared with the previous analysis at 3 years, there was no increase in grade 3 or 4 AEs in the overall population at data cutoff (17% at both time points), nor did any additional patients discontinue treatment. There was a slight increase in the numbers of patients with hypothyroidism, hyperthyroidism and colitis at 4 years.

Long-term outcomes in patients (Pts) with advanced melanoma treated with pembrolizumab (Pembro): 4-year overall survival (OS) results from KEYNOTE-001. 7th European Post-Chicago Melanoma/Skin Cancer Meeting; June 29-30, 2017; Munich, Germany. Abstract 8.

Pembrolizumab (Keytruda) provides a long-term survival benefit in both ipilimumab-naïve and ipilimumab-treated patients with advanced melanoma.

Pembrolizumab Demonstrates Long-Term OS Benefit in Advanced Melanoma

Immune checkpoint inhibitors against PD-1 and PD-L1 are showing promise across clinical trials for patients with Merkel cell carcinoma (MCC), with an approval already granted for avelumab (Bavencio) and another pending for pembrolizumab (Keytruda).

Despite the rarity of MCC, more than 4 studies have already reported results for PD-1/PD-L1 inhibitors, including a phase II trial of pembrolizumab, a phase I/II of nivolumab (Opdivo), and two phase II studies of avelumab. The importance of PD-1/PD-L1 inhibitors in MCC was emphasized during a talk by Celeste Lebbé, MD, PhD, at the 2017 European Post-Chicago Melanoma/Skin Cancer Meeting in Munich, Germany.

“The take home message is that anti—PD-1/PD-L1 inhibitors are a breakthrough for patients with a rare cancer with an unmet medical need and hopefully they should soon become available as first-line therapy worldwide,” said Lebbé, from the Hôpital Saint Louis, in Paris, France. “I think it’s unusual to have such a large amount of clinical data for a rare cancer even though they are small clinical trials and I hope this will be a good example to follow for other rare cancers.”

The historic standard of care for MCC has been chemotherapy. In the frontline setting, the objective response rate (ORR) with chemotherapy is around 57%, which drops to 23% with limited durability (around 4 months) in the second-line setting. Median progression-free survival (PFS) in the first- and second-line setting are 3 months and 61 days, respectively.

There is a strong rationale for targeting PD-1/PD-L1 in MCC, Lebbé explained. MCC is characterized by PD-L1 expression on tumor cells (TC) and adjacent immune cell infiltrates (IC). Additionally, the Merkel cell polyomavirus (MCPyV), which occurs in 80% of tumors, causes T cell dysfunction (CD8

 T cells increase with larger tumor burden, exhausted phenotype [PD-1

]) and tumors that are MCPyV-negative tend to have higher mutation and neoantigen burdens, which also signal better efficacy with anti—PD-1/PD-L1 agents.

In the studies for patients with MCC, response rates were similar to chemotherapy with durations of response that were not yet reached with more than a year of follow-up in some scenarios. Patient populations in these studies were relatively small, reflective of the rare status of MCC.

The pembrolizumab study enrolled 26 patients with primarily stage IV MCC (92%). Fifty-six percent of tumors were PD-L1—positive on at least 1% of cells. The ORR was 56%, and, after a median follow-up of 33 weeks, the median duration of response was not yet reached (range, 2.2-9.7+ months). The PFS rate at 6 months was 67%.

The nivolumab study enrolled 25 patients with MCC who received ≤2 prior lines of therapy. Twenty percent of tumors were positive for PD-L1. The ORR was 64% and 75% of responses occurred at approximately 8 weeks. At the time of data cutoff, 75% of responses were ongoing. The median PFS was 9 months and the overall survival (OS) rate was 80% at 9 months.

In the JAVELIN Merkel 200 study, which led to the approval of avelumab, 88 patients received treatment with the PD-L1 inhibitor. Patients in the trial received ≥3 prior therapies and all had metastatic MCC (66% were PD-L1&shy;&shy;—positive). After at least 1 year of follow-up in the first avelumab study, the ORR was 33% and 10 patients had experienced a complete response (11%), with 72% of responses still ongoing. The median time to response was 6.1 weeks. The PFS rate at 1 year was 30% and the median PFS was 2.7 months. Median OS was 12.9 months.

A second study of avelumab in untreated patients with stage IV MCC was presented at the 2017 ASCO Annual Meeting from an interim analysis of 29 patients. The trial plans to enrolled 112 total participants. The ORR at this analysis was 63% after ≥13 weeks of follow-up.

“So what are the next steps for anti-PD1/PD-L1 inhibitors in MCC?” asked Lebbé. “Luckily for patients we have decided to not go for a randomized trial comparing PD-1 inhibitors with chemotherapy. The next steps will certainly consist of evaluating combinations and sequences with chemotherapy and radiotherapy. MCC, in contrast with melanoma, is radiosensitive.”

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Immune checkpoint inhibitors against PD-1 and PD-L1 are showing promise across clinical trials for patients with Merkel cell carcinoma.

PD-1/PD-L1 Inhibitors Arrive in Merkel Cell Carcinoma

Monotherapy with potent BRAF inhibitor dabrafenib (Tafinlar) resulted in a disease control rate of 83% in patients with 

-mutant melanoma and brain metastases, according to a retrospective study presented during the 7th European Post-Chicago Melanoma/Skin Cancer Meeting, which took place June 29 to 30 in Munich, Germany.

A single-center, controlled retrospective study was performed in Hungary between 2014 and 2017 looking at 30 patients with advanced 

-mutant melanoma and brain metastases. Patients in the retrospective part of the study received dabrafenib following local control of brain metastases. The control arm of the study comprised 204 melanoma patients with brain metastases from a melanoma database in Budapest, all of whom were treated with local therapies and/or chemotherapy between 2003 and 2015.

Patients in the retrospective group had a median age of 59.2 years (range, 21.8-75.1) and were evenly divided by gender. Patients had an ECOG performance status (PS) of 0 to 2, including 27% with a PS of 0, and 40% with a PS of 1.

The median tumor Breslow depth was 3.9 mm (range, 0.7-21.0). More than half of patients (57%) had elevated lactate dehydrogenase (LDH) levels at baseline and almost three-quarters had more than 2 brain metastases (70%). Similar proportions of patients had 1 or 2 brain metastases (17% and 13%, respectively). Twenty-one patients (70%) had 2 or fewer extracranial organs with metastases. A majority of patients had a

Previous therapies included surgical resection (30%), stereotactic radiosurgery (33%), whole-brain radiotherapy (53%), chemotherapy (20%), and vemurafenib (Zelboraf) therapy (7%).

Baseline characteristics appeared to be similar between the study and control groups. In the control group, the median age was 56.7 years (range, 21.0-83.1). There were more males than females (64% vs 36%, respectively) and like in the study arm, the majority of patients had an ECOG PS of 1 (51%). Slightly more patients had a PS of 2 (29%), compared with the study arm and 41 patients (20%) had a PS of 0.

Fewer patients in the control group had more than two brain metastases (45%), compared with the study group. Approximately one-third of patients had only 1 metastatic brain lesion and 40 patients (20%) had 2 brain metastases. Eighty-three percent of patients in the control arm had no more than 2 extracranial organs with metastatic involvement.

With respect to previous therapy, 90 patients (44%) in the control group had undergone resection, 88 (43%) had undergone stereotactic radiosurgery, 145 (71%) had undergone whole-brain radiotherapy, and 149 (73%) had received chemotherapy.

In the retrospective arm, 4 patients (13%) experienced a complete response, 9 (30%) had partial responses, and 12 (40%) had stable disease. After a median follow-up of 14 months, the median progression-free survival was 5.5 months, and the median overall survival (OS) was 8.8 months.

When calculated from the onset of brain metastases, the median OS was significantly longer in the study group compared with controls (11.8 vs 6.0 months, respectively; HR, 0.45; P = .0014).

Study author Kata Czirbesz, MD, from the National Institute of Oncology in Budapest, Hungary, told

that “in addition to the intracranial response rate, 27% of patients had an ECOG PS of 2 and the prognosis for these patients is usually pretty dismal. So, I think, in this study population, this is a very good result.”

However, patients with a higher ECOG performance status were still at a significantly higher risk of progression (HR, 4.06; 

 = .00027) as were patients with involvement in more than 2 extracranial organs (HR, 3.4; 

 = .0077). In addition, patients with elevated LDH levels at baseline tended to have a worse clinical outcome; however, this finding was nonsignificant.

Dabrafenib has also shown intracranial activity in previous clinical studies, such as in the phase II BREAK-MB study of melanoma patients with brain metastases.

 In patients with untreated brain metastases the intracranial disease control rate was 80% to 90% in patients with 

-mutant melanoma and 50% in patients with a V600K mutation. Activity was also seen in patients with previously treated and progressed brain metastases.

The investigators of the retrospective analysis concluded that their study confirms dabrafenib’s “remarkable” intracranial activity as observed in real-world practice.

1) Gorka E, Fabó D, Gézsi A, et al. Dabrafenib therapy in 30 patients with melanoma metastatic to the brain: a single-centre controlled retrospective study in Hungary. Poster presented at: 7th European Post-Chicago Melanoma/Skin Cancer Meeting; June 29-30, 2017; Munich, Germany. Abstract 3.

1) Long GV, Trefzer U, Davies MA, et al. Dabrafenib in patients with Val600Glu or Val600Lys BRAF-mutant melanoma metastatic to the brain (BREAK-MB): a multicentre, open-label, phase 2 trial. 

. 2012;13(11):1087-1095. doi: 10.1016/S1470-2045(12)70431-X.

Monotherapy with potent BRAF inhibitor dabrafenib (Tafinlar) resulted in a disease control rate of 83% in patients with BRAF-mutant melanoma and brain metastases.

Dabrafenib Shows Remarkable Intracranial Activity in Patients With BRAF-Mutant Melanoma and Brain Metastases

 (Yervoy) has been shown to improve overall survival (OS), and the FDA approved the anticytotoxic T-lymphocyte antigen-4 (CTLA-4) antibody for use in patients with unresectable or metastatic melanoma in 2011. However, improved OS often comes with toxicity, and while those adverse events (AEs) are often mild to moderate, they are common, appearing in 70% to 88% of patients.

Jean Jacque Grob, MD, PhD, professor of Dermatology at the Hospital de la Timone, discussed the challenge of balancing safety and efficacy in his presentation at the 7

 European Post-Chicago Melanoma/Skin Cancer Meeting. The choice, he said, depends on the setting. In the curative setting, providers need to prioritize efficacy especially if there is an immediate threat to the patient, such as brain metastases.

Grob summarized results from four key studies of patients with advanced melanoma, CA184169, CheckMate 067, CheckMate 204, and KEYNOTE-029.

In the CA184169 study, median OS was significantly longer in patients with metastatic melanoma who received the higher ipilimumab dose of 10 mg/kg versus those patients receiving the lower dose of 3 mg/kg but the rate of grade 3-5 adverse events was markedly higher, 34% versus 19%.

In CheckMate 067, investigators saw only a modest OS benefit with ipilimumab 3 mg/kg plus nivolumab (Opdivo), compared with nivolumab or ipilimumab alone in patients with advanced melanoma.

“If improvement in intracranial progression-free survival (PFS) is confirmed at the 1- and 2-year time points then severe toxicity would be more acceptable,” said Grob.

In the KEYNOTE-029 trial, treatment with very-low-dose ipilimumab, 1 mg/kg, appeared to be efficacious in combination with pembrolizumab, and was associated with lower toxicity than ipilimumab 3 mg/kg.

“Overall, the toxicity:efficacy ratio appears to be better with lower ipilimumab doses in the curative setting,” Grob said. However, he noted that there isn’t enough data to draw strong conclusions.

In contrast, Grob said tolerability is more important in the adjuvant setting where recurrence is low and quality of life concerns are high. Tolerability is even more important for the patient groups considered to be “lower risk” but who account for the majority of deaths from melanoma, said Grob.

Duration and reversibility of adverse events also need to be taken into consideration, he said, and there is some risk administering treatment in this setting could decrease the efficacy of the same drugs when administered later for metastatic disease.

That said, there are clear survival advantages associated with adjuvant ipilimumab. Results from EORTC 18071 showed that 10 mg/kg ipilimumab produced a significantly higher 5-year OS compared with placebo in patients with high-risk stage III melanoma (65% vs 54%; HR, 0.72; 95% CI, 0.58-0.88; 

 = .001). However, 54.1% of patients in the ipilimumab group experienced a grade 3-5 AE.

That incidence rate for grade ≥3 AEs is similar to what investigators have observed in ECOG 1609. In that study, patients with resected stage IIIB, IIIC, M1a and M1b melanoma are randomly assigned to 3 mg/k then 10 mg/kg in a 2-step fashion or high-dose interferon alfa-2b.

Preliminary efficacy and toxicity results show that the relapse-free survival (RFS) rates at 3 years were similar between the two doses of ipilimumab whereas toxicity was substantially higher in the ipilimumab 10 mg/kg arm, 56.5% versus 36.6%.

Grob said that 3 mg/kg ipilimumab appears to be better tolerated than 10 mg/kg ipilimumab, but this trial was not designed to test this comparison.

“The high toxicities associated with ipilimumab 10 mg/kg are not acceptable in the adjuvant setting, and even the toxicity observed with ipilimumab 3 mg/kg is still not that low,” he said. He noted that 3 mg/kg ipilimumab is associated with acceptable toxicity, but efficacy has yet to be established. “If you look at all the trials we have in the adjuvant setting with IPI 3 and IPI 10, the toxicity is much lower with the IPI 3 dose. This makes ipilimumab a difficult drug to administer in the adjuvant setting.

“Ipilimumab 3 mg/kg plus nivolumab is still the reference immunotherapy regimen in the adjuvant setting but may become obsolete if not repositioned in a relevant subgroup, such as very aggressive melanoma.”

Grob said the balance between safety and efficacy for 10 mg/kg ipilimumab is barely acceptable for stage III melanoma patients, and debatable for stage III C-D patients.

He added that the balance between efficacy and tolerability of different regimens containing ipilimumab need to be assessed in light of other combinations with potentially better risk/benefit ratios.

Treatment with ipilimumab has been shown to improve overall survival; however, this efficacy often comes with toxicity.

Weighing Efficacy and Tolerability for Adjuvant Ipilimumab in Advanced Melanoma

Several clinical trials are examining the use of adjuvant PD-1 inhibition for patients with melanoma, with a potential new standard of care on the horizon for those at high risk of recurrence following resection, according to Paul Lorigan, MD, at the 2017 European Post-Chicago Melanoma/Skin Cancer Meeting in Munich, Germany.

“It’s likely there will be a new standard of care for adjuvant therapy within the next 3 to 5 years,” said Lorigan, Professor of Medical Oncology, Melanoma, University of Manchester, Manchester, United Kingdom. “This might be PD-1 inhibitors alone, PD-1 combinations, or BRAF combinations.”

The PD-1 inhibitors, such as nivolumab (Opdivo) and pembrolizumab (Keytruda), have rapidly become the standard of care for metastatic melanoma, due to having a favorable ratio of activity to toxicity. It is intuitive to explore PD-1 inhibitors in the adjuvant setting, given the activity and FDA approval of the CTLA-4 inhibitor ipilimumab (Yervoy), Lorigan added.

Some of the challenges of assessing PD-1 inhibitors in the adjuvant setting include choosing a comparator arm, due to the standard of care being unclear, patient selection, unexpected toxicity, and deciding how long to treat the patient. Another challenge is presented by the selection of a meaningful primary endpoint, whether that be overall survival (OS) or recurrence-free survival (RFS). “OS was the gold standard until 2010 but now is increasingly difficult to show with the advent of potent new salvage therapies,” said Lorigan. Disease-free survival is another goal of adjuvant therapy as patients value their time without disease and also consider it a ‘bridge’ to better treatments in the future, he added.

Based on aggregated data, Lorigan said “for CTLA-4 inhibitors it is likely RFS predicts for OS. If you go for a leap of faith you might say that for immunotherapy treatment with checkpoint inhibitors there is a signal. But that remains to be seen of course.”

To potentially provide the answers to these questions, Lorigan highlighted 4 pivotal, phase III trials evaluating PD-1 inhibitors in the adjuvant setting:

SWOG S1404 is comparing pembrolizumab at 200 mg every 3 weeks for 1 year with physician’s choice, which could consist of ipilimumab at 10 mg/kg or high-dose interferon alfa-2b, for patients with high-risk resected melanoma that is stage IIIa (N2a), IIIb/c, or IV with no evidence of disease (NED) following surgery. The coprimary endpoints are OS and RFS in the overall population and in a PD-L1&shy;—positive subgroup (NCT02506153).

CheckMate 238 is comparing nivolumab with ipilimumab in patients with resected stage IIIb/c melanoma or stage IV with NED who are at high risk of recurrence. The primary endpoint is RFS (NCT02388906).

KEYNOTE-054 aims to address the question of whether adjuvant pembrolizumab is more effective than pembrolizumab in the metastatic setting in patients with resected stage III a/b/c melanoma. Co-primary endpoints are RFS in the overall study population and in patients with PD-L1—positive tumors (NCT02362594).

CheckMate-915 is exploring nivolumab plus ipilimumab versus ipilimumab alone or nivolumab alone for patients with completely resected stage IIIb/c/d or stage IV melanoma (NCT03068455).

PD-L1 testing has been incorporated into all current studies, suggesting there should be a substantial accumulation of data over the next few years on the effectiveness of this marker, Lorigan noted. Additionally, he added, molecular profiling has potential to provide a further level of discrimination. The most mature data for molecular testing in the adjuvant space come from the DecisionDX gene expression profile test, which is based on a panel of 31 genes; however, at this time, “there is no evidence yet that molecular profiling is predictive,” Lorigan noted. “Unlike the Oncotype DX test in breast cancer, molecular profiling in melanoma so far is purely prognostic.”

There have been signs that mutations play a role in outcomes. The adjuvant phase III AVAST-M study showed intriguing prognostic differences in outcomes for patients with various mutations. In this phase III trial, the VEGF inhibitor bevacizumab (Avastin) was compared with observation for patients with melanoma at high risk of recurrence. Patients received bevacizumab at a dose of 7.5 mg/kg every 3 weeks for 1 year.

 status was evaluated for those in the bevacizumab arm. Patients with 

-mutant melanoma tended to have a longer disease-free interval (DFI) and OS compared with wild-type individuals (DFI hazard ratio [HR], 0.79; 95% CI, 0.58-1.08; 

-mutant melanoma tended to have a shorter DFI (HR, 1.39; 95% CI, 1.03-1.88; 

 = .03) and OS (HR, 1.18; 95% CI, 0.88-1.62; 

In the future, Lorigan anticipates greater usage of circulating tumor DNA for molecular testing, with a focus on patient selection.

Another challenge is being able to determine whether or not it is better to treat the patient in the adjuvant setting or to wait and administer the treatment as salvage therapy. “There’s a suggestion that due to the primed immune system you get more toxicity in the adjuvant setting than in the advanced disease setting,” said Lorigan.

Several clinical trials are examining the use of adjuvant PD-1 inhibition for patients with melanoma, with a potential new standard of care on the horizon for those at high risk of recurrence following resection.

Melody Watson