Combos Mark Next Step in Melanoma Immunotherapy

Tara C. Mitchell, MD

Evidence continues to build for the long-term efficacy of PD-1—targeting immunotherapies in melanoma, including fresh data indicating when patients can stop taking the drugs and still maintain a response, according to Tara C. Mitchell, MD. The future will bring an increased focus on novel combinations and more informative biomarkers.

Those insights were among the observations that Mitchell made during a presentation at the 13th Annual International Symposium on Melanoma and Other Cutaneous Malignancies® that Physicians’ Education Resource^® (PER®) hosted in Sunny Isles Beach, Florida, on February 11.

Single-agent PD-1 blockade with nivolumab (Opdivo) or pembrolizumab (Keytruda) has become a standard- of-care first-line option for patients with metastatic or unresectable melanoma in the National Comprehensive Cancer Network guidelines, noted Mitchell.

“Ongoing clinical trials will likely lead to improved combination regimens with improved toxicity profiles and, most importantly, individualizing combination therapy remains a challenge and an area of active research,” said Mitchell, an assistant professor of medicine at Abramson Cancer Center at the University of Pennsylvania.

Single-Agent PD-1 Inhibitor Efficacy

Reflecting on 2016 clinical findings and FDA approvals, MItchell said that pembrolizumab, nivolumab, the PD-L1 inhibitor atezolizumab (Tecentriq), the oncolytic virus talimogene laherparepvec (T-VEC; Imlygic), and the CTLA-4 inhibitor ipilimumab (Yervoy), have all demonstrated encouraging and durable responses, which have been confirmed with longer follow-up. The question is where the field will go next.Long-term follow-up from the phase I KEYNOTE- 001 trial, in which patients were randomly assigned to receive pembrolizumab or ipilimumab, demonstrated that those who received pembrolizumab had an improvement in survival versus those who had treatment with the CTLA-4 inhibitor.¹

“We’ve had the opportunity to get longer survival data on these single agents since the first drugs entered clinical trials in 2010 and 2011,” Mitchell said. “Going back to the phase I study of pembrolizumab that accrued 655 patients, we saw in 2016 that the 2-year survival was 50% and the 3-year survival was 40%. These patients treated with pembrolizumab were patients either with or without prior therapy.”

“In the subset of 152 patients who were treatment- naïve, there was a 2-year overall survival [OS] rate of 61% and a 3-year OS rate of 45%,” she added. “The big question, in our clinical practice, is: can we stop therapy?”

Dual Checkpoint Therapy

Additionally, Mitchell noted that patients enrolled on the initial pembrolizumab trial achieved a complete response (CR), with the majority of patients responding at the 9- or 12-week mark of their first imaging assessment. “In all of the patients except for 2, the response was ongoing after stopping pembrolizumab,” said Mitchell. “We now know we can stop PD-1 blockade after a confirmed CR. In this case, 97% of patients will have an ongoing CR that is durable after stopping therapy.“Immunotherapy combination regimens for patients with melanoma were investigated as frontline treatment in the randomized, doubleblind, multicenter, phase III CheckMate-067 trial.² Here, nivolumab and ipilimumab were explored as monotherapy and in combination in a 1:1:1 ratio in a total 945 patients. They were treated with nivolumab alone (n = 316), nivolumab plus ipilimumab followed by nivolumab alone (n = 314), or ipilimumab alone (n = 315), with the co-primary endpoints being progression-free survival (PFS) and OS.

The initial data from the CheckMate-067 trial formed the basis of the FDA’s January 2016 approval of the nivolumab/ipilimumab combination and nivolumab monotherapy for the first-line treatment of patients with advanced melanoma harboring BRAF V600 mutations. Prior to that, the agency approved the combination and single-agent nivolumab for BRAF V600 wild-type patients with advanced melanoma.

Eighteen-month follow-up results of the CheckMate-067 study were presented during the 2016 ASCO Annual Meeting.³ Findings showed that the combination arm led to a 58% reduction in the risk of disease progression compared with ipilimumab monotherapy in advanced melanoma. Additionally, single-agent nivolumab lowered the risk of progression by 45% compared with ipilimumab alone.

Moreover, the 18-month PFS rates were 46% for the combination arm, 39% for the nivolumab-alone arm, and 14% for the ipilimumab-alone arm. The overall response rates (ORR) with the combination and nivolumab alone were 58% and 44%, respectively, versus 19% with ipilimumab monotherapy (P <.0001). The CR rates were 12% (n = 38), 10% (n = 31), and 2% (n = 7), respectively.

The partial response (PR) rates were 46% (n = 143), 34% (n = 107), and 17% (n = 53), respectively. “Ipilimumab and nivolumab is approved, with objective responses and durable responses similar to single-agent therapy,” Mitchell said in summarizing the CheckMate-067 findings. “It’s been shown in a randomized large phase III study to have significant improvement in PFS [over ipilimumab alone]. However, it has not been compared with single-agent PD-1 blockade in a randomized phase III trial, and we are awaiting longer follow-up from the combination, as well.”

The impressive findings showed a significant increase in PFS with nivolumab over ipilimumab, and with nivolumab/ipilimumab versus ipilimumab alone, Mitchell added.

Data also were reported last year from the phase II CheckMate-069 study, which randomized patients 2:1 to receive an intravenous (IV) infusion of nivolumab 1 mg/kg plus ipilimumab 3 mg/kg or ipilimumab 3 mg/kg plus placebo every 3 weeks for 4 doses.^4,5 Patients who were treated with the combination received nivolumab 3 mg/kg every 2 weeks until disease progression or unacceptable toxicity, while patients on the ipilimumab-alone arm were given placebo biweekly.

Safety Concerns

At a median 24.5-month follow-up of BRAF wild-type patients, “we can see that the ipilimumab and nivolumab arm had a 1-year survival rate of 73% and a 2-year survival rate of 64%,” she concluded.Although dual-checkpoint blockade treatment has demonstrated long-term potential, several concerns remain in light of the significant increase in grade 3/4 adverse events (AEs) compared with single-agent PD-1 therapy, Mitchell said.

In the long-term reports from CheckMate-067, the rate of grade 3/4 AEs was higher with the combination (56.5%) versus single-agent nivolumab (19.8%) and ipilimumab alone (27%). The rates of discontinuation due to treatment-related AEs were 38.7%, 10.5%, and 15.4%, respectively.

The most frequently reported all-grade AEs with nivolumab/ipilimumab versus ipilimumab alone included increased ALT levels (17.9% vs 3.9%), increased AST levels (15.7% vs 3.9%), diarrhea (45.4 % vs 33.8%), colitis (11.5% vs 11.3%), rash (28.4% vs 21.2%), pruritus (35.1% vs 36.3%), hypothyroidism (16% vs 4.5%), hyperthyroidism (10.2% vs 1%), elevated creatinine (4.2% vs 1.6%), and pneumonitis (6.7% vs 1.6%).³

“The toxicity is manageable and reversible in most cases,” noted Mitchell. “The emphasis should really be on patient communication reporting and patient access to the physician at all times to report new symptoms and early intervention. Many patients did have to discontinue treatment due to AEs.” However, whether patients stopped treatment because they achieved a CR or due to an intolerable AE, responses were still ongoing even after discontinuation. Before deciding to discontinue therapy, Mitchell emphasized that a biopsy should be done to assess for pathological complete response in patients with indeterminate residual lesions.

Novel Combinations for 2017 Biomarker Research

“You should consider stopping therapy for severe AEs, especially in those who already have a response,” she said, adding that researchers must work on improving the toxicity profiles with combination immunotherapy while maintaining an increase in efficacy.A major question the melanoma community is facing in 2017, Mitchell said, is how to determine which patients are likely to respond to combination immunotherapy upfront versus single-agent PD-1.

“As of now, we don’t have a very good biomarker for that, but that is a huge area of research,” she said. “We need to verify which patients will benefit from this upfront. We need to better define the efficacy of second-line ipilimumab in patients not responding to PD-1 blockade versus upfront dual checkpoint blockade. We see patients who are not responding to PD-1, we move them to ipilimumab, and they have an immediate and dramatic response. Clearly, there is some overlap synergy.”

PD-1 Plus IDO

Investigational combination therapies are on the horizon, she said. She honed in on 3 novel combinations during her presentation.IDO1, a tryptophan-catabolizing enzyme, is overexpressed in several tumor types and induces immune tolerance by suppressing T-cell responses, Mitchell said. IDO1 expression is also associated with more rapid tumor progression and poor survival.

Additionally, targeting IDO1 has proved to be synergistic with PD-1 antibodies. In phase I results of the ECHO-202/KEYNOTE-037 trial,⁶ which were presented at the 2016 ESMO Congress, 22 patients with melanoma and select solid tumors were randomized to receive 2 mg/kg IV pembrolizumab plus the IDO1 inhibitor epacadostat at 25, 50, or 100 mg every 3 weeks or epacadostat at 300 mg twice a day plus pembrolizumab at 200 mg IV every 3 weeks. There was also a dose-expansion phase of epacadostat at 50, 100, or 300 mg twice a day plus pembrolizumab at 200 mg IV every 3 weeks.

Table. Response Rates in Combination Trial ECHO-202/KEYNOTE-037

In the small study MItchell, who is the lead author, said that results showed objective and durable responses in 58% of patients (Table).

Regarding safety, there were no increased toxicities compared with pembrolizumab alone. The median PFS had not been reached, and the 100 mg twice daily epacadostat was selected as the recommended phase II dose.

PD-1 Plus T-VEC

A phase III portion of this study for treatment- naïve patients with melanoma is ongoing (NCT02752074).The October 2015 approval of T-VEC for the local treatment of unresectable cutaneous, subcutaneous, and nodal lesions in patients with melanoma recurrent after initial surgery was an important advance in the treatment landscape.

Now, Mitchell said, the question is whether investigators can capitalize upon the efficacy associated the first-in-class oncolytic immunotherapy through synergy with PD-1 blockade.

Findings of the small phase I MASTERKEY-265 (NCT02263508) trial explored this strategy with T-VEC plus pembrolizumab; preliminary findings in 21 patients showed a confirmed ORR of 57.1%, with 23.8% confirmed CR.⁷ The unconfirmed ORR was 66.7%, and the unconfirmed CR rate was 28.8%. The disease control rate (including stable disease, PR, and CR) was 71.4%. The median PFS was not reached.

PD-L1 Plus MEK/BRAF

"There was no increased toxicity that we saw,” said Mitchell, a finding that was similar to ECHO-202/KEYNOTE-037. “Therefore, this study is also up for a randomized phase III study.”Additional pivotal research being conducted in 2017 is the combination of the PD-L1 inhibitor atezolizumab along with cobimetinib (Cotellic) and vemurafenib (Zelboraf) in patients with unresectable BRAF-mutant melanoma.⁸

Early phase Ib results demonstrated that the ORR with the triplet was 83%, which included 3 CRs (10%) and 21 PRs (72%). Overall, 28 of 29 patients were evaluable for response; 1 patient experienced primary progressive disease. At the time of the analysis, median duration of response and PFS were not yet reached. Safety data also showed no increase in toxicity versus either drug alone.

A phase III study is being conducted to explore atezolizumab with and without the cobimetinib plus vemurafenib combination in patients with BRAF mutation-positive unresectable locally advanced or metastatic melanoma (NCT02908672).

References

1. Robert C, Ribas A, Hamid O, et al. Three-year overall survival for patients with advanced melanoma treated with pembrolizumab in KEYNOTE-001. J Clin Oncol. 2016;34(suppl; abstr 9503). meetinglibrary.asco.org/content/167363-176.
2. Larkin J, Chiarion-Sileni V, Gonzalez R, et al. Combined nivolumab and ipilimumab or monotherapy in untreated melanoma. N Engl J Med. 2015;373(1):23-34. doi: 10.1056/NEJMoa1504030.
3. Wolchok JD, Chiarion-Sileni V, Gonzalez R, et al. Updated results from a phase III trial of nivolumab (NIVO) combined with ipilimumab (IPI) in treatment-naïve patients (pts) with advanced melanoma (MEL) (CheckMate 067). J Clin Oncol. 2016;34(suppl; abstr 9505). meetinglibrary.asco.org/content/165588-176.
4. Hodi FS, Chesney J, Pavlick AC, et al. Combined nivolumab and ipilimumab versus ipilimumab alone in patients with advanced melanoma: 2-year overall survival outcomes in a multicentre, randomised, controlled, phase 2 trial. Lancet Oncol. 2016;17(11):1558-1568. doi: 10.1016/S1470-2045(16)30366-7.
5. Postow M, Chesney J, Pavlick AC, et al. Initial report of overall survival rates from a randomized phase II trial evaluating the combination of nivolumab (NIVO) and ipilimumab (IPI) in patients with advanced melanoma (MEL). In: Proceedings from the AACR 107th Annual Meeting, April 16-20, 2016, New Orleans, LA. Abstract CT002. doi: 10.1158/1538-7445.AM2016-CT002.
6. Gangadhar TC, Hamid O, Smith DC, et al. Epacadostat plus pembrolizumab in patients with advanced melanoma and select solid tumors: Updated phase 1 results from ECHO-202/KEYNOTE-037. Ann Oncol. 2016;27(6):379-400. doi: 10.1093/annonc/mdw379.
7. Long GV, Dummer R, Ribase A, et al. Efficacy analysis of MASTERKEY-265 phase 1b study of talimogene laherparepvec (T-VEC) and pembrolizumab (pembro) for unresectable stage IIIB-IV melanoma. J Clin Oncol 2016;34(suppl; abstr 9568). meetinglibrary.asco.org/content/166223-176.
8. Sullivan RJ, Hamid O, Gonzalez R, et al. Safety and clinical activity of atezolizumab + cobimetinib + vemurafenib in BRAFV600-mutant metastatic melanoma. In: Proceedings from the 2016 Society for Melanoma Research Annual Meeting, November 6-9, 2016, Boston, MA.