Make it a Double: Immunotherapy Combinations for Advanced Melanoma


Increasingly, immunotherapy drugs for advanced melanoma are being studied in combination.

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. Gangadhar, M.D. She said she expects an increased focus on novel combinations and genetic biomarkers that will help predict who will benefit from the regimens.

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

Checkpoint inhibitors, or blockades, are immunotherapies that block the activity of the proteins PD-1 (programmed cell death 1), PD-L1 or CTLA-4. These proteins normally keep the immune system in check, preventing it from going into tissuedamaging overdrive; blocking their activity does the opposite, freeing up the immune system’s T cells to better recognize and attack cancer. The PD-1 inhibitors Opdivo (nivolumab) and Keytruda (pembrolizumab), used as single agents, have become a standard-of-care, firstline option for patients with metastatic or unresectable melanoma under the National Comprehensive Cancer Network clinical treatment guidelines, noted Gangadhar, an assistant professor of medicine at Abramson Cancer Center at the University of Pennsylvania.

Reflecting on 2016 clinical findings and Food and Drug Administration (FDA) approvals of immunotherapies, Gangadhar said that Keytruda; Opdivo; the PD-L1 inhibitor Tecentriq (atezolizumab); Imlygic (also known as T-VEC or talimogene laherparepvec), a vaccine made from an oncolytic virus, which specifically infects and kills cancer cells; and the CTLA-4 inhibitor Yervoy (ipilimumab) have all demonstrated encouraging and durable responses, which have been confirmed with longer follow-up. The question is where the field will go next.

Ongoing clinical trials will likely lead to combination regimens with improved toxicity profiles. Most importantly, individualizing combination therapy remains a challenge and an area of active research,” Gangadhar said.

Data Accruing on Single-Agent Efficacy

Long-term follow-up from the phase 1 KEYNOTE-001 trial, in which patients with advanced melanoma were randomly assigned to receive Keytruda or Yervoy, demonstrated that those who received Keytruda had an improvement in survival compared with those treated with the CTLA-4 inhibitor.

“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,” Gangadhar said. “Going back to the phase 1 study of Keytruda that accrued 655 patients (regardless of their histories of prior therapy), we saw in 2016 that the two-year survival was 50 percent and the three-year survival was 40 percent. In the subset of 152 patients who were treatment-naïve, there was a two-year overall survival (OS) rate of 61 percent and a three-year OS rate of 45 percent,” she added. “The big question in our clinical practice is: (Once a patient has had a good response,) can we stop therapy?” This is an important question, given the short- and long-term side effects that can come with immunotherapy.

Gangadhar noted that 48 of the 581 patients with measurable disease at baseline in that initial Keytruda trial, as assessed by an independent review team, achieved a complete response (CR), with the majority responding at the nine- or 12-week mark that coincided with their first imaging assessment.

“In all of those patients except for two, the response was ongoing after stopping Keytruda,” said Gangadhar. “We now know we can stop PD-1 blockade after a confirmed CR. Among these cases, 97 percent of patients will have an ongoing CR that is durable after stopping therapy.”

Mixing and Matching Immunotherapies

As did KEYNOTE-001, an investigation of multiple checkpoint inhibitors found that an inhibitor of PD-1, either alone or combined with a CTLA-4 inhibitor, is more effective than a CTLA-4 inhibitor on its own.

Combinations for patients with advanced melanoma were investigated as frontline treatments in the phase 3 CheckMate-067 trial. Here, Opdivo and Yervoy were explored as monotherapies and in combination in a total of 945 patients. The patients were divided into equally sized groups and treated with Opdivo alone, Opdivo plus Yervoy followed by Opdivo alone, or Yervoy alone. Researchers evaluated how the regimens affected progression-free survival (PFS) and OS.

Initial promising data from the trial formed the basis of the FDA’s January 2016 approval of the Opdivo/Yervoy combination and Opdivo monotherapy for the firstline treatment of patients with advanced melanoma harboring BRAF V600 gene mutations. Prior to that, the agency had approved the combination and single-agent Opdivo for patients with advanced melanoma that does not express BRAF V600 mutations.

Eighteen-month follow-up results from the CheckMate-067 study were presented during the 2016 Annual Meeting of the American Society of Clinical Oncology, held June 3-7, 2016, in Chicago. Investigators reported that the combination regimen had sparked a 58 percent reduction in the risk of disease progression compared with Yervoy by itself in advanced melanoma. Additionally, single-agent Opdivo lowered the risk of progression by 45 percent compared with Yervoy alone.

Moreover, the 18-month PFS rates were 46 percent for the combination arm, 39 percent for the Opdivo-alone arm and 14 percent for the Yervoy-alone arm. The overall response rates (ORR), meaning the rates of patients having any level of positive response to the treatments, were 58 percent and 44 percent, respectively, with the combination and Opdivo alone, versus 19 percent with Yervoy monotherapy. The CR rates were 12 percent, 10 percent and 2 percent, respectively. The partial response (PR) rates, meaning that tumors shrank but didn’t disappear, were 46 percent, 34 percent and 17 percent, respectively.

While the combination is approved for these patients, its effectiveness is comparable to that of some single-agent therapies, Gangadhar cautioned. She said that more evidence is needed to support the use of the pairing.

Safety Concerns

Although dual-checkpoint blockade treatment has demonstrated long-term potential, several concerns remain in light of the significant increase in serious or severe (grades 3 and 4) side effects associated with these combinations compared with single-agent PD-1 therapy, Gangadhar said.

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

The most frequently reported all-grade side effects with Opdivo/Yervoy versus Yervoy alone included increased ALT levels in the blood, an indication of potential liver damage (17.9 percent vs. 3.9 percent); increased AST levels, also a potential indicator of liver damage (15.7 percent vs. 3.9 percent); diarrhea (45.4 percent vs. 33.8 percent); colitis, an inflammation of the colon’s lining (11.5 percent vs 11.3 percent); rash (28.4 percent vs. 21.2 percent); hypothyroidism (16 vs. 4.5 percent); hyperthyroidism (10.2 vs. 1 percent); elevated creatinine, signaling potential kidney malfunction (4.2 percent vs. 1.6 percent); and pneumonitis, a lung inflammation (6.7 vs. 1.6 percent). Itchiness occurred with similar frequency on the combination versus the single-agent regimen, at 35.1 percent vs. 36.3 percent.

“The toxicity is manageable and reversible in most cases,” noted Gangadhar. “The emphasis should really be on patient communication, patient access to the physician at all times to report new symptoms, and early intervention. Many patients did have to discontinue treatment due to (side effects).”

However, whether patients stopped treatment because they achieved a complete response or due to an intolerable side effects, responses remained ongoing even after discontinuation. Before deciding to discontinue therapy, Gangadhar emphasized that a biopsy should be done to assess for pathological complete response in patients with indeterminate residual lesions.

“You should consider stopping therapy for severe (side effects), 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.

Novel Combinations: Who Will They Help?

A major question the melanoma community is facing in 2017, Gangadhar said, is how to determine which patients are likely to respond to combination immunotherapy, compared with a single-agent PD-1 inhibitor, as a firstline treatment.

“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 up front.”

In addition, she said, “We need to better define the efficacy of secondline Yervoy in patients not responding to PD-1 blockade versus up-front dual checkpoint blockade. We see patients who are not responding to PD-1, we move them to Yervoy, and they have an immediate and dramatic response. Clearly, there is some overlap synergy.

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