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Pembrolizumab plus ipilimumab safe, effective for advanced melanoma
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CHICAGO — Combined treatment with pembrolizumab and ipilimumab demonstrated robust antitumor activity and acceptable toxicity in patients with advanced melanoma, according to data from the KEYNOTE-029 trial presented at the ASCO Annual Meeting.
The anti–PD-1 antibody pembrolizumab (Keytruda, Merck) is approved in the United States and internationally for the treatment of advanced melanoma. Data from the KEYNOTE-006 trial showed pembrolizumab conferred superior OS over ipilimumab (Yervoy, Bristol-Myers Squibb).
Georgina V. Long
A prior phase 3 trial demonstrated that pembrolizumab, in combination with ipilimumab or nivolumab (Opdivo, Bristol-Myers Squibb), extended PFS and produced a higher overall response rate than any checkpoint inhibitor alone, although toxicity also increased with the combinations.
Preliminary results from the phase 1 KEYNOTE-029 study suggested that standard-dose pembrolizumab and reduced-dose ipilimumab induced robust responses and appeared safe.
Georgina V. Long, BSc, PhD, MBBS, FRACP, chief of melanoma medical oncology and translational research at University of Sydney and clinical researcher at Melanoma Institute Australia, presented data from the expansion cohort of the study.
The expansion cohort included data from 153 patients (median age, 60 years; range, 22-82; 66% men) with advanced melanoma and no brain metastases. None of the patients received prior immunotherapy.
The researchers assigned patients to four doses of pembrolizumab (2 mg/kg) and ipilimumab (1 mg/kg) every 3 weeks, followed by pembrolizumab monotherapy every 3 weeks for up to 2 years, or until progression or intolerable toxicity.
Safety served as the primary endpoint. Secondary endpoints included ORR, OS, PFS and duration of response.
Median follow-up was 10 months (range, 0.8-14.1).
Seventy-two percent of patients (n = 110) received all four doses of ipilimumab, and 56% (n = 86) remained on pembrolizumab at the time of reporting. Forty-four percent of patients (n = 67) have discontinued all treatment.
Reasons for therapy cessation included adverse events (n = 31), disease progression (n = 29), complete response (n = 3), patient withdrawal (n = 2), death (n = 1) or change in therapy (n = 1).
Ninety-five percent (n = 145) of the cohort experienced an adverse event, with 58% (n = 89) experiencing an immune-mediated adverse event. The most common treatment-related adverse events included fatigue (any grade, 46%), pruritus (any grade, 39%), rash (any grade, 39%; grade 3-4, 3%) diarrhea (any grade, 24%; grade 3-4, < 1%), lipase increase (any grade, 18%; grade 3-4, 14%) and vitiligo (any grade, 18%).
Common immune-mediated adverse events included hypothyroidism, hyperthyroidism, hypophysitis, pneumonitis, hepatitis and colitis.
The cohort had an ORR of 57% (95% CI, 49-65) and a disease control rate of 78% (95% CI, 71-85). Fifteen patients (10%) achieved a complete response as best overall response, and 72 patients (47%) achieved a partial response. Thirty-three patients (22%) achieved stable disease and 30 patients (20%) experienced disease progression.
All but two of the 87 responding patients maintained their responses at the time of data cutoff, with response duration ranging from greater than 6 weeks to greater than 43 weeks.
Median PFS and OS have not been reached. Seventy percent of patients were progression free at 6 months, Long said. – by Cameron Kelsall
Reference:
Long GV, et al. Abstract 9506. Presented at: ASCO Annual Meeting; June 3-7, 2016; Chicago.
Disclosure: Merck funded this study. Long reports honoraria from and/or consultant roles with Amgen, Bristol-Myers Squibb, Merck, Novartis, Provectus and Roche. Please see the abstract for a list of all other researchers’ relevant financial disclosures.
Perspective
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Robert H.I. Andtbacka, MD, CM
The challenge with combination treatments for melanoma is that we have been seeing good responses with fairly high toxicities. In this study, Long and colleagues used the normal dose of pembrolizumab (Keytruda, Merck), but lowered the dose of ipilimumab (Yervoy, Bristol-Myers Squibb) from the standard dose of 3 mg/kg to 1 mg/kg because most of the toxicity comes from ipilimumab. Results showed the toxicity of the combination is still more than with pembrolizumab or ipilimumab alone at their standard doses, with a 42% rate of grade 3 or grade 4 adverse events.
We need to look at this in comparison with other combinations of immunotherapy. For instance, a study of ipilimumab with nivolumab (Opdivo, Bristol-Myers Squibb) on which Jedd Wolchok, MD, PhD, presented an update at the ASCO Annual Meeting had a grade 3 or higher adverse event rate greater than 55%. That study used both drugs at their standard doses. Lowering the ipilimumab dose seems to reduce the adverse events, but we have not compared the two combinations in a head-to-head manner. It goes to show that we need to think about lowering some of these doses.
The pembrolizumabipilimumab study had an ORR of 57%, which was similar to the response rate of the ipilimumabnivolumab study. This is encouraging because it suggests that we can achieve good responses while decreasing toxicity with lower doses.
Having said that, we still need to look at other modalities of combining these therapies to produce high response rates with truly minimal toxicities. One way to do that could be by combining oncolytic immunotherapies with checkpoint inhibitors like pembrolizumab or ipilimumab. Whether this is done with talimogene laherparepvec (Imlygic; BioVex/Amgen) or HF10 (Takara Bio), we have found that there is minimal added toxicity when these agents are combined with immunotherapy. Preliminary data have shown very good response rates with these combinations. As we move forward, it will be important to look at other modalities and therapies that go beyond ipilimumab and a PD-1 inhibitor.
It also is really important to consider the cost. As we add these agents together, the cost increases. The response is important, but how long patients stay on these therapies is important, as well.
In addition to the cost of the drugs, we must also consider the cost of managing the toxicities. That is rarely spoken of, but it is so important, especially if a patient is hospitalized.
Reference:
Wolchok J, et al. Abstract 9505. Presented at: ASCO Annual Meeting; June 3-7, 2016; Chicago.
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