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Pembrolizumab demonstrates efficacy in advanced head and neck cancers
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CHICAGO — The anti–PD-1 antibody pembrolizumab demonstrated strong activity in patients with recurrent or metastatic head and neck squamous cell carcinoma, according to study results presented at the ASCO Annual Meeting.
The findings suggest immune checkpoint blockade could be a viable treatment option for patients with previously treated advanced disease, who typically only survive for about 6 months.
“This is by far the largest experience with immunotherapy in head and neck cancer,” Tanguy Seiwert, MD, assistant professor of medicine and associate head and neck cancer program leader at University of Chicago, said during a press conference. “The efficacy we saw really is remarkable for this disease, especially considering this is a heavily pretreated population.”
Tanguy Seiwert
Standard first-line therapy for recurrent or metastatic head and neck squamous cell carcinoma (HNSCC) consists of platinum-based doublet chemotherapy with or without the EGFR inhibitor cetuximab (Erbitux; Bristol-Myers Squibb, Lilly). Second-line therapies include cetuximab, docetaxel and methotrexate.
Fewer than 15% of patients respond to single-agent cetuximab, and HPV status appears to influence outcomes, according to study background. Chemotherapy — although effective — is associated with considerable adverse effects.
Previously released results of the KEYNOTE 012 trial showed pembrolizumab (Keytruda, Merck) — administered in 10-mg/kg doses every 2 weeks — induced response in 20% of patients with PD-L1–positive recurrent or metastatic HNSCC.
In the current study, Seiwert and colleagues assessed outcomes of a KEYNOTE 102 expansion cohort that included 132 patients (mean age, 58.9 years; 83% male) with advanced HNSCC. Researchers enrolled participants regardless of PD-L1 expression or HPV status. More than half (59%) of patients had undergone at least two lines of prior therapy for recurrent disease.
All patients received pembrolizumab 200 mg via IV every 3 weeks. Treatment continued until disease progression.
Seiwert reported results for 117 patients (HPV-positive, n = 34; HPV-negative, n = 81). Median follow-up was 5.7 months (range, 0.2-8.7).
Results showed 56% of patients experienced some decrease in tumor size. Overall, 29 patients (24.8%) demonstrated objective response and 29 (24.8%) demonstrated stable disease, equating to a disease control rate of about 50%. Median time to response was 9 weeks (range, 7.6-18).
Researchers reported comparable response rates among patients with HPV-negative tumors (27.2%) and HPV-positive tumors (20.6%).
At the time of analysis, 40 patients remained on therapy, and 25 of the 29 (86%) of responders remained in response.
The response rate — about twice as high as previously reported with cetuximab — may underestimate pembrolizumab’s activity in these patients, and survival assessments are needed to better understand the overall benefit, Seiwert said.
“We know from other diseases, where the experience with immunotherapy is larger, that patients who have disease stabilization or even initially experience disease progression upon receiving immunotherapy ultimately may derive significant benefit that can translate into longer survival,” Seiwert said in a press release.
The regimen appeared well tolerated, Seiwert said.
Results showed 59.8% of patients experienced drug-related adverse events, the most common of which were fatigue (15.2%), hypothyroidism (9.1%), decreased appetite (7.6%), rash (7.6%), dry skin (6.8%) and pyrexia (6.8%).
Researchers determined 9.8% of patients experienced grade 3 to grade 5 drug-related adverse events. These included swelling face (1.5%) and pneumonitis (1.5%).
No treatment-related deaths occurred. Four patients discontinued treatment due to adverse events — two due to grade 3 pneumonitis, one due to grade 2 interstitial lung disease and one due to grade 3 colitis.
Evaluation of PD-L1 expression of the cohort is ongoing. The optimal cutoff for PD-L1 expression — as well as the clinical utility of PD-L1 as a diagnostic tool in patients with head and neck cancers — have not been established, Seiwert said.
Two phase 3 studies are underway to compare pembrolizumab with standard therapy in patients with recurrent or metastatic HNSCC.
Although the question of which patients are most likely to benefit from pembrolizumab remains unanswered, an interferon-gamma expression signature has demonstrated an 85% negative predictive value and a 40% positive predictive value.
“If validated, this gene signature and other novel biomarkers may help us predict more reliably when to use this treatment,” Seiwert said. “Another opportunity is in combination. If we can combine this with chemotherapy, or if we can do it in the adjuvant setting, this may be much more broadly applicable. I think these opportunities will arise very quickly in many cancer types, including head and neck cancers.” – by Mark Leiser
For more information:
Seiwert TY, et al. Abstract LBA6008. Presented at: ASCO Annual Meeting; May 29-June 2, 2015; Chicago.
Disclosure: The researchers report institutional research funding and honoraria from, consultant or advisory roles with, employment with, and stock ownership or other interests in Merck. See the study for a full list of all researchers’ relevant financial disclosures.
Perspective
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Jeffery Russell, MD, PhD
The KEYNOTE-012 head and neck squamous cell carcinoma expansion cohort results are impressive and very exciting for head and neck oncology patients. For many years we’ve used standard combinational chemotherapies with very modest response rates. When people progress past first line therapy, the overall response rates are quite poor. Head and neck cancers have definitely been lagging in the development of targeted therapy and lack isolated genetic events that we can target. The immunotherapies are potentially a huge boon for this disease, because there are just not that many other options.
The data presented are from the expansion cohort from the phase 1 study. While, the ultimate goal was safely and tolerability, researchers were able to monitor for responses in this phase 1b cohort. They clearly saw tumor shrinkage or stability in over 56% of cases, with a relatively modest number of either partial or complete responses, around 20% to 25%, which matched very closely to the original response rates from the phase 1 data. So now we have over 150 patients who have been treated with a PD-1 inhibitor and have shown some positive responses. It’s very exciting for those patients now who are in the trials in phase 2 and phase 3 as we may have a new tool in our arsenal to treat head and neck cancers.
Questions still linger regarding the biomarker of PDL-1 or PD-1 as patient selection criteria. Differences in assay quality and acceptable “cut-off” limits makes the interpretation of these data difficult. Other abstracts presented at ASCO proposed evaluation of interferon (IFN)-gamma signatures for patients who may respond better to immunotherapy agents. Additionally, the assessment of mutational burden or presence of neo-epitopes may also identify patient populations that may benefit from these therapies.
The other interesting data from this study relates to HPV status. As we know, head and neck cancers, especially of the oropharynx, are strongly associated with an HPV infection. There is a lot of consideration that the viral-associated tumors may actually have a better response. But again, independent of HPV status, the PD-1 agents seems to work in both populations. Based on the numbers researchers quoted, the HPV-negative cohort actually had a marginally better response rate than the HPV-positive group but was not statistically significant. We look forward to the results of the ongoing studies.
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