We recently spoke with Luciano Rossetti from Merck about the JAVELIN Merkel 200 clinical development program that led to the approval of avelumab, the first immunotherapy treatment indicated in the EU and the first US FDA-approved systemic therapy for merkel cell carcinoma. Click here to find out more avelumab in this related research article from Future Oncology.
Could you give us a brief overview of the JAVELIN clinical development program?
The clinical development program for avelumab, known as JAVELIN, involves at least 30 clinical programs, including nine Phase III trials, and more than 6300 patients across more than 15 different tumor types. In addition to Merkel cell carcinoma (MCC), these cancers include non-small cell lung, breast, head and neck, Hodgkin’s lymphoma, melanoma, mesothelioma, gastric/gastro-esophageal, ovarian, renal cell carcinoma, urothelial carcinoma (UC), colorectal, adrenocortical and prostate.
Could you tell us about the JAVELIN Merkel 200 study?
JAVELIN Merkel 200 is an international, multi-center, single-arm, open-label Phase II study that was originally designed to assess the safety and efficacy of avelumab in patients with metastatic MCC (mMCC), as measured by objective response rate. The study consists of two parts: Part A includes 88 patients with mMCC whose disease had progressed after at least one chemotherapy treatment, and Part B which will ultimately include 112 patients with histologically confirmed mMCC who were treatment-naïve to systemic therapy in the metastatic setting.
What were the main results obtained from this study?
The results from JAVELIN Merkel 200 include:
Part A included 88 patients with mMCC whose disease had progressed after at least one chemotherapy treatment. The objective response rate was 33%, with 11% of patients experiencing a complete response (CR) and 22% of patients experiencing a partial response (PR). At the time of analysis, tumor responses were durable, with 93% of responses lasting at least 6 months (n=25) and 71% of responses lasting at least 12 months (n=13). Duration of response (DOR) ranged from 2.8 to more than 24.9 months.
Part B, at the time of the data cutoff, included 39 patients with histologically confirmed mMCC who were treatment-naïve to systemic therapy in the metastatic setting. The objective response rate was 62%, with 14% of patients experiencing a CR and 48% of patients experiencing a PR. 67% percent of patients were progression-free for 3 or more months.
The safety of avelumab has been evaluated in 1738 patients with solid tumors, including mMCC (N=88) receiving 10 mg/kg every 2 weeks of avelumab in clinical studies:
1,738 patients with solid tumors received 10 mg/kg every 2 weeks. In this patient population, the most common adverse reactions were fatigue (32.4%), nausea (25.1%), diarrhea (18.9%), decreased appetite (18.4%), constipation (18.4%), infusion-related reactions (17.1%), weight decreased (16.6%) and vomiting (16.2%). The most common Grade ≥ 3 adverse reactions were anemia (6.0%), dyspnea (3.9%) and abdominal pain (3.0%). Serious adverse reactions were immune related adverse reactions and infusion related reactions.
What is the potential clinical significance of these results?
Patients with mMCC face a very poor prognosis, with fewer than half of patients surviving more than 1 year and fewer than 20% surviving beyond 5 years. Although chemotherapy is considered a treatment option for mMCC, it has not been a standard of care. Guidelines have historically recommended that these patients participate in clinical trials.
The results from the JAVELIN Merkel 200 study represent a meaningful development for patients suffering from mMCC, who previously had limited treatment options.
What are the next steps for the clinical development of avelumab?
As a next step, we anticipate obtaining data from our pivotal Phase III studies in second-line treatment of non-small cell lung cancer (NSCLC patients who had disease progression on a platinum-based combination chemotherapy) and third-line gastric cancer (patients with advanced adenocarcinoma of the stomach or the gastroesophageal junction (GEJ) cancer whose disease had progressed after two prior chemotherapy regimens).
We are committed to exploring potential monotherapy indications and a diverse range of novel combinations with avelumab, including those that leverage the pipelines of Merck and Pfizer, as well as through strategic collaborations.
The European Commission recently approved avelumab as a monotherapy for the treatment of adult patients with metastatic Merkel cell carcinoma. Could you tell us about the significance of this approval?
Following two accelerated approvals of avelumab in the US, this European approval further demonstrates the continued momentum of the alliance and our commitment to meeting the needs of patients with hard-to-treat cancers.
Avelumab is the first immunotherapy treatment indicated for mMCC in the EU. In Europe, approximately 2,500 new cases of MCC are diagnosed each year. Approximately 5-12% of patients with MCC are initially diagnosed with metastatic disease. Many patients diagnosed with early stage tumors experience progression to metastatic disease. This approval is important for the alliance but, most importantly, it is significant for patients affected by this devastating disease.
Luciano Rossetti is Executive Vice President, Global Head of Research & Development and a member of the Healthcare Executive Committee for the biopharmaceutical business of Merck.
Before joining the biopharmaceutical business of Merck, Rossetti acted as Senior Vice President, Late Stage Development at Merck Sharp & Dohme, or MSD. In this position, he was responsible for the entire clinical development from Phase II to Phase V across all therapeutic areas. At MSD, he played a key role in shaping and implementing the development strategy of several potential breakthrough compounds such as anti PD-1. He also restructured the clinical genetics group to better leverage the collaboration between discovery and clinical development.
Prior to joining MSD in 2006, Luciano spent 18 years in academia during which he had considerable involvement with the pharmaceutical industry in both discovery and development. In his latest assignment, he was Professor of Medicine and led the Diabetes Research & Training Center at the Albert Einstein College of Medicine (NY, USA).
He is a Post-Doctoral Fellow of Rome University Medical School (Italy) and of Yale University Medical School (CT, USA). He holds a Doctorate in Medicine from the Trieste University Medical School, Italy.