First-Line Pembrolizumab Yields Robust Tumor Control, Favorable OS Over Chemo in Advanced MCC
In a recent interview with Oncology Learning Network, Adam Riker, MD, FACS, Professor and Chief of Surgical Oncology at Louisiana State University (LSU) Health New Orleans School of Medicine, discussed the findings and clinical significance of a recent study that he and his team of co-investigators, including Brian C. Boulmay, MD, Associate Professor of Clinical Medicine and HemOnc Fellowship Program Director at LSU Health New Orleans School of Medicine, conducted on the use of first-line pembrolizumab therapy in patients with advanced merkel cell carcinoma (MCC).
The study by Dr Riker and colleagues featured the longest clinical follow-up period for any anti–PD-1 drug administered as first-line treatment for advanced MCC and provides significant insight into the long-term effects of a primary treatment option for this rare malignancy (J Clin Oncol. 2019 Feb 6. Epub ahead of print).
What is the current standard of care for patients with MCC?
It is important to be clear about the initial stage of MCC and how the patient presents to the physician. For early stage MCC (stage I, II), the standard of care is the surgical resection of the primary MCC, with a concomitant examination of the draining lymph node basin with a sentinel lymph node mapping procedure. Upon successful surgical resection, many clinicians will recommend the addition of locoregional radiation therapy, to the primary site and possibly the nodal basin.
The standard of care for metastatic MCC (stage IV), as recently as 2016, listed only chemotherapy as the sole treatment by the National Comprehensive Cancer Network treatment guidelines. In 2017, pembrolizumab, the PD-1 pathway inhibitor, was recommended after chemotherapy.
At present, in 2019, the standard of care and first-line treatment for advanced MCC, is a PD-1 inhibitor, of which there are 3 PD-1 inhibitors that are now FDA-approved for first-line treatment. These PD-1 inhibitors are avelumab, nivolumab and pembrolizumab, with the latter (pembrolizumab) PD-1 inhibitor utilized in our study. For this clinical trial, advanced MCC is considered stage IIIB disease that is unresectable, and stage IV disease, which is metastatic.
What existing data led you and your co-investigators to assess durable tumor regression and overall survival (OS) in patients being treated with first-line pembrolizumab?
Previously, it was recognized that advanced MCC was a type of cancer that appeared responsive to the human immune system. This was based on several previous clinical trials demonstrating that a PD-1 inhibitor was superior to standard chemotherapy and effective in patients who had failed first-line chemotherapy.
The very first PD-1 inhibitor that was found to be effective as a first-line therapy for patients with metastatic MCC was the PD-1 inhibitor, avelumab, showing an 62% objective response rate. These responses appeared to be durable; however, the median follow-up period was quite short at 5.1 months.
Next, investigators examined a second PD-1 inhibitor, nivolumab, in patients with advanced MCC who were either treatment-naïve, or whom had failed standard chemotherapy. They found a similar objective response rate of 64%, with a much longer median follow up period of 1 year. The median progression-free survival (PFS) and OS for this trial were not reached during this observation period and are ongoing.
Lastly, many of the authors on this current manuscript also participated in a previous clinical trial examining the utility of pembrolizumab as a first-line therapy in 26 patients with advanced MCC. This clinical trial also showed markedly durable responses, with an objective response rate of 56% (N Engl J Med. 2016;374:2542-2552). Thus, the premise for this current clinical trial was to further explore the long-term outcomes in a larger group of treatment-naïve patients with advanced MCC treated with pembrolizumab as first-line therapy.
Please briefly describe your study and its findings. Were any of the outcomes particularly surprising?
For our clinical trial, a total of 50 treatment-naïve patients with advanced MCC were treated with pembrolizumab as first-line therapy. The breakdown of their disease stage was either stage IIIB (14% of the patients in this study) or stage IV (86%) MCC. Patients were treated every 3 weeks with pembrolizumab for up to 2 years.
The objective response rate to pembrolizumab was 56%, broken down further into those that developed a complete response to treatment (24%), and a partial response of 32% (a total of 56% for this trial).
The median follow-up time was 14.9 months, with a range of 0.4 to 36.4+ months. Importantly, among the 28 responders, the median duration of response was not yet reached. The 2-year PFS rate was 48.3%, with an OS of 68.7%, with the median OS time not yet reached.
There was significant grade 3, treatment-related adverse events and toxicities in 28% of the patients, leading to discontinuation of the therapy in 7 (14%) of 50 patients, including one treatment-related death.
This trial represents the longest clinical follow-up period for any of the other anti–PD-1 drugs administered as first-line treatment for advanced MCC.
What are the possible real-world applications of these findings in clinical practice?
MCC is a rare malignancy, with a previously uniformly poor prognosis and outcome. Recent advances in our understanding of the human immune system and how it has the capacity to fight off and destroy cancer within our own body has been nothing short of groundbreaking.
Due to the results of several clinical trials that have examined the utility and efficacy of a novel immunotherapy that targets the PD-1, these new anti–PD-1 antibodies have become the mainstay of first-line treatment for patients with advanced MCC.
Do you and your co-investigators intend to expand upon this research? If so, will you be incorporating any new therapies, end points, or patient populations?
Although this type of immunotherapy for patients with advanced MCC is quite effective, it should be noted that only 28% had a complete response to therapy, meaning the complete shrinkage and disappearance of all visible disease as identified by standard imaging. The other 32% of the responding patients had a partial resolution of their disease.
We need to better understand why certain patients respond extremely well to pembrolizumab, whereas others respond only partially or not at all to therapy.
Another question arises as to when the optimal time is to treat such patients with MCC with a PD-1 inhibitor. It may be even more effective in the adjuvant setting, once the patient has surgically been rendered to have no evidence of disease.
As we have seen in other types of cancer, such as melanoma, giving anti–PD-1 therapy to the surgically treated patient is beneficial in terms of longer PFS and OS rates. Thus, it remains an important question as to whether applying pembrolizumab to the patient with stage III, completely resected disease will yield similar results.