Point/Counter

Is neoadjuvant immunotherapy the best treatment approach for regionally advanced Merkel cell carcinoma?

Click here to read the Cover Story, “Growing incidence of Merkel cell carcinoma draws researchers’ attention.”

POINT

Yes.

Checkpoint inhibitors — specifically avelumab and pembrolizumab — have revolutionized the management of unresectable metastatic Merkel cell carcinoma, but they have not been extensively evaluated in the adjuvant or neoadjuvant settings. Nevertheless, the ability of these agents to induce rapid shrinkage of bulky nodal metastases and other manifestations of regionally advanced Merkel cell carcinoma, combined with the potential to control occult systemic metastases, makes neoadjuvant immunotherapy an attractive approach that is starting to be implemented both in clinical trials and in off-protocol clinical use.

Vernon K. Sondak, MD
Vernon K. Sondak

Alternative approaches to regionally advanced Merkel cell carcinoma — such as chemoradiation — are more toxic, less effective and have never been formally evaluated in large prospective trials. Neoadjuvant therapy with single-agent nivolumab was evaluated in a clinical trial presented at ASCO Annual Meeting in 2018. Two doses of nivolumab administered to 29 patients approximately 4 weeks before surgery appeared safe. The regimen induced radiographic and major pathologic tumor responses among 40% of those with locally advanced Merkel cell carcinoma and 65% of those with regionally metastatic disease. Some patients avoided more extensive surgery.

In our clinical experience, neoadjuvant use of avelumab or anti-PD-1 agents has resulted in pathologic complete responses in bulky primary and nodal tumors, with imaging studies often underestimating the extent of the histologic response. In melanoma, patients with a pathologic complete response after neoadjuvant immunotherapy have excellent long-term outcomes, and there is reason to believe the same will hold true in Merkel cell carcinoma. Although we strongly encourage participation in prospective clinical trials, at this point we believe the available evidence supports the use of neoadjuvant immunotherapy for patients with advanced locally recurrent tumors, resectable in-transit metastases and clinically detectable nodal metastases at least 1.5 cm in diameter (the RECIST definition of ‘measurable’ nodal metastases).

As yet, no single standard neoadjuvant regimen has been defined, so our preferred approach is to administer therapy for 3 months to 6 months and operate after maximal response has been achieved. For patients with residual viable tumor at the primary site or in the nodal basin, postoperative radiation therapy generally is employed. Postoperatively, adjuvant use of the same agent often is employed to complete a year of therapy.

More investigation clearly is warranted to define optimal regimens for neoadjuvant therapy, and to determine when postoperative immunotherapy and radiation should be used after neoadjuvant therapy. For now, however, the benefits of neoadjuvant immunotherapy have been sufficiently demonstrated to support its use for appropriate patients receiving treatment in centers with experience in the medical and surgical management of Merkel cell carcinoma and the appropriate management of immune-related adverse events of therapy.

Reference:

Topalian SL, et al. Abstract 9505. Presented at: ASCO Annual Meeting; June 1-5, 2018; Chicago.

Vernon K. Sondak, MD, is Richard M. Schulze Family Foundation distinguished endowed chair in cutaneous oncology and chair of the department of cutaneous oncology at H. Lee Moffitt Cancer Center. He is also a HemOnc Today Editorial Board Member. He can be reached at vernon.sondak@moffitt.org. Disclosure: Sondak reports consultant roles with Array BioPharma, Bristol-Myers Squibb, Genentech/Roche, Merck, Novartis, Oncolys BioPharma, Pfizer, Polynoma, Regeneron and Replimune.

COUNTER

No.

Neoadjuvant immunotherapy may result in some challenges that may negatively affect patient outcomes.

Sunandana Chandra, MD, MS
Sunandana Chandra

Merkel cell carcinoma is a rare and aggressive cancer that traditionally has been associated with high rates of mortality when in the advanced stages. Immunotherapy has been proven to be efficacious with a tolerable safety profile in metastatic Merkel cell carcinoma. For the first time, we are seeing durable responses in this previously incurable cancer.

Adjuvant immunotherapy for patients who have resectable disease is being studied in two randomized clinical trials in the United States. However, in regionally advanced Merkel cell carcinoma, the question of whether neoadjuvant therapy is safe and efficacious remains unanswered. Factors that lead to a delay in initiation of neoadjuvant therapy — including multidisciplinary coordination between surgical oncology and medical oncology, and even radiation oncology, as well as insurance approvals — may impact timing of therapy. Moreover, response times may vary and the duration of neoadjuvant therapy is unknown. Additionally, the importance of attaining a complete pathologic response in Merkel cell carcinoma and the need for and duration of adjuvant therapy are unclear.

As has been well-documented, immunotherapy is not benign. The side effects from the drugs can be life-altering and even life-threatening. At the very least, management of the side effects may be prolonged and may impact the surgical window of complete resectability. These factors may negatively alter the resectability of the tumor, thereby removing a potentially curative modality for the patient.

Given the efficacy data seen with immunotherapy for patients with metastatic Merkel cell carcinoma, it is imperative that neoadjuvant immunotherapy be studied. However, neoadjuvant therapy as a safe and potentially efficacious means of management needs to be studied in rigorously controlled, well-designed clinical trials. At this time, it is not advisable to use neoadjuvant immunotherapy as a therapeutic approach outside of a clinical trial.

Sunandana Chandra, MD, MS, is assistant professor in the division of hematology and oncology at Northwestern University Feinberg School of Medicine. She can be reached at sunandana.chandra@northwestern.edu. Disclosure: Chandra reports advisory board roles with Bristol-Myers Squibb and EMD Serono, as well as a speakers bureau role with Bristol-Myers Squibb.

Click here to read the Cover Story, “Growing incidence of Merkel cell carcinoma draws researchers’ attention.”

POINT

Yes.

Checkpoint inhibitors — specifically avelumab and pembrolizumab — have revolutionized the management of unresectable metastatic Merkel cell carcinoma, but they have not been extensively evaluated in the adjuvant or neoadjuvant settings. Nevertheless, the ability of these agents to induce rapid shrinkage of bulky nodal metastases and other manifestations of regionally advanced Merkel cell carcinoma, combined with the potential to control occult systemic metastases, makes neoadjuvant immunotherapy an attractive approach that is starting to be implemented both in clinical trials and in off-protocol clinical use.

Vernon K. Sondak, MD
Vernon K. Sondak

Alternative approaches to regionally advanced Merkel cell carcinoma — such as chemoradiation — are more toxic, less effective and have never been formally evaluated in large prospective trials. Neoadjuvant therapy with single-agent nivolumab was evaluated in a clinical trial presented at ASCO Annual Meeting in 2018. Two doses of nivolumab administered to 29 patients approximately 4 weeks before surgery appeared safe. The regimen induced radiographic and major pathologic tumor responses among 40% of those with locally advanced Merkel cell carcinoma and 65% of those with regionally metastatic disease. Some patients avoided more extensive surgery.

In our clinical experience, neoadjuvant use of avelumab or anti-PD-1 agents has resulted in pathologic complete responses in bulky primary and nodal tumors, with imaging studies often underestimating the extent of the histologic response. In melanoma, patients with a pathologic complete response after neoadjuvant immunotherapy have excellent long-term outcomes, and there is reason to believe the same will hold true in Merkel cell carcinoma. Although we strongly encourage participation in prospective clinical trials, at this point we believe the available evidence supports the use of neoadjuvant immunotherapy for patients with advanced locally recurrent tumors, resectable in-transit metastases and clinically detectable nodal metastases at least 1.5 cm in diameter (the RECIST definition of ‘measurable’ nodal metastases).

As yet, no single standard neoadjuvant regimen has been defined, so our preferred approach is to administer therapy for 3 months to 6 months and operate after maximal response has been achieved. For patients with residual viable tumor at the primary site or in the nodal basin, postoperative radiation therapy generally is employed. Postoperatively, adjuvant use of the same agent often is employed to complete a year of therapy.

More investigation clearly is warranted to define optimal regimens for neoadjuvant therapy, and to determine when postoperative immunotherapy and radiation should be used after neoadjuvant therapy. For now, however, the benefits of neoadjuvant immunotherapy have been sufficiently demonstrated to support its use for appropriate patients receiving treatment in centers with experience in the medical and surgical management of Merkel cell carcinoma and the appropriate management of immune-related adverse events of therapy.

Reference:

Topalian SL, et al. Abstract 9505. Presented at: ASCO Annual Meeting; June 1-5, 2018; Chicago.

Vernon K. Sondak, MD, is Richard M. Schulze Family Foundation distinguished endowed chair in cutaneous oncology and chair of the department of cutaneous oncology at H. Lee Moffitt Cancer Center. He is also a HemOnc Today Editorial Board Member. He can be reached at vernon.sondak@moffitt.org. Disclosure: Sondak reports consultant roles with Array BioPharma, Bristol-Myers Squibb, Genentech/Roche, Merck, Novartis, Oncolys BioPharma, Pfizer, Polynoma, Regeneron and Replimune.

PAGE BREAK

COUNTER

No.

Neoadjuvant immunotherapy may result in some challenges that may negatively affect patient outcomes.

Sunandana Chandra, MD, MS
Sunandana Chandra

Merkel cell carcinoma is a rare and aggressive cancer that traditionally has been associated with high rates of mortality when in the advanced stages. Immunotherapy has been proven to be efficacious with a tolerable safety profile in metastatic Merkel cell carcinoma. For the first time, we are seeing durable responses in this previously incurable cancer.

Adjuvant immunotherapy for patients who have resectable disease is being studied in two randomized clinical trials in the United States. However, in regionally advanced Merkel cell carcinoma, the question of whether neoadjuvant therapy is safe and efficacious remains unanswered. Factors that lead to a delay in initiation of neoadjuvant therapy — including multidisciplinary coordination between surgical oncology and medical oncology, and even radiation oncology, as well as insurance approvals — may impact timing of therapy. Moreover, response times may vary and the duration of neoadjuvant therapy is unknown. Additionally, the importance of attaining a complete pathologic response in Merkel cell carcinoma and the need for and duration of adjuvant therapy are unclear.

As has been well-documented, immunotherapy is not benign. The side effects from the drugs can be life-altering and even life-threatening. At the very least, management of the side effects may be prolonged and may impact the surgical window of complete resectability. These factors may negatively alter the resectability of the tumor, thereby removing a potentially curative modality for the patient.

Given the efficacy data seen with immunotherapy for patients with metastatic Merkel cell carcinoma, it is imperative that neoadjuvant immunotherapy be studied. However, neoadjuvant therapy as a safe and potentially efficacious means of management needs to be studied in rigorously controlled, well-designed clinical trials. At this time, it is not advisable to use neoadjuvant immunotherapy as a therapeutic approach outside of a clinical trial.

Sunandana Chandra, MD, MS, is assistant professor in the division of hematology and oncology at Northwestern University Feinberg School of Medicine. She can be reached at sunandana.chandra@northwestern.edu. Disclosure: Chandra reports advisory board roles with Bristol-Myers Squibb and EMD Serono, as well as a speakers bureau role with Bristol-Myers Squibb.

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