With high rates of metastasis and progression, locally advanced/oligometastatic melanoma is a challenging disease to treat. According to results of a trial recently presented at the European Medical Society for Oncology (ESMO) Virtual Congress, neoadjuvant ipilimumab/nivolumab is a safe and effective treatment for patients with this disease. In this interview with i3 Health, lead study author Emilia Cocorocchio, MD, discusses the benefits of neoadjuvant ipilimumab/nivolumab and shares advice for members of the cancer care team treating patients with locally advanced/oligometastatic melanoma.
Can you comment on the significance of your findings regarding neoadjuvant ipilimumab/nivolumab for patients with locally advanced/oligometastatic melanoma?
Emilia Cocorocchio, MD: The most surprising result of our study was the pathological response rate achieved by ipilimumab/nivolumab. The rates of pathological complete remission and pathological overall response were 58% and 79%, respectively, in patients who underwent surgery for locally advanced/oligometastatic melanoma. The follow-up is still short, but we hope to confirm the observation that pathological complete response rate should be considered a surrogate marker of long-term response and survival, as also seen in the OPacin trial.
The major concern of using combination immunotherapy as a neoadjuvant approach was the incidence of severe adverse events. However, we found that ipilimumab/nivolumab schedule modification is the key to reducing toxicity, making this schedule feasible in the majority of patients. An ongoing aim of the trial is to investigate the tumor cells, tumor microenvironment, and host immune system interactions before, during, and after treatment, in order to individualize prognostic and predictive characteristics of response and survival. This will allow us to further calibrate the entire treatment program.
How do you see the treatment of locally advanced/oligometastatic melanoma evolving in the coming years?
Dr. Cocorocchio: Recent trials have shown the efficacy of ipilimumab/nivolumab in patients with locally advanced/oligometastatic melanoma. CheckMate 067 demonstrated 5-year progression free survival and overall survival rates of 36% and 60%, respectively, a benefit which was evident in both BRAF-mutated and BRAF wild-type patients. Moreover, the plateau of the survival curves makes these results particularly intriguing, justifying subsequent trials in the adjuvant and neoadjuvant settings. Anti-programmed death ligand 1 (anti–PD-L1) antibodies such as nivolumab and pembrolizumab are already the standard of care as adjuvant treatment in stage III and IV melanoma, and dabrafenib/trametinib is the standard of care for stage III BRAF-mutated patients.
Targeted therapy is under evaluation in the neoadjuvant setting, with very promising results. In the results of the REDUCTOR trial, which were presented at ESMO, neoadjuvant dabrafenib/trametinib allowed R0 resection (resection with tumor-free margins) in more than 90% of surgically treated patients, with pathological complete and near pathological complete response rates of almost 50%. Considering the conservative standard in managing newly diagnosed melanoma—avoiding up-front lymphadenectomy in clinically occult sentinel lymph node metastasis—I think that neoadjuvant treatment will probably be crucial for locoregional relapse. This will allow us to tailor treatment in patients who obtain pathological complete response after therapy. Many additional combinations of immunotherapy and targeted therapy are currently under investigation.
Do you have any words of advice for community oncologists and other members of the cancer care team treating patients with locally advanced/oligometastatic melanoma?
Dr. Cocorocchio: In the last 20 years, the best therapeutic options for melanoma patients have come from clinical trials evaluating targeted therapies, immunotherapies, and conservative surgical approaches, all of which have dramatically improved quality of life and survival. Neoadjuvant therapy provides an important opportunity in locally advanced/oligometastatic melanoma, allowing us to study the unique interaction between tumor and host and to better understand which patients will achieve the most benefit. I surely recommend all of my colleagues to invite their patients to participate in active neoadjuvant trials so that we may fully contribute to improving patient health and knowledge.
About Dr. Cocorocchio
Emilia Cocorocchio, MD, is a medical oncologist in the Melanoma, Sarcoma, and Rare Tumors Division at the Istituto Europeo di Oncologia in Milan, Italy. She has authored and coauthored numerous peer-reviewed publications focused on developing new treatments and improving outcomes for patients with cancer.
For More Information
Cocorocchio E, Pala L, Nezi L, et al (2020). Primary ipilimumab/nivolumab immunotherapy followed by adjuvant nivolumab in locally advanced or oligometastatic melanoma: primary results. Ann Oncol (ESMO Virtual Congress Abstracts), 31(suppl_4):S672-S710. Abstract 1147P. DOI:10.1016/annonc/annonc280
Rozeman EA, Menzies AM, van Akkooi ACJ, et al (2019). Identification of the optimal combination dosing schedule of neoadjuvant ipilimumab plus nivolumab in macroscopic stage III melanoma (OpACIN-neo): a multicentre, phase 2, randomised, controlled trial. Lancet Oncol, 20(7):948-960. DOI:10.1016/S1470-2045(19)30151-2
Rohaan M, Blankenstein S, Klop M, et al (2020). Neoadjuvant cytoreductive treatment with BRAF/MEK inhibition of prior unresectable regionally advanced melanoma to allow complete surgical resection, REDUCTOR: A prospective single arm phase II trial. Ann Oncol (ESMO Virtual Congress Abstracts), 31(suppl_4). Abstract 1098P. DOI:10.1016/annonc/annonc280
Transcript edited for clarity. Any views expressed above are the speaker's own and do not necessarily reflect those of i3 Health.