Correspondence: Pier Francesco Ferrucci (Email address: pier.ferrucci@ieo.it)
Journal of Translational Medicine 2022; 20(1): 10.
Background: We investigated the role of neoadjuvant combination immunotherapy, followed by surgery and adjuvant immunotherapy for locally advanced or oligometastatic melanoma patients (pts), within an open label, single arm and two sites study (European Institute of Oncology in Milan and University of Turin).
Material and Methods: Treatment schedule consisted in four primary cycles of inverted dose Ipilimumab 1 mg/kg and Nivolumab 3 mg/kg every 3 weeks, followed by radical surgery and adjuvant Nivolumab 480 mg every 4 weeks for 6 cycles. Primary objective was pathological complete remission (pCR) rate, according to International Neoadjuvant Melanoma Consortium (INMC) criteria, while secondary objectives were: safety, feasibility and efficacy; QoL; identification of molecular and immunological biomarkers of response and resistance; degree of immune activation; evaluation of the gut microbioma.
From March 2019 to April 2021, 43 pts were enrolled in the trial and, with an intent to treat of 35 pts, 34 completed the primary phase, 31 surgery and 26 the adjuvant phase (plus 2 pts who are still on-treatment). Four pts were withdrawn during primary phase for progression (2), toxicity (1) and consent withdrawal (1).
Results: Of the 31 pts who underwent surgery, 20 reached a pCR/near pCR (65%), while a pathological partial remission (pPR) was obtained in 4 (13%) and pathological no response (pNR) in 7 (22%) pts.
With a median follow-up of 17 months, 33/35 pts are alive. Treatment failure occurred in 9 pts: 2 pts progressed during primary phase and did not undergo surgery; 7 pts progressed during adjuvant (3 pts) or follow-up phase (4 pts). Six out of these 7 pts were classified as pNR at surgery, while the other, classified as pCR, did not receive adjuvant therapy. Both pts in stage IV relapsed, while 2 died as consequence of melanoma progression, and one for ischemic stroke after 5 months from adjuvant therapy while on CR.
Treatment related toxicities were mainly G1-2 and only 6 pts (17%) developed G3-4 adverse events (AE): 3 transaminitis, 1 pneumonitis, 1 myocarditis, 1 CPK increase and 1 dermatomiositis; all of them but two underwent to surgery after toxicity resolution.
Translational studies are ongoing on samples collected before and during therapy: whole exome sequencing and gut microbiota dynamics on longitudinal samples appear to be intriguing, showing some relationships with responses.
Conclusions: In conclusion, primary immunotherapy with Ipilimumab/Nivolumab is a feasible therapeutic option, able to achieve a high pCR/near pCR rate in pts affected by locally advanced/oligometastatic melanoma (primary objective met). Toxicity was lower than previously reported. Translational data evaluated longitudinally on each patient will be available at the time of the meeting and presented.