Advice on next steps after progression on Ipi/Nivo

Background: Age 74, previously healthy and active, diagnosed with localized prostate cancer (Gleason score 7) in 2018 & completed proton beam radiation treatment in January 2019. Possible history of ulcerative colitis (1 episode in 2016 – likely diagnosis, but never confirmed). Melanoma with unknown primary diagnosed as solitary lung met in January 2020. BRAF wild type (positive for mutations in ATRX, MYC, TP53, NF1 and GNAS). His melanoma oncologist is Dr. Lawrence at Mass General.

January 2020 – VAT surgery to remove 4.5 cm lung mass in lower left lobe (originally misdiagnosed as primary lung adenocarcinoma, but pathology after surgery came back as melanoma – big surprise, given no prior history of melanoma). The decision was to “watch and wait” and re-scan in 6 weeks, rather than immediately starting immunotherapy – this was based on the fact that it presented as one solitary met (as therefore could have perhaps been slow growing), and the potential history of ulcerative colitis.

March 2020 – Scans showed new lung nodules (up to 1.6 cm) and a new 1.5 cm lesion in the brain

April 2020 – Craniotomy to remove the brain lesion (tolerated and recovered well, other than developing a blood clot in one calf – currently on Xarelto). Started Pembrolizumab, and received 4 doses total. Well-tolerated, no side effects at all.

June 2020 – Scans showed progression – increase in the number and size of bilateral lung nodules (largest 2.4 cm), and suspicion of possible small mets in other areas (one nodule each in kidney, retroperitoneal space, S1, and T8). Brain scan clear. Decision made to switch to Ipi/Nivo combo (given that Pembro was well tolerated). Received 2 doses of the combo (on 6/24/20 & 7/14/20) – initially well tolerated.

August 3, 2020 – 3rd dose of combo held due to rising AST (51)/ALT (45). Plan was to re-check in 1 week.

August 9, 2020 – Onset of severe headaches and fevers – admitted to hospital for scans and workup. Brain MRI clear. CT showed increase in size of some lung nodules (up to 2.7 cm), but nothing new. LFTs peaked on 8/13/20 to 609 (AST) and 352 (ALT). 60 mg prednisone started, and liver biopsy indicated immune checkpoint induced hepatitis. Developed an additional blood clot in the same leg. Discharged on 8/15/20 feeling well, and remains active (walks 2 miles/day).

Current situation – He is on a prednisone taper (60 mg week 1, 50 mg week 2, 30 mg weeks 3 and 4) – current LFT is AST=46, ALT=71. Dr. Lawrence said that even though the radiologist read the most recent scan as overall progression, he saw a few areas on the lung that looked smaller. The current plan is to re-scan in a few weeks once he is down to a lower dose of prednisone. If there is any evidence of response, Dr. Lawrence will consider giving another dose of Ipi/Nivo (with close monitoring of liver function), given that there are limited other options. Our understanding is that his recent history of prostate cancer, and now the high-grade hepatitis, disqualify him from most clinical trials. There is a phase 1 trial he may be eligible for that involves adoptive cell therapy with a MAGE-A4 target T-cell (Surpass: ADP-A2M4CD8 in HLA-A2+ Subjects With MAGE-A4 Positive Tumors – NCT04044859) – but he would need to match on HLA type and have MAGE-A4 tumor expression (we don’t know yet if he qualifies). He also has a subcutaneous nodule on his scalp that could potentially be melanoma – so another option is to biopsy the nodule to see if it’s melanoma, and if so, consider TVEC.

Are there any other treatments that we should be considering, or other potential clinical trials that he may qualify for?

Thank you so much in advance for reading this long post, and for any input or advice.