Sunday, April 26, 2015

BRAFi better when combined with or after immunotherapy and surgery!!!

Response to BRAF inhibition in melanoma is enhanced when combined with immune checkpoint blockade.  Cooper, Juneja, Sage, et al.  Cancer Immunology Research.  April 2015.

"BRAF targeted therapy results in objective responses in the majority of patients, however responses are short lived (approx - 6 months).  In contrast, immunotherapy results in lower response rates, but responses tend to be more durable. BRAF inhibition results in a more favorable tumor microenvironment in patients, with an increase in CD8+ T cell infiltrates and a decrease in immunosuppressive cytokines.  However, there is also increased expression of the immunomodulatory molecule PD-L1, which may contribute to resistance."  So, with that info these peeps figured that BRAF therapy may play well with the PD-1 pathway to get rid of tumors.  They produced mice with BRAF positive melanoma and found that sure enough BRAF inhibition increased intratumoral CD8+ T cell density and cytokine production like it does in people.  When they gave the mice anti-PD1 or anti-PD-L1 WITH the BRAF inhibitors the got an "enhanced response, significantly prolonging survival and slowing tumor growth, as well as significantly increasing the number and activity of tumor infiltrating lymphocytes....demonstrating synergy between combined BRAF-targeted therapy and immune checkpoint blockade."

Durable complete responses off all treatment in patients with metastatic malignant melanoma after sequential immunotherapy followed by a finite course of BRAF inhibitor therapy.  Wyluda, Cheng, Schell, et al.  Cancer Biol Ther.  March 2015.

"We report 3 cases of complete response in patients with BRAF-mutated metastatic melanoma who were initially treated unsuccessfully with sequential immunotherapies (HD IL2 followed by ipi with or without concurrent radiation).  After progression during or post immunotherapy, these patients were given BRAFi and developed complete responses.  Based on the concomitant presence of autoimmune manifestations (vitiligo and hypophysitis), we postulated that there was a synergistic effect between the prior immune therapy and the BRAFi.  Accordingly, the inhibitors were gradually weaned off beginning at 3 months and were stopped completely at 9-12 months.  The 3 patients remain well and in CR off all therapy at up to 15 months with radiographic follow-up....with high levels of non-T-regulatory CD4 positive effector phenotype T cells, which persisted after completion of therapy."

Successful (neo)adjuvant BRAF-targeted theapy in patient with locally advanced BRAF V600E mutant melanoma.  Seremet, Suppa, Trepant, et al.  Melanoma Research. January 2015.

62 year old patient, dx'd with Stage IIIB melanoma with large, inoperable, primary lesion surrounded by ~25 secondary satellite and intransit lesions.  She started on 960 mg daily vemurafenib.  Stopped and resumed at 720 mg twice daily.  Was then placed on combined dabrafenib and trametinib to decrease side effects.  Successive exams showed gradual reduction in the thickness of the lesion.  After about 5 months of therapy, surgery was performed and the path analysis showed almost complete regression of tumor cells.  Dabrafenib/trametinib therapy was continued only 3 months after surgery and stopped at the patient's request.  She remains in complete remission 8 months after surgery.

My thoughts:
1.  Really heartening to hear that BRAF inhibitors can improve outcomes in these patients.
2.  Especially so, when these responses are already more durable than is typically seen when BRAF inhibitors are given alone AND responses have continued with patients OFF the meds!!!
3.  Combining BRAFi and immunotherapy can cause real problems with side effects.
4.  Like the rest of us, it remains to be seen how durable these "durable" responses will be.

Go, ratties!  GO! - c

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