Table 1.
Clinical trials investigating combination MAPK inhibition and immunotherapy
| Agents | Phase | Status/preliminary results |
|---|---|---|
| Targeted + checkpoint inhibition | ||
| D + T → I; D + T → I + N; D → I + N; T → I + N, I alone, I + N (NCT01940809) |
I | Recruiting patients |
| D ± T + I (NCT01767454) | I | D + I was tolerable with no dose limiting toxicities or grades 3/4 hepa- totoxicity.Triple combination led to 2/7 patients developing colon perforation [53]. |
| V + I (NCT01400451) | I | 7/12 patients had hepatic dose limiting toxicities [54••]. |
| V ± cobimetinib + MPDL3280A (NCT01656642) | Ib | Recruiting patients |
| T ± D (D added to BRAF mutant, omitted from BRAF wild type) + MEDI4736 (NCT02027961) |
I/II | Treatment was relatively well tolerated with no unexpected toxicities [55••]. Preliminary results showed response rates with triple therapy, doublet concurrent therapy, and doublet sequential therapy of 69, 21, and 13 %, respectively, and disease control rates of 100, 79, and 80, respectively. |
| D + T + MK-3475 (NCT02130466) | I/II | Recruiting patients |
| V → I → V retreatment if no unacceptable toxicity and no progression (NCT01673854) |
II | 27 patients received sequential vemurafenib followed by ipilimumab therapy [56]. Thirty-three percent had grade 3/4 skin AEs, 22 %grade 3/4 GI AEs, and 4.3 % grade 3/4 hepatobiliary events. Median PFS 4.4 months, and overall survival 20.3 months |
| LGX818/MEK162 until PD → I + N; I + N until PD → LGX818/ MEK162; LGX818/MEK162 → I + N → LGX818/MEK162 (NCT02631447) |
II | Not open for recruitment |
| D + T until PD → I + N; I + N until PD → D + T (NCT02224781) | III | Suspended recruitment due to drug supply issues |
| Targeted + cytokine | ||
| V+ high dose interferon alpha-2b (NCT01943422) | I/II | Recruiting patients |
| V+ interferon alpha-2b + IL-2 (NCT01603212) | I/II | Ongoing, not recruiting |
| V+ pegylated-interferon (NCT01959633) | I/II | Recruiting patients |
| V+ aldesleukin (NCT01754376) | II | Grade 4 delirium seen in 1/6 evaluated patients. Grade 3 fatigue, hypo- tension, arthralgia, and capillary leak seen. Median PFS was 35.8 weeks [57]. |
| Targeted + adoptive T cell therapy | ||
| V + adoptive cell transfer (NCT01659151) | II | Recruiting patients |
D dabrafenib, T trametinib, V vemurafenib, I ipilimumab, N nivolumab, AEs adverse events, PFS progression-free survival