The efficacy of re-challenge with BRAF inhibitors after previous progression to BRAF inhibitors in melanoma: A retrospective multicenter study

Julia K Tietze, Andrea Forschner, Carmen Loquai, Heidrun Mitzel-Rink, Lisa Zimmer, Frank Meiss, David Rafei-Shamsabadi, Jochen Utikal, Maike Bergmann, Friedegund Meier, Nicole Kreuzberg, Max Schlaak, Carsten Weishaupt, Claudia Pföhler, Mirjana Ziemer, Michael Fluck, Jessica Rainer, Markus V Heppt, Carola Berking, Julia K Tietze, Andrea Forschner, Carmen Loquai, Heidrun Mitzel-Rink, Lisa Zimmer, Frank Meiss, David Rafei-Shamsabadi, Jochen Utikal, Maike Bergmann, Friedegund Meier, Nicole Kreuzberg, Max Schlaak, Carsten Weishaupt, Claudia Pföhler, Mirjana Ziemer, Michael Fluck, Jessica Rainer, Markus V Heppt, Carola Berking

Abstract

BRAF and MEK inhibition is efficient in patients with BRAF V600-mutated metastatic melanoma, but due to acquired resistance the duration of response (DoR) is often only short-lived. In this retrospective multicenter study with 60 patients suffering from inoperable or metastatic melanoma we evaluated the efficacy of re-challenge with a BRAF inhibitor (BRAF2) with or without MEK-inhibition after progressive disease upon previous treatment with a BRAF inhibitor (BRAF1) with or without MEK inhibition. Treatment with BRAF1 led to a disease control rate (DCR) of 90% with 12% complete responses (CR), 58% partial responses (PR) and 20% stable diseases (SD), the median progression-free survival (PFS) was 9.9 and DoR 10.7 months. BRAF2 with (68%) or without (32%) additional MEK inhibition was initiated after a median interval of 3.4 months. DCR after re-challenge with BRAF2 was 57%, 8% CR, 20% PR and 28% SD, median PFS was 5.0 and DoR 14.0 months. The duration of the treatment interval or the treatment in the interval did not influence the DCR or PFS to BRAF2. The only predictive factor for response to BRAF2 was previous response to BRAF1; all patients with CR to BRAF1 achieved disease control with BRAF2, but only 60% of the patients with PR to BRAF1 (p=0.002). Addition of MEK inhibition to BRAF2 after treatment with BRAF1 as monotherapy did not significantly increase the DCR or PFS compared to patients treated solely with mono- or combination therapy. In conclusion re-challenge with a BRAF inhibitor is a meaningful therapeutic option for patients with BRAF V600-mutated metastatic melanoma.

Keywords: BRAF-inhibition; BRAFV600 mutation; MEK-inhibition; melanoma; re-challenge.

Conflict of interest statement

CONFLICTS OF INTEREST J.K.T.: speaker's honoraria from BMS, MSD, Novartis, Roche, Almiral, travel support from BMS and consultant honoraria from BMS; A.F.: speaker's honoraria from Roche, Novartis, BMS, MSD, consultant honoraria and travel support from Roche, Novartis and BMS, C.L.: advisory for Roche, Amgen, Novartis, BMS, MSD, Leo, Pierre Fabre, speaker's honoraria from Roche, BMS, MSD, Novartis, Leo, Pierre Fabre, Amgen and travel reimbursement from Roche, BMS, MSD, Novartis, Leo, Pierre Fabre, Amgen; H.MR.: no conflicts of interest, L.Z.: speaker's and consulting honoraria from Roche, BMS, MSD, Novartis, travel support form MSD, Novartis, BMS, Amgen, Pierre Fabre, F.M.: speaker's honoraria from MSD, Novartis, advisory for Roche, Novartis, travel support from Novartis, Roche and BMS, D.RS: no conflicts of interest, J.U.: speaker's and consulting honoraria from Amgen, BMS, Novartis, MSD, Roche, research funding from Biotech, Elsalys, Rheacell, travel support Amgen, BMS, MSD, Novartis, Roche, M.B.: no conflicts of interest, F.M.: no conflicts of interest, N.K: consultant's honoraria BMS, Novartis, Roche and travel support from Novartis, BMS, M.S.: consultant honoraria from Jenapharm, Amgen, Roche, BMS, Novartis, MSD, travel support from Amgen, C.W.: speaker's honoraria from Amgen, MSD, Roche, advisory board BMS, Novartis, Takeda, C.P.: speaker's honoraria: GSK, Roche, BMS, MSD, Janssen, Novartis, Merck Serono and Bencard, consultant honoraria Roche, BSM, Novartis, Merck Serono, travel support from GSK, Roche, BMS, MSD, Janssen, Novartis, Merck Serono and Bencard, M.Z.: speaker's honoraria from BMS, MSD, Novartis, Roche, Amgen, Pfizer, Merck, advisory for BMS, MSD, Novartis, Roche, Amgen, Pfizer, Merck, travel support from BMS, Amgen, M.F.: consultant honoraria and travel support from Roche, Merck, BMS, Novartis, J.R: No conflict of interest, M.V.H.: speaker's honoraria from Roche, Novartis, BMS, MSD and travel support from BMS, C.B.: speaker's honoraria from Amgen, AstraZeneca, BMS, MSD, Novartis, Pierre Fabre, and Roche, consultant's honoraria from Amgen, AstraZeneca, BMS, MSD, Novartis, Pierre Fabre, and Roche and travel support from Amgen and MSD.

Figures

Figure 1
Figure 1
Comparison of response rates of initial BRAF inhibitor (BRAF1) therapy and of re-challenge with BRAF inhibitor 2 (BRAF2) (A). There was no significant difference in the PFS with BRAF1 or BRAF2 (B). The DoR was significantly higher after response to BRAF2 compared to BRAF1 (C).
Figure 2
Figure 2
The number of patients diagnosed with brain metastases (A) and with increased LDH levels (B) differed significantly before re-challenge with BRAF inhibitor (BRAF2) compared to initial therapy with BRAF inhibitor 1 (BRAF1).
Figure 3
Figure 3
The PFS after BRAF2 correlated with the levels of LDH (A) and S100 (B) before initiation of BRAF2. Neither the time interval between initial therapy with BRAF1 and re-challenge with BRAF2 (C) nor subsequent treatment with ICB (D) was correlated with the response to BRAF2. The response to BRAF1 significantly correlated with the response to re-challenge with BRAF2 (E).
Figure 4
Figure 4
The PFS (A) or OS (B) after BRAF2 did not differ significantly between patients in Group A, who were treated with BRAF1 and BRAF2 as monotherapy, and patients in Group B, who were treated with BRAF1 as monotherapy and with BRAF2 as a combination therapy with MEK inhibition, and patients in Group C, who were treated with BRAF1 and BRAF2 as a combination therapy with MEK inhibition.

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