Produção Nacional
Revisado por pares
Tyrosine Kinase Inhibitor and Immune Checkpoint Inhibitor Responses in KIT-Mutant Metastatic Melanoma
2018; Elsevier BV; Volume: 139; Issue: 3 Linguagem: Inglês
10.1016/j.jid.2018.10.009
ISSN1523-1747
AutoresMeredith McKean, Junna Oba, Junsheng Ma, Katherine G. Roth, Wei‐Lien Wang, Mariana Petaccia de Macêdo, Fernando C. L. Carapeto, Lauren E. Haydu, Alan Siroy, Phuong Vo, David S. Hong, Agda Karina Eterovic, Keyur P. Patel, Roland L. Bassett, Elizabeth A. Grimm, Alexander J. Lazar, Scott E. Woodman,
Tópico(s)CAR-T cell therapy research
ResumoKIT is a frequently mutated gene identified in acral lentiginous, mucosal, and non-acral cutaneous melanoma (Woodman and Davies, 2010Woodman S.E. Davies M.A. Targeting KIT in melanoma: a paradigm of molecular medicine and targeted therapeutics.Biochem Pharmacol. 2010; 80: 568-574Crossref PubMed Scopus (108) Google Scholar). Targeting oncogenic KIT mutations with tyrosine kinase inhibitors (TKIs) in melanoma has demonstrated response rates up to 29%, with progression-free survival (PFS) of 3.5 months (Carvajal et al., 2011Carvajal R.D. Antonescu C.R. Wolchok J.D. Chapman P.B. Roman R.A. Teitcher J. et al.KIT as a therapeutic target in metastatic melanoma.JAMA. 2011; 305: 2327-2334Crossref PubMed Scopus (636) Google Scholar). Immune checkpoint inhibitors (ICIs) have shown overall survival (OS) benefit in cutaneous melanoma, but to our knowledge no prior study has evaluated responses of KIT-mutant melanomas to ICI (Hodi et al., 2010Hodi F.S. O'Day S.J. McDermott D.F. Weber R.W. Sosman J.A. Haanen J.B. et al.Improved survival with ipilimumab in patients with metastatic melanoma.N Engl J Med. 2010; 363Crossref PubMed Scopus (11191) Google Scholar). This retrospective study investigates TKIs and ICIs in KIT-mutant melanoma to determine genetic and clinical factors associated with response, PFS, and OS. All patients were treated at The University of Texas MD Anderson Cancer Center and signed informed consent for collection and analysis of their tumor samples. This protocol was approved by the Institutional Review Board. Nineteen patients were identified with a KIT-activating mutation that received TKI treatment (Supplementary Table S1 online). Although the TKI analysis may be complicated by the grouping of three distinct KIT inhibitor TKIs, we observed an overall response rate of 20% for TKI treatment, similar to prior prospective clinical trials (Carvajal et al., 2011Carvajal R.D. Antonescu C.R. Wolchok J.D. Chapman P.B. Roman R.A. Teitcher J. et al.KIT as a therapeutic target in metastatic melanoma.JAMA. 2011; 305: 2327-2334Crossref PubMed Scopus (636) Google Scholar, Guo et al., 2011Guo J. Si L. Kong Y. Flaherty K.T. Xu X. Zhu Y. et al.Phase II, open-label, single-arm trial of imatinib mesylate in patients with metastatic melanoma harboring c-Kit mutation or amplification.J Clin Oncol. 2011; 29: 2904-2909Crossref PubMed Scopus (527) Google Scholar, Guo et al., 2017Guo J. Carvajal R.D. Dummer R. Hauschild A. Daud A. Bastian B.C. et al.Efficacy and safety of nilotinib in patients with KIT-mutated metastatic or inoperable melanoma: final results from the global, single-arm, phase II TEAM trial.Ann Oncol. 2017; 28: 1380-1387Abstract Full Text Full Text PDF PubMed Scopus (98) Google Scholar, Hodi et al., 2013Hodi F.S. Corless C.L. Giobbie-Hurder A. Fletcher J.A. Zhu M. Marino-Enriquez A. et al.Imatinib for melanomas harboring mutationally activated or amplified KIT arising on mucosal, acral, and chronically sun-damaged skin.J Clin Oncol. 2013; 31: 3182-3190Crossref PubMed Scopus (404) Google Scholar, Kalinsky et al., 2017Kalinsky K. Lee S. Rubin K.M. Lawrence D.P. Iafrarte A.J. Borger D.R. et al.A phase 2 trial of dasatinib in patients with locally advanced or stage IV mucosal, acral, or vulvovaginal melanoma: a trial of the ECOG-ACRIN Cancer Research Group (E2607).Cancer. 2017; 123: 2688-2697Crossref PubMed Scopus (68) Google Scholar, Lee et al., 2015Lee S.J. Kim T.M. Kim Y.J. Jang K.T. Lee H.J. Lee S.N. et al.Phase II trial of nilotinib in patients with metastatic malignant melanoma harboring KIT gene aberration: a multicenter trial of Korean Cancer Study Group (UN10-06).Oncologist. 2015; 20: 1312-1319Crossref PubMed Scopus (49) Google Scholar), and 32% when evaluating patients treated with a TKI concurrently with another agent (Table 1, Supplementary Table S2 online). Half of patients had >20% tumor reduction (Figure 1a). Older patients were more likely to have clinical response (P = 0.047) (Supplementary Table S3 online). All six responses were noted in patients with exon 11 KIT mutations, including patients receiving combination treatment of TKI and either temozolomide (n = 1) or ipilimumab (n = 2) (Figure 1a) (Supplementary Table S4 online). Four patients received additional lines of TKI after initial progression, with stable disease as best response (Figure 1b, Supplementary Table S4).Table 1Compilation of response to tyrosine kinase inhibitors (KIT-mutant melanoma)VariableStudy First Author (Year)Present StudyGuo et al., 2011Guo J. Si L. Kong Y. Flaherty K.T. Xu X. Zhu Y. et al.Phase II, open-label, single-arm trial of imatinib mesylate in patients with metastatic melanoma harboring c-Kit mutation or amplification.J Clin Oncol. 2011; 29: 2904-2909Crossref PubMed Scopus (527) Google ScholarCarvajal et al., 2011Carvajal R.D. Antonescu C.R. Wolchok J.D. Chapman P.B. Roman R.A. Teitcher J. et al.KIT as a therapeutic target in metastatic melanoma.JAMA. 2011; 305: 2327-2334Crossref PubMed Scopus (636) Google ScholarHodi et al., 2013Hodi F.S. Corless C.L. Giobbie-Hurder A. Fletcher J.A. Zhu M. Marino-Enriquez A. et al.Imatinib for melanomas harboring mutationally activated or amplified KIT arising on mucosal, acral, and chronically sun-damaged skin.J Clin Oncol. 2013; 31: 3182-3190Crossref PubMed Scopus (404) Google ScholarKalinsky et al., 2017Kalinsky K. Lee S. Rubin K.M. Lawrence D.P. Iafrarte A.J. Borger D.R. et al.A phase 2 trial of dasatinib in patients with locally advanced or stage IV mucosal, acral, or vulvovaginal melanoma: a trial of the ECOG-ACRIN Cancer Research Group (E2607).Cancer. 2017; 123: 2688-2697Crossref PubMed Scopus (68) Google ScholarGuo et al., 2017Guo J. Carvajal R.D. Dummer R. Hauschild A. Daud A. Bastian B.C. et al.Efficacy and safety of nilotinib in patients with KIT-mutated metastatic or inoperable melanoma: final results from the global, single-arm, phase II TEAM trial.Ann Oncol. 2017; 28: 1380-1387Abstract Full Text Full Text PDF PubMed Scopus (98) Google ScholarLee et al., 2015Lee S.J. Kim T.M. Kim Y.J. Jang K.T. Lee H.J. Lee S.N. et al.Phase II trial of nilotinib in patients with metastatic malignant melanoma harboring KIT gene aberration: a multicenter trial of Korean Cancer Study Group (UN10-06).Oncologist. 2015; 20: 1312-1319Crossref PubMed Scopus (49) Google ScholarTherapyImatinib, dasatinib, or sorafenibImatinibImatinibImatinibDasatinibNilotinibNilotinibPatients, n19342113224227CR, n (%)1 (5.3)—2 (9.5)———1 (3.7)PR, n (%)5 (26.3)9 (26.5)4 (19.0)7 (53.8)4 (18.2)11 (26.2)5 (18.5)SD, n (%)10 (52.6)13 (38.2)9 (42.9)3 (23.1)7 (31.8)20 (47.6)9 (33.4)PD, n (%)3 (15.8)12 (35.3)6 (28.6)3 (23.1)6 (27.3)10 (23.8)10 (37.0)Unknown, n (%)—————1 (2.4)2 (7.4)ORR, %31.626.528.653.818.226.222.2Abbreviations: CR, complete response; ORR, overall response rate; PD, progressive disease; PR, partial response; SD, stable disease. Open table in a new tab Abbreviations: CR, complete response; ORR, overall response rate; PD, progressive disease; PR, partial response; SD, stable disease. Median follow-up was 15.8 (range 3.1–110.3) months, median OS was 18.9 (95% confidence interval [CI] = 11.0–not reached) months and median PFS was 6.1 (95% CI = 3.0–18.9) months. Univariate Cox analysis did not demonstrate any pathologic or clinical factors significantly associated with OS (not shown) or PFS (Supplementary Table S5 online). Thirty-five patients treated with anti–CTLA4 were identified with a 20% overall response rate (Figures 1c–1d) (Supplementary Tables S6, S7 online). Clinical responses were seen in patients with KIT exon 11, 13, and 17 mutations (Supplementary Table S8 online). Median follow-up was 63.7 (range 1.5–108.7) months. Median OS was 11.8 (95% CI = 8.4–35.6) months and median PFS was 3.0 (95% CI = 2.8–5.8) months. Univariate Cox analysis demonstrated a trend toward OS benefit in patients treated with local therapy after initiation of ipilimumab, but not for other factors for PFS or OS (Supplementary Tables S9, S10 online) (P = 0.052). Of the 13 patients that received local and systemic therapies, 9 received radiation for central nervous system disease progression and 2 received radiation elsewhere. Twenty patients treated with anti-PD1 were identified with an overall response rate of 35% (Figure 1e, 1f; Supplementary Tables S11, S12 online). Median follow-up was 7.9 (range 0.9–35.2) months, OS was 22.5 (95% CI = 7.4–not reached) months, and PFS was 3.2 (95% CI = 2.7–not reached) months. KIT exon mutations 2, 11, and 17 demonstrated clinical responses to anti-PD1 (Supplementary Table S13 online). No patient with an exon 13 KIT mutation met inclusion criteria. Univariate Cox analysis for PFS (Supplementary Table S14 online) and OS (data not shown) demonstrated no significant prognostic factors. Clinical response to at least one ICI was noted in patients with exon 2, 11, 13, and 17 mutations. Fifteen patients treated with both anti-CTLA4 and anti-PD1 demonstrated that only one patient responded to both ICIs, while 7 patients responded to either anti-CTLA4 or anti-PD1 treatment. TKI response rates and PFS in our retrospective review were similar to prior clinical trial results in patients with activating KIT mutations (Guo et al., 2017Guo J. Carvajal R.D. Dummer R. Hauschild A. Daud A. Bastian B.C. et al.Efficacy and safety of nilotinib in patients with KIT-mutated metastatic or inoperable melanoma: final results from the global, single-arm, phase II TEAM trial.Ann Oncol. 2017; 28: 1380-1387Abstract Full Text Full Text PDF PubMed Scopus (98) Google Scholar, Hodi et al., 2013Hodi F.S. Corless C.L. Giobbie-Hurder A. Fletcher J.A. Zhu M. Marino-Enriquez A. et al.Imatinib for melanomas harboring mutationally activated or amplified KIT arising on mucosal, acral, and chronically sun-damaged skin.J Clin Oncol. 2013; 31: 3182-3190Crossref PubMed Scopus (404) Google Scholar). Additionally, we documented exceptional responders showing durable responses up to 18 months. Several of the tumor responses to imatinib were achieved when combined with ICI or chemotherapy, which is consistent with our previous work showing that KIT inhibition can enhance the effect of immune-based treatment in a KIT-mutant cancer mouse model (Yang et al., 2012Yang Y. Liu C. Peng W. Lizee G. Overwijk W.W. Liu Y. et al.Antitumor T-cell responses contribute to the effects of dasatinib on c-KIT mutant murine mastocytoma and are potentiated by anti-OX40.Blood. 2012; 120: 4533-4543Crossref PubMed Scopus (52) Google Scholar). Recently, we demonstrated that TKI therapy is markedly enhanced with concurrent blockade of the HGF–MET axis (Oba et al., 2018Oba J. Kim S.H. Wang W.L. Macedo M.P. Carapeto F. McKean M.A. et al.Targeting the HGF/MET axis counters primary resistance to KIT inhibition in KIT-mutant melanoma.JCO Precis Oncol. 2018; : 2018Google Scholar). These data indicate that combination approaches will be needed to enhance TKI response in KIT-mutant melanoma. Analysis by exon indicated KIT mutations likely to respond to TKIs. Responses in tumors harboring recurrent missense mutations in exon 11, such as L576P, V560D, and W557R, were consistent with prior data (Figure 1). The clinical response observed in a tumor harboring KIT Q575_F584dup in exon 11 is previously unreported in melanoma, to our knowledge, but is akin to deletion and insertion mutations noted to respond in gastrointestinal stromal tumor (Yan et al., 2015Yan L. Zou L. Zhao W. Wang Y. Liu B. Yao H. et al.Clinicopathological significance of c-KIT mutation in gastrointestinal stromal tumors: a systematic review and meta-analysis.Sci Rep. 2015; 5: 13718Crossref PubMed Scopus (40) Google Scholar). Our study demonstrated higher response rates with imatinib than dasatinib, consistent with prior clinical trials, and our review does not lend support for treating after initial progression on a TKI with another TKI used in this study (Kalinsky et al., 2017Kalinsky K. Lee S. Rubin K.M. Lawrence D.P. Iafrarte A.J. Borger D.R. et al.A phase 2 trial of dasatinib in patients with locally advanced or stage IV mucosal, acral, or vulvovaginal melanoma: a trial of the ECOG-ACRIN Cancer Research Group (E2607).Cancer. 2017; 123: 2688-2697Crossref PubMed Scopus (68) Google Scholar, Kluger et al., 2011Kluger H.M. Dudek A.Z. McCann C. Ritacco J. Southard N. Jilaveanu L.B. et al.A phase 2 trial of dasatinib in advanced melanoma.Cancer. 2011; 117: 2202-2208Crossref PubMed Scopus (119) Google Scholar). We noted a trend toward response in nonvisceral disease, as seen in subgroup analyses of trials with ICI and BRAF/MEK inhibition (Hodi et al., 2010Hodi F.S. O'Day S.J. McDermott D.F. Weber R.W. Sosman J.A. Haanen J.B. et al.Improved survival with ipilimumab in patients with metastatic melanoma.N Engl J Med. 2010; 363Crossref PubMed Scopus (11191) Google Scholar, Robert et al., 2015Robert C. Karaszewska B. Schachter J. Rutkowski P. Mackiewicz A. Stroiakovski D. et al.Improved overall survival in melanoma with combined dabrafenib and trametinib.N Engl J Med. 2015; 372: 30-39Crossref PubMed Scopus (1825) Google Scholar). Therefore, patients with disease limited to soft tissue or nonvisceral sites may be more likely to benefit from TKI treatment. Approximately 25% of patients with KIT-mutant melanoma present with a de novo missense mutation in exon 17, many of which are resistant to currently available KIT inhibitor TKIs (Carvajal et al., 2011Carvajal R.D. Antonescu C.R. Wolchok J.D. Chapman P.B. Roman R.A. Teitcher J. et al.KIT as a therapeutic target in metastatic melanoma.JAMA. 2011; 305: 2327-2334Crossref PubMed Scopus (636) Google Scholar). We observed marked tumor responses to ICI in half of patients with KIT exon 17 mutant melanoma, demonstrating ICI as a viable treatment for TKI-resistant KIT mutations. The trend toward OS benefit in patients that received local therapies after initiating anti-CTLA4 was primarily driven by radiation for central nervous system metastases. Because central nervous system metastasis is a poor prognostic factor, yet local therapies demonstrated a trend toward OS benefit, this indicates a role for local therapy in patients that may achieve stable disease or mixed response (Gershenwald et al., 2017Gershenwald J.E. Scolyer R.A. Hess K.R. Sondak V.K. Long G.V. Ross M.I. et al.Melanoma staging: evidence-based changes in the American Joint Committee on Cancer eighth edition cancer staging manual.CA Cancer J Clin. 2017; 67: 472-492Crossref PubMed Scopus (1206) Google Scholar). The potential synergy of ICI and radiation warrants further investigation. Patients with KIT-mutant melanoma have a variety of systemic treatment options with TKI treatment primarily yielding response rates up to 30% in exon-selective scenario. Our analysis indicates that ICIs appear to be KIT-mutant exon-agnostic. Additional studies will be needed to further investigate predictive clinical and pathologic factors for response to KIT inhibition and/or ICI to guide treatment planning. Clinical trials assessing combinations of chemotherapy, TKIs, ICIs, and radiation may lead to innovative treatment approaches. All authors state no conflict of interest. Part of this study was presented at 2018 ASCO-SITC Annual Meeting. This work was supported by the Conquer Cancer Foundation Young Investigator Award (MAM); Dr Miriam and Sheldon G. Adelson Medical Research Foundation, Aim at Melanoma Foundation and the Miriam & Jim Mulva Foundation (all to EAG); University of Texas System Rising Star Award, National Cancer Institute SPORE in Melanoma (P50 CA093459) Developmental Research Project Award, National Institutes of Health/National Cancer Institute Cancer Center Support Grant P30 CA016672 Faculty Award, the University of Texas MD Anderson Cancer Center Melanoma Moon Shot Program (all to SEW). Download .pdf (.71 MB) Help with pdf files Supplementary Tables S1–S14 and Supplementary Methods
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