The official journal of INTERNATIONAL FEDERATION OF PIGMENT CELL SOCIETIES · SOCIETY FOR MELANOMA RESEARCH
PIGMENT CELL & MELANOMA Research Highlights of melanoma research presented at the 49th annual meeting of the American Society of Clinical Oncology in Chicago, 2013 Clemens Krepler and Dorothee Herlyn
DOI: 10.1111/pcmr.12182 Volume 27, Issue 1, Pages E1–E5 If you wish to order reprints of this article, please see the guidelines here
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Pigment Cell Melanoma Res. 27; E1–E5
MEETING REPORT
Highlights of melanoma research presented at the 49th annual meeting of the American Society of Clinical Oncology in Chicago, 2013 Clemens Krepler and Dorothee Herlyn Molecular and Cellular Oncogenesis Program, The Wistar Institute, Philadelphia, Pennsylvania, USA CORRESPONDENCE Clemens Krepler, e-mail:
[email protected]
doi: 10.1111/pcmr.12182
Introduction This 2013 American Society of Clinical Oncology (ASCO) meeting report focuses on melanoma, clinical findings in immunotherapy with immune checkpoint inhibitors and therapy with small molecule inhibitors targeting kinases involved in signaling pathways. Highlights were the immunemodulatory antibodies targeting CTLA4 and PD-1, and kinase inhibitors targeting BRAF and MEK1/2. The meeting was attended by more than 25 000 clinical oncologists and basic cancer researchers.
Immune checkpoint inhibitors T cells are predominantly found in the blood and tissues, including tumors. In their activated state, T cells may destroy tumor cells. However, tumor-infiltrating T cells are often anergized, rendering tumor cells resistant to their cytotoxic effects. Several modulators may activate T cells by blockade of T cell-inhibitory molecules and are therefore candidates for immunotherapy. Anti-CTLA-4 antibody ipilimumab When ipilimumab (or tremelimumab, another anti-CTLA-4 antibody used in the clinical setting) bind to the inhibitory molecule CTLA-4 on T cells, these can become activated and destroy tumor cells. Ipilimumab was approved in the USA for treatment of metastatic melanoma in 2011, based on a study in 676 patients with melanoma at 125 centers in 13 countries presented at the 2012 ASCO meeting and published in the New England Journal of Medicine in June 2010. At the 2013 ASCO meeting, 5-yr survival data of patients with metastatic melanoma from four phase II trials after treatment with anti-CTLA4 antibody ipilimumab were presented by C. Lebbe (Hopital Saint-Louis, Paris, France; poster abstract No: 9053). Regardless of prior treatment ª 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
of the patients, 12–50% of the treated patients remained alive 5 yr after the start of treatment. However, increase in overall survival of patients treated in phase III randomized trials with the antibody was modest and adverse effects were frequent (presented at the 2012 ASCO meeting). Many institutions therefore focused on combination therapies with anti-CTLA4 antibody and other agents. Significant improvement in overall survival and reduction in toxicity were reported when ipilimumab was combined with the cytokine GM-CSF (presented by S. Hodi, Dana-Farber Institute, Boston, MA, USA; oral abstract No: CRA9007). The rationale for including GMCSF in this trial was based on preclinical data in a mouse model and clinical responses seen in prostate and ovary carcinomas. GM-CSF enhances the activities of dendritic cells and T and B cells in the tumor environment. In the phase II study of ipilimumab and GM-CSF combined, 245 previously treated patients with metastatic melanoma received either ipilimumab (10 mg/kg every 12 weeks) or the combination of ipilimumab (same schedule) and GMCSF (sargramostim; 250 lg daily on days 1–14 of a 21-day cycle, for four cycles). Although the power of this phase II study was limited, the addition of GM-CSF to ipilimumab improved overall survival from a median of 12.7 months with ipilimumab alone to 17.5 months. This difference was statistically significant. However, the primary endpoint progression-free survival (PFS) and response rates were not significantly different between the two treatment arms, a discordance often seen with immunotherapies. Importantly, the combination was associated with fewer serious side effects, especially pulmonary and gastrointestinal side effects. Potential mechanisms underlying this observation were discussed by S. Hodi and are based on studies in GM-CSF knock-out mice. These mice exhibited colitis and lymphoid hyperplasia in lungs. Thus, GM-CSF is an important factor for lymphoid homeostasis in these organs. There were two possible E1
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treatment-related deaths in the combination arm versus seven in the single agent arm. This is a very high treatment mortality rate for ipilimumab as a single agent, which could possibly result from less high-performance patients in this study? In mechanistic studies, ipilimumab was suggested to enhance induction of T cells with cytotoxic potential against melanoma-associated antigens (presented by J. Haanen, The Netherlands Cancer Institute, Amsterdam, the Netherlands; poster abstract No: 9078). Combination of ipilimumab and BRAF inhibitor In a fully retrospective study on 173 BRAF positive patients; when ipilimumab was given first to patients with melanoma, followed by BRAF inhibitor, clinical beneficial responses were higher than when the drugs were reversed in sequence of administration (P.A. Ascierto, Unit of Medical Oncology and Innovative Therapies, Istituto Nazionale Tumori Fondazione Pascale, Naples, Italy; poster abstract No: 9035). Furthermore, in patients who first received BRAF inhibitor and failed on this therapy, the investigators were not able to complete the following schedule of ipilimumab which further emphasized that ipilimumab should be given first when considering this kind of sequential therapy due to the retrospective nature of this study, the sequence of therapies was not randomized but based on clinical judgment; this likely introduced a bias regarding the observed outcomes. Recently, a phase I trial investigating concurrent administration of vemurafenib and ipilimumab has been closed to accrual due to liver toxicity (A. Ribas et al., New England Journal of Medicine 2013). Anti-PD-1 antibodies In addition to the T cell-inhibitory molecule CTLA-4, PD-1 is a key mediator of T cell exhaustion. PD-1 is highly expressed on tumor-infiltrating lymphocytes, and binding of PD-1 to its ligand PD-L1 on tumor cells inhibits killing of tumor cells by T cells. Blockade of this interaction by anti-PD-1 antibody or anti-PD-L1 antibody can lead to tumor cell killing. The anti-PD-1 antibodies nivolumab and lambrolizumab and the anti-PD-L1 antibody MPDL3280A were administered to patients with advanced melanoma in phase I/II clinical trials. Within these non-comparative studies, lambrolizumab, used alone, seemed to have the highest response rate, followed by nivolumab and MPDL3280A. Nivolumab was administered to 107 patients with stage IV melanoma at doses between 0.1 and 10 mg/kg (four doses per cycle; 80% at 12 weeks was observed in up to 41% of the patients, depending on drug dosage used. Grade 3/4 toxicity, mainly immune-related inflammation, was reported in 53% of the treated patients and was manageable. Even patients who had little benefit from previous treatment with ipilimumab had significant tumor shrinkage after treatment with nivolumab. This combination therapy is slated for a randomized phase III study in June 2013. In another phase I/II trial with 80 patients presented by J. Weber (Moffitt Cancer Center, Tampa, FL, USA; oral abstract No: 9011), objective clinical responses to nivolumab were observed in patients with melanoma after failing ipilimumab and to ipilimumab after failing nivolumab. There was a trend of superiority of the combination treatment versus either treatment alone, although a direct comparison of the two treatments was not possible as the studies were not done performed side by side and randomized. ª 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
Highlights of melanoma research at ASCO 2013
Anti-PD–L1 antibody MPDL3280A The anti-PD–L1 antibody MPDL3280A is a genetically engineered antibody, which lacks the Fc portion to avoid direct tumor cell killing by the antibody in conjunction with effector cells (presented by O. Hamid, The Angeles Clinic and Research Institute, Los Angeles, CA, USA; oral abstract No: 9010). This antibody exhibited much lower toxicity in patients with melanoma (n = 45) than the anti-PD1 and anti-CTLA-4 antibodies described above. Pneumonitis and colitis, often seen with anti-PD1 antibodies, were not seen with the anti-PD-L1 antibody MPDL3280A. The overall response rate in patients with melanoma to this antibody was 27% and was much higher in patients with PD-L1 positive tumors. Patients who progressed on vemurafenib (BRAF inhibitor) responded to MPDL3280A. In another trial, the antibody was administered to 140 patients with metastatic, incurable cancers of various tumor types, and preliminary results suggest that ~20% of patients are responding (presented by R. Herbst, Yale Cancer Center, New Haven, CT, USA; oral abstract No: 3000). Taken together, this drug has a better safety profile than the anti-PD-1 and anti-CTLA-4 antibodies and possibly works in more tumor types. In future studies, targeting of other immune inhibitory molecules on T cells, such as Tim3 and LAG-3 may prove to be clinically effective (A. Sharpe, Harvard Medical School, Boston, MA, USA, discussant). Combination of anti-PD-1 antibody nivolumab with tumor vaccines As immune checkpoint blockade with antibodies to CTLA-4 or PD-1/PD-L1 activates the immune system, the administration of tumor vaccines in combination with the antibodies seems paramount. Thus, nivolumab (anti-PD-1 antibody) was combined with a melanoma peptide vaccine (gp 100, MART-1, NY-ESO-1) in resected, high-risk patients with melanoma (presented by G. T. Gibney, Moffitt Cancer Center and Research Institute, Tampa, FL, USA; poster abstract No: 9056). Seven of 33 patients have relapsed after 14 months of treatment. Non-relapsing patients had higher pretreatment PD-1 expression on regulatory T cells (Treg) and CD4+ T cells and a greater increase in Treg.
Small molecule kinase inhibitors Although targeted therapy was not as strongly represented at this year’s meeting, many studies are ongoing and three small molecule kinase inhibitors are now FDAapproved for the treatment of metastatic BRAFV600E mutant melanoma: the two BRAFV600E inhibitors (BRAFi) vemurafenib and dabrafenib and the MEK1/2i trametinib. At last year’s and this year’s ASCO meeting, exciting results from dabrafenib/trametinib combination trials were presented with confirmed partial responses in more than 50% of patients. Following the approval of both as single agents, this combination therapy has also recently been submitted for FDA approval.
ª 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
BRAF and MEK1/2 inhibitor combination A retrospective analysis of the activity of dabrafenib in combination with trametinib in BRAFi-naive versus BRAFi-resistant patients was presented by J. A. Sosman, Vanderbilt University, Nashville, TN, USA (oral abstract No: 9005). Patients from the phase I (n = 50) and phase II (n = 97) trials were included in this analysis. BRAFi resistance was defined as progression on a BRAFi. Patient characteristics were comparable in both groups. The combination therapy (dabrafenib 300 mg + trametinib 2 mg) improved patient outcome compared with dabrafenib alone (K. T. Flaherty et al., New England Journal of Medicine 2012). In the phase I study, PFS was 10.8 months in the BRAFi na€ıve versus 3.6 months in the BRAFi-resistant patients. In the phase II study, PFS was 9.4 months in the BRAFi-na€ıve patients versus 3.6 months in the BRAFi-resistant patients. Complete responses were seen in 8% of BRAFi-na€ıve patients in both trials but in none of the BRAFi-resistant patients. The authors conclude that the combination therapy is superior in BRAFi-na€ıve versus BRAFi-resistant patients and that once BRAFi resistance has occurred, this therapy is far less effective. This could be due to resistance mechanisms emerging in BRAFi-treated patients that also render tumors resistant to other MAPK pathway inhibitors or combinations. The results make a strong point for upfront BRAF/MEKi combination therapy in BRAFV600 mutant patients, although high-grade toxicities, especially pyrexia, will have to be taken into account. Also, an adjuvant trial of this combination therapy in high-risk BRAF mutant melanoma patients is underway (ClinicalTrials.gov Identifier:NCT01682083). Initial results from a phase I trial (n = 54) of the BRAF inhibitor LGX818 were presented (R. Dummer, University Hospital Zurich; poster abstract No: 9028). At a dose of 450 mg/day partial responses were seen in about 60% of patients. Eleven% of patients who had relapsed on BRAF inhibitors previously showed responses. Interestingly, responses were observed at the starting dose of 50 mg/ kg, giving a nearly 10-fold range of active doses compared with a less than fivefold range for vemurafenib and dabrafenib between initial activity and maximum tolerated dose. Promising preliminary results from a phase I/II study (n = 20) of LGX818 in combination with the MEK1/ 2 inhibitor MEK162 were presented (R. Kefford, Melanoma Institute, Sydney, NSW, Australia; poster abstract No: 9029). Partial responses were seen in 70% of BRAF inhibitor-na€ıve patients with a favorable toxicity profile. A phase III trial with LGX818 at 450 mg and MEK162 at 45 mg is planned. MEK1/2 inhibitor monotherapy Selumetinib is an inhibitor of MEK1/2, directly downstream of BRAF. Results of a randomized phase II study in treatment na€ıve patients harboring a V600E BRAF mutation, comparing selumetinib plus dacarbazine versus
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placebo plus dacarbazine, were presented (M. R. Middleton, Oxford University Hospitals NHS Trust, Oxford, UK; oral abstract No: 9004). Ninety-one patients were randomized 1:1. The data reported for the primary endpoint overall survival were relatively mature; therefore, no substantial changes are expected. Again, it has to be noted that the power of this phase II study was limited The combination arm showed a better outcome; median overall survival was 13.9 months in the combination therapy arm versus 10.5 months in the chemotherapy alone arm, although this was not statistically significant. However, there was a significant difference in PFS with 5.6 months in the combination and 3 months in the dacarbazine arm. The confirmed response rate for the combination treatment was rather small at 29%, but still higher than chemotherapy alone at 13%. However, the rate of serious, but transient adverse events was also higher in the combination arm, especially acneiform dermatitis, diarrhea, vomiting and peripheral edema. Selumetinib was compared with temozolomide chemotherapy in patients with uveal melanoma with gnaq/ Gna11 (Gq/11) mutant tumors, based on the finding that the MAPK pathway is activated upstream of MEK1/2 by oncogenic gnaq/11 (R. D. Carvajal, Memorial SloanKettering Cancer Center, New York City, NY, USA; oral abstract No: CRA9003). Ninety-eight patients were enrolled with a primary endpoint of PFS. Crossover from the temozolomide arm was allowed after progression. Median PFS in selumetinib-treated patients was 15.9 weeks versus 7 weeks in temozolomide-treated patients (P-value = 0.0005). The overall response rate in the selumetinib group was 15%. There were no responders in patients crossing over from temozolomide. Thirteen percent of patients on selumetinib experienced grade 3 creatine phosphokinase increase and 15% experienced grade 3 AST/ALT (liver function markers) increase. Rash, edema, or dyspnea was seen in 2% of patients. All adverse effects were manageable with dose reduction. Selumetinib is the first drug to show significant clinical activity in uveal melanoma compared with chemotherapy. Targeted therapy resistance mechanisms and heterogeneity Targeted therapies are now firmly established in melanoma therapy. Their success is based on identification of single point mutations in one tumor sample as predictive biomarkers of response. Open key questions are whether there is tumor heterogeneity within a patient either before or as response to targeted therapy. Whole exome and transcriptome sequencing results of tumors from four patients relapsed on the combination of BRAF/MEK inhibitors were performed to shed light on this question (N. Wagle, Dana-Farber Cancer Institute, Boston, MA, USA; poster abstract No: 9015). With this combination likely to become standard targeted therapy in BRAF mutant melanoma, there is a great need to understand its underlying mechanisms. The authors conclude that the E4
combination of whole exome sequencing and RNA sequencing data proved to be complimentary and advantageous to identify clinical resistance mechanisms in these patients. As in previous studies on BRAFi resistance, the pattern was very heterogeneous. Furthermore, similar to BRAFi resistance, MEK1 and MEK2 mutations, BRAF amplification and a BRAF splice isoform were found in BRAF/MEKi resistant melanomas. Another important aspect of acquired resistance to targeted inhibitors of the MAPK pathway is the possible co-existence of multiple resistance mechanisms in the same tumor and/or in different metastatic sites. One such case was presented (O. Michielin, University Hospital, Lausanne, Switzerland; poster abstract No: 9014).Two lesions from the same patient resistant to vemurafenib showed mutations in NRAS in one and a BRAF splice variant in the other as possible mechanism of resistance. The authors conclude that not only continuation of treatment beyond tumor progression should be considered but also that single biopsy analysis at progression might not be sufficient to guide optimal second line therapies. Multitargeted kinase inhibitors The multitargeted kinase inhibitor lenvatinib showed a manageable safety profile and 23% durable stable disease in 93 patients with BRAF wild type melanoma in a phase II study (presented by S. O’Day, Beverly Hills Cancer Center, Beverly Hills, CA, USA; poster abstract No: 9026). Interestingly, a biomarker study was attached to this trial (presented by P. Sachdev, Eisai Inc., Woodcliff Lake, NJ, USA; poster abstract No: 9058). Lenvatinib treatment resulted in consistent decrease in soluble vascular endothelial growth factor receptor (VEGFR) 2–3 and increased VEGF and placental growth factor (PGF) levels in blood. Furthermore, low baseline angiopoietin (ANG)-2 levels were associated with longer survival and improved response. Thus, a potential predictive role for angiogenic factors in lenvatinib response should be evaluated further in larger studies.
Predictive biomarkers for immunotherapy and targeted therapy Predictive biomarkers for immunotherapy and therapies targeting signaling pathways could lead to selection of patients with an enhanced therapeutic benefit. Thus, following treatment with ipilimumab, there was a trend for improved survival in patients with melanoma (n = 72) with wild type BRAF and NRAS, compared with the expression of the mutant genes (presented by J. Mangana, University Hospital Zurich, Switzerland; poster abstract No: 9025). Furthermore, the immunoglobulin IgG2a isotype of monoclonal murine anti-CTLA4 antibodies has been associated with antitumor activity of the antibody in animal models (presented by A. Korman, Bristol-Myers Squibb, Redwood City, CA, USA; poster ª 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
Highlights of melanoma research at ASCO 2013
abstract No: 9055). Presumably, anti-CTLA4 antibodies of IgG2a isotype reduce intratumoral regulatory T cells (Treg) at the tumor site, thereby releasing the inhibitory effect of the Treg on effector T cells. Ongoing studies of this research group on the isotypes of tumor-infiltrating lymphocytes of untreated melanoma patients may reveal human immunoglobulin isotypes associated with tumor regression. In a retrospective study, eosinophil granulocyte counts in patients with melanoma (n = 123) before treatment with ipilimumab were significantly positively associated with overall survival after treatment (presented by K. Schindler, Medical University of Vienna, Vienna, Austria; poster abstract No: 9024). Granulocytes may represent possible antitumor effector cells in immune-mediated effects of anti-CTLA4 antibodies; altogether, these cells may also have immune-suppressive effects as suggested by previous studies. And finally, RNA-transcripts in pretreatment samples of patients with metastatic melanoma (n = 218) undergoing therapy with the anti-CTLA4 antibody tremelimumab revealed four transcripts prognostic of survival after therapy: cathepsin D, phospholipase A2, thioredoxin reductase and interleukin-1 receptor-associated kinase 3 (presented by Y. Saenger, Mount Sinai School of Medicine, New York, NY, USA; poster abstract No: 9080). Conflicting data have been reported on the utility of PD-L1 expression by melanoma cells as a biomarker for patients’ beneficial responses to anti-PD-1 antibody treatment (J. Weber, Moffitt Cancer Center, Comprehensive Melanoma Research Center, Tampa, FL, USA, oral abstract No: 9011; S. Topalian, The John Hopkins University School of Medicine, Baltimore, MD, USA; oral abstract No: 3002). Thus, tumor expression of PD-L1, which may be enhanced by IFN gamma secreted by T-effector cells, may be associated with, but not predictive of response. The presence of NRAS mutations in tumors correlated with higher objective response rates in patients with melanoma (n = 173) treated with antibodies to PD-1 or PD-L1 (D. Johnson, Vanderbilt-Ingram Cancer Center, Nashville, TN, USA; poster abstract No: 9019) Collectively, these biomarker studies may greatly influence future
ª 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
selection of patients for treatment with anti-CTLA4 antibodies, ultimately leading to improvement in this type of therapy. The question whether blood can replace the need for tissue for eligibility assessment of patients for kinase inhibitor therapy was investigated in two studies. In the first (presented by D. Polsky, NYU Langone Medical Center, New York, NY, USA; poster abstract No: 9023), 94 patients with stage 3 and 4 melanoma were analyzed. Using plasma-based BRAF and NRAS mutation detection, a high specificity of the plasma-based assay could be determined, with a potential of this assay to detect relapses subclinically. In another study (presented by D. Schadendorf, Universit€ atsklinikum, Essen, Germany; poster abstract No: 9020), plasma samples of over 300 patients with advanced BRAFV600E-positive melanoma were analyzed. The PCR assay used to detect circulating cell-free DNA (cfDNA) encoding BRAFV600E, showed 70% specificity. The patients in this study were treated with either chemotherapy or trametinib (MEKi) and patients with undetectable V600E or V600K cfDNA at baseline showed a higher response rate to both therapies.
Outlook Combining immune checkpoint blocking antibodies with small molecule kinase inhibitors may prove to be most effective treatment option for melanoma, based on the synergism and complementarity of these two approaches. Thus, immunotherapy targets both dividing and non-dividing cells and may be dependent on major histocompatibility complex (MHC) expression by tumor cells for effector T cells to kill tumors. Whereas kinase inhibitors target mainly dividing cells and are not dependent on MHC expression by tumor cells. It remains to be seen whether the emergence of tumor resistance mechanisms seen with both therapy approaches in isolated form, can be overcome by combing them. Randomized controlled phase III studies with these combination therapies are in progress.
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