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Long-term survival as a treatment benchmark in melanoma: latest results and clinical implications:

Long-term survival as a treatment benchmark in melanoma: latest results and clinical implications: 572284 TAM0010.1177/1758834015572284Therapeutic Advances in Medical OncologyKF Grossmann and K Margolin research-article2015 Therapeutic Advances in Medical Oncology Review Ther Adv Med Oncol Long-term survival as a treatment 2015, Vol. 7(3) 181 –191 DOI: 10.1177/ benchmark in melanoma: latest results and © The Author(s), 2015. Reprints and permissions: clinical implications http://www.sagepub.co.uk/ journalsPermissions.nav Kenneth F. Grossmann and Kim Margolin Abstract: Historically, stage III–IV melanoma patients have had few options to achieve long-term survival. For patients with stage III disease, surgery alone may be curative for approximately 50%. Adjuvant treatment with a slightly greater impact on relapse-free survival at the cost of substantial toxicity, and studies are ongoing to test the adjuvant benefit of other immunotherapies that appear more active and less toxic in advanced melanoma. Achieving long term survival for stage IV patients had been rare until recently and progress was painfully slow with traditional cytotoxic chemotherapy; review of multiple phase II studies showed universally poor results. Fortunately, since the approval by the US Food and Drug Administration of agents targeting the cytotoxic T lymphocyte antigen-4 (CTLA-4) receptor, as well as those targeting B-raf and mitogen-activated protein kinase kinase (MEK) in the mitogen-activated protein kinase (MAPK) pathway for patients whose melanoma is ‘driven’ by a BRAF mutation, long-term survival of stage IV melanoma is increasing substantially. Here we review the examples of studies documenting potentially curative approaches to melanoma and propose suggestions for the use of various treatments in achieving this important goal. Keywords: melanoma, immunotherapy, targeted therapy, b-raf, ipilimumab, nivolumab, pembrolizumab, vemurafenib, dabrafenib, trametinib Correspondence to: Historical background patients, but identifying patients prospectively for Kenneth F. Grossmann, Starting in the 1980s, highly selected patients enhanced surveillance based on risk factors with MD, PhD Division of Oncology, treated with high-dose interleukin-2 (IL-2) could the goal of early detection of metastatic lesions Department of Medicine, achieve durable remissions, and combinations of resectable for curative intent is another challenge University of Utah School of Medicine, Salt Lake City, IL-2, interferon-α (IFN-α) and cisplatin-based requiring further investigation. Furthermore, it Utah, USA combination chemotherapies showed high overall may eventually be possible to identify different kenneth.grossmann@hci. utah.edu response rates with some durable remissions markers of risk that lead to different approaches. Kim Margolin, MD [Atkins et  al. 1999; Bedikian et  al. 2008]. For example, frequent scanning to identify surgi- Division of Oncology, Unfortunately, the therapeutic index of both cally resectable disease versus the use of a circulat- Stanford University, Stanford, CA, USA approaches is poor, and in particular, biochemo- ing biomarker that identifies patients more likely therapy has proven less active than originally to benefit from adjuvant or systemic interventions reported [Atkins et  al. 2008]. While high-dose before the development of more overt signs of IL-2 is still used in some centers and current series metastatic disease. suggest selected clinical factors associated with more favorable outcomes [Payne et al. 2014], IL-2 as a single agent has for the most part been Adjuvant treatment may represent the best replaced by other forms of immunotherapy with a opportunity to cure patients after surgery more favorable therapeutic index. Multiple phase and to prevent morbidity from progression II studies have been conducted in search of other Following surgery for melanoma with a high risk active agents for melanoma during this era, but of relapse and death [many patients from stage produced disappointing results (Korn et al. 2008). IIB (>4 mm Breslow depth) and most from IIIA Surgery for oligometastatic stage IV disease does through IIIC], melanoma patients currently have provide durable disease control in a fraction of two treatment options approved by the US Food http://tam.sagepub.com 181 Therapeutic Advances in Medical Oncology 7(3) and Drug Administration: high-dose IFN-α With regard to which characteristics will identify (HDI) and pegylated IFN (PEG-IFN) (PEG- patients most likely to benefit from treatment, a IFN is approved for patients with nodal metasta- predictive biomarker is presently lacking for FDA sis only). The patterns of relapse in this population approved treatment options. High dose IFN-α is show that 51% of the relapses occur at distant the best studied treatment for patients with high sites [Romano et al. 2010], so treatment to delay risk resected melanoma with three completed relapse can be a significant benefit to patients, multicenter US intergroup trials: E 1684 even if the therapy does not increase long-term [Kirkwood et  al. 1996]; E1690 [Kirkwood et  al. overall survival (OS). Curing patients in this pop- 2000]; and E1694 [Kirkwood et al. 2001]. These ulation at high risk for relapse and death ideally studies showed a consistent benefit in relapse-free would require the pretreatment ability to identify survival (RFS), and two of the three studies which patients are destined for relapse (prognos- showed an OS benefit when compared with an tic information) and, among those at highest risk, inactive control (1684 versus observation, and who will benefit from a particular adjuvant inter- 1694 versus a ganglioside vaccine). Other dosing vention (predictive characteristics) which may regimens of IFN-α-2b have also been studied, relate to patient, tumor and therapy. and in a meta-analysis of data from over 10,000 patients who participated in studies of adjuvant To answer the first question, years of work have IFN-α with a ‘no treatment’ comparator cohort, a been devoted to evaluating clinical and pathologic RFS benefit [hazard ratio (HR) 0.83 (0.78–0.87)] risk factors related to the primary melanoma, and and OS benefit [HR 0.91 (0.85–0.97)] were the presence or absence of tumor in draining reported [Mocellin et al. 2013]. lymph nodes, which is the single most important determinant of survival. The current American Polyethylene glycol-conjugated PEG-IFN-α has Joint Committee on Cancer (AJCC) staging sys- also been studied in the adjuvant setting and tem recognizes the importance of ulceration of received FDA approval for stage III melanoma the primary tumor, mitotic rate, and the number following report of the European Organisation for and size of tumor bearing lymph nodes [Balch Research and Treatment of Cancer (EORTC) et al. 2009, 2010]. Further refinement of this sys- trial demonstrating a relapse free survival benefit tem is needed, because even with a full knowledge [HR = 0.82 (0.71–0.96) at 3.8 years follow up, of all of these factors, many patients defined as and HR = 0.87 (0.76–1.00) at 7.6 years follow high risk by AJCC criteria are likely cured by sur- up] without OS benefit [Eggermont et  al. 2008, gery and may be receiving adjuvant therapy for no 2012]. However, retrospective subset analysis benefit. revealed that patients who had ulcerated primary lesions and microscopic nodal disease derived the The potential for using molecular classifications to most benefit, including significantly improved define risk is best exemplified in uveal melanoma survival [Eggermont et  al. 2012], and a subse- based on gene expression profile data, where 459 quent study [ClinicalTrials.gov identifier: patients were followed prospectively after surgery. NCT01502696] was designed to confirm those Gene expression profiling segregated tumors into findings. Confirmation about whether ulceration class 1 with a very low 1.1% incidence of develop- is also useful as a predictive marker for high-dose ing distant metastasis at a mean follow up of IFN-α may come from the ongoing intergroup 18 months, compared with patients with a class study investigating IFN in comparison with ipili- 2 tumor who experienced a relapse rate of 25.9% mumab (E1609) [ClinicalTrials.gov identifier: over the same time interval [Onken et  al. 2012]. NCT01274338]. While retrospective subgroup Surveillance of these patients included blood test- analyses do not provide sufficiently robust data ing of liver functions every 6 months and liver for the identification of predictive biomarkers of imaging [usually computerized tomography (CT) benefit, they often provide hypothesis-generating with contrast] at 1 year intervals, but the contribu- data that can then be tested prospectively in con- tion of surveillance to OS is not clear, since ther- firmatory trials. apy for uveal melanoma with distant relapse has rarely been associated with prolonged survival. Other recent adjuvant trials for high risk mela- Several groups are further developing expression noma include the US cooperative group study of assays in cutaneous melanoma, which may soon biochemotherapy versus high-dose IFN-α prove to be useful tools in addition to the AJCC (S0008); an earlier US cooperative group trial risk stratification presently in use. (E4697) investigating the immunomodulatory 182 http://tam.sagepub.com KF Grossmann and K Margolin effects of granulocyte-monocyte colony-stimulat- Ipilimumab ing factor (GM-CSF); a melanoma antigen (gp- Ipilimumab is the first drug in the history of sys- 100)-derived peptide vaccine (this study included temic therapy for melanoma to demonstrate an patients with fully-resected oligometastatic mela- OS advantage in a randomized controlled trial in noma); and most recently, a placebo-controlled patients with metastatic melanoma [Hodi et  al. trial of a different melanoma antigen (MAGE-A3, 2010]. The toxicity of the drug, although signifi- GDK-2132231A) [ClinicalTrials.gov identifier: cant, has well-established management algo- NCT00796445]. The vaccine trials and the rithms, making it a generally safe and effective GM-CSF study have thus far failed to produce a front-line treatment for stage IV melanoma meaningful benefit. However, the biochemother- [Weber et  al. 2012]. Response rates to the drug apy study did show some intriguing results. have been modest (10–15%), but the achieve- Biochemotherapy was selected as a potentially ment of long-term progression-free survival better option for eradicating micrometastatic dis- (PFS) among patients whose best response is sta- ease owing to its higher response rate in stage IV ble disease rather than objective response has led cancer (30–50% versus 15% for HDI). The RFS to the concept of a ‘disease control rate’ based on advantage of 2 years median for biochemotherapy the sum of the rate of objective response plus sta- in comparison with HDI does corroborate that ble disease at the time of first post-therapy assess- extrapolation, but the lack of OS benefit similarly ment and beyond [Wolchok et  al. 2009]. mirrors the experience in advanced melanoma, Long-term follow-up data of the patients treated where the pooled data demonstrate that increas- in the phase II program of ipilimumab demon- ing the objective response rate fails to enhance strate that, in treatment-naïve patients treated survival [Atkins et al. 2008]. at the highest dose of ipilimumab (10 mg/kg), 37.7–49.5% of patients were living 4 years or The most recently reported data were from a longer [Wolchok et  al. 2013b]. Experience with global adjuvant trial of ipilimumab versus placebo the drug in 833 patients in the Italian expanded which remarkably mirrored the PEG-IFN-α data access program, which was less stringent in terms in demonstrating an overall RFS advantage and a of patient eligibility, showed that although the strong association of benefit with ulceration of the median PFS and OS were 3.7 and 7.2 months, primary melanoma [Eggermont et  al. 2014]. respectively [Ascierto et al. 2014b], a very encour- Further investigation of the immunologic corre- aging long RFS plateau around 20% was reported. lates of ulceration that explain this association This important benchmark appears to be a pla- with favorable adjuvant therapy outcomes may teau in the PFS curve, suggesting that patients lead to better patient selection for individual types who achieve PFS at the inflection point of 2.5–3.0 of adjuvant therapy and, importantly, for those years may not relapse and may effectively be who cannot benefit or who do not need adjuvant cured of their melanoma. While there remains a therapy. The potential for long-term OS benefit possibility that aftertherapies such as surgery for will also require both longer follow up and a care- residual oligometastases contributed to durable ful assessment of the effects of subsequent ther- control, the role of ipilimumab seems incontro- apy on patients who relapse. However, rapid vertible in the ultimate success of preventing these developments in the field of immune checkpoint patients’ death from advanced melanoma. blockade for melanoma have already permitted the development of the next important adjuvant Although clearly exciting, the low overall clinical trial, which will compare the PD-1 blocking anti- benefit rate and the notoriously slow or delayed body, pembrolizumab, with HDI for patients with regressions of metastatic melanoma in patients resected melanoma at high risk of relapse (S1404). treated with ipilumumab, together with the advent In parallel, the molecularly-targeted agents that of mutation-directed molecularly targeted agents, have shown important activity in advanced dis- have led to the development of combination regi- ease are also under evaluation in the adjuvant set- mens designed to exploit both immunologic and ting for patients with BRAF-mutated melanoma; molecularly directed mechanisms of antitumor due to their distinct mechanisms of action and activity. Unfortunately, the toxicity of ipilimumab toxicities, these agents are being compared to pla- has made it difficult to combine with the B-raf cebo rather than IFN (vemurafenib versus placebo inhibitor vemurafenib [Ribas et al. 2013] or with [ClinicalTrials.gov identifier: NCT01667418] the cytotoxic agent dacarbazine [Robert et  al. and dabrafenib plus trametinib versus placebo 2011]. In both cases, there was an increase in the [ClinicalTrials.gov identifier: NCT01682083]). frequency of high-grade hepatotoxicity, which is a http://tam.sagepub.com 183 Therapeutic Advances in Medical Oncology 7(3) very low frequency event with any of the single treatment, including the contribution of post pro- agents. Furthermore, the addition of dacarbazine gression therapies to long-term survival. did not appear to increase the activity of ipilumumab or downmodulate any of the other One concern about the use of single agent B-raf toxicities, making this an unattractive combina- blockade is the multitude of resistance mecha- tion. Combining molecularly targeted drugs with nisms that evolve on therapy [Bucheit and Davies, other immunomodulators for advanced disease 2014]. This leads to PFS times for vemurafenib continues to be an active area of investigation: and dabrafenib of approximately 6 months dabrafenib +/- trametinib plus ipilimumab [Chapman et  al. 2011; Hauschild et  al. 2012]. [ClinicalTrials.gov identifiers: NCT01767454, Combining B-raf and mitogen-activated protein NCT01940809, NCT02200562]; and vemu- kinase kinase (MEK) blockade, using the oral rafenib plus IL-2 [ClinicalTrials.gov identifiers: agent trametinib has led to improved PFS and OS NCT01683188, NCT01754376]. in a randomized trials; PFS 9.4 months with com- bination dabrafenib/trametinib, versus 5.8 months in the dabrafenib monotherapy group, and OS at Long-term survival on targeted therapy 12 months 72% combination versus 65% vemu- Approximately half of cutaneous melanomas rafenib alone (HR 0.69; 95% CI 0.53–0.89) (40–60%) harbor a B-raf mutation [Davies and [Flaherty et  al. 2012; Robert et  al. 2015a]). A Samuels, 2010]. In the first reports of clinical recently completed phase III placebo-controlled activity, response rates were impressive for both randomized trial also showed an improved PFS vemurafenib (FDA approved in 2011) [Flaherty (HR 0.75, p = 0.035) in favor of dabrafenib plus et al. 2010; Sosman et al. 2012], and dabrafenib trametinib in comparison with dabrafenib alone as (approved in 2013) [Ascierto et  al. 2013]. first-line therapy [Long et al. 2014]. The combina- Longer term follow-up data are maturing for tion of dabrafenib and trametinib were granted the randomized trial comparing vemurafenib accelerated approval for the use in patients with with dacarbazine in patients with unresectable advanced B-raf V600 mutated melanoma in stage IIIC or IV melanoma with a B-raf muta- January 2014. Similar results have been seen with tion. The first report of this trial showed signifi- vemurafenib and cobimetinib (a second MEK cant improvements for both OS and PFS inhibitor) combinations that have similar mecha- [Chapman et al. 2011]. Given the 44% crosso- nisms but a slightly different toxicity spectrum; ver from dacarbazine to vemurafenib, longer PFS 9.9 months combination versus 6.2 months term follow up was needed to estimate the vemurafenib; OS 9 month OS 81% versus 73% impact of this effect. Uncensored data show (HR = 0.65; 95% CI 0.42–1.00) [Larkin et  al. that the 18 month OS was 39% [95% confi- 2014]). There are also newer investigational agents dence interval (CI) 33–45] in the vemurafenib undergoing testing to overcome mechanisms of group and 34% (95% CI 29–40) in the dacar- resistance and the emergence of a successful regi- bazine group [McArthur et al. 2014]. Although men from these studies is likely to provide further the difference seen in this subset analysis small, survival benefits to selected patients. it is statistically significant (HR 0.76, 95% CI 0.63–0.93, p = 0.0068). PD-1 blockade This crossover impact suggests that patients can Patients treated with targeted drugs first, followed be rescued with highly active treatment following by immunotherapy upon disease progression, progression, but the lower OS associated with this appeared to benefit to a lesser extent and to experi- sequencing, together with the likely morbidity of ence greater toxicities than those receiving immu- progression events, toxicities and time to recover notherapy as their first treatment. The data from cytotoxic therapy before targeted therapy, demonstrating this phenomenon [Ackerman et  al. makes targeted therapy a better first choice in 2014; Ascierto et al. 2014a] may reflect a bias in the strategies to achieve long-term survival. What is assignment of patients with more aggressive disease very encouraging about the longer term follow up to initial targeted therapy due to its high response is that there appears to be a subset of patients who rate and rapid action. Immunotherapies that have are surviving out to 2 years (>20%). The charac- been available so far (high-dose IL-2 and ipilu- teristics of these long-term survivors are not mumab) benefit only a small fraction of patients known yet, but are under intense investigation and have a very unfavorable (IL-2) or moderately focused on characteristics of patient, tumor and unfavorable (ipilimumab) therapeutic index. 184 http://tam.sagepub.com KF Grossmann and K Margolin However, recent advances in the understanding year, while among the patients responding to of immune checkpoint blockade have led to the pembrolizumab, a median response duration had development of a class of fully human or human- not been reached at 11 months’ follow up. ized antibodies that interrupt a different, more Importantly, over half of the patients whose dis- tumor-specific checkpoint. So far, these agents, ease had progressed on prior ipilimumab experi- which block either programmed death-1 (PD-1) enced clinical benefit (objective response or mediated negative signaling on ‘exhausted’ T cells disease stabilization) with pembrolizumab (21/29 or its main ligand, PD-1 ligand (PD-L1) on tumor patients). Both reagents have similarly favorable and/or stroma, appear to have higher activity, toxicity profiles with <12% Gr3/4 adverse event lower toxicity and the potential for synergy with (AE) rates, which supports the safety and feasibil- cytotoxic T lymphocyte antigen-4 (CTLA4) ity of combining PD-1 blockade with other agents blocking antibodies. and suggests that these combinations will be safer and more effective than ipilimumab-based com- Nivolumab, targeting PD-1, has provided objec- binations. Results of combining ipilimumab with tive response rates of approximately 30% in stage nivolumab have shown high response rates (53%), IV melanoma [Topalian et  al. 2012]. When used but high-grade toxicities, generally inflammatory/ in the front-line setting, it has also shown an autoimmune in nature, have also emerged in improvement in OS in comparison with dacar- about half of the patients treated with the doses bazine in B-raf wildtype patients (HR 0.42, that provided the highest disease control rates p < 0.001) [Robert et al. 2015b]. A second PD-1 [Wolchok et  al. 2013a]. Longer follow up from antibody, pembrolizumab, has also shown similar large ongoing and other planned trials will better results with a response rate of 38% across all dose demonstrate the contribution of PD-1 blockade levels in a phase I study focusing on melanoma to long-term survival of melanoma patients and patients [Hamid et al. 2013]. It was data from this where this form of therapy best fits in the treat- large phase I study (n = 411) that led to the FDA ment algorithm. approval of pembrolizumab in patients with unre- sectable or metastatic melanoma and disease pro- gression following ipilimumab and, if B-raf V600 High-dose IL-2 mutation positive, a B-raf inhibitor. Recent High-dose IL-2 remains an important treatment updates have confirmed the response rate and option for patients with stage IV melanoma that durability of pembrolizumab with 1 year OS being has been available for many years to selected reached in 71% of all patients enrolled [Ribas patients at experienced centers. The most recently et  al. 2014]. Nivolumab shows similarly encour- published update on the activity of IL-2 from a aging longer term follow-up data with 2 and 3 multicenter experience showed that in melanoma, year OS rates of 48 and 41%, respectively [Hodi the response rate was about 16%, with long-term et  al. 2014]. Nivolumab was also granted FDA survival in approximately 10% of the patient popu- approval in December 2014 for the same indica- lation [Atkins et al. 1999]. Patients with melanoma tion as pembrolizumab (see above). and residual single lesions of unknown nature have often undergone excision, which may have contrib- In these landmark studies, the antitumor response uted to long-term RFS, and while a few patients also appears more quickly following initiation of relapse from radiologic complete response, there therapy than has been observed with CTLA4 are additional patients with radiologic partial blockade, which often takes 12–24 weeks before response who never relapse. A recently published tumor regression or confirmed stabilization is single institution experience with 314 melanoma achieved; furthermore some patients will experi- patients among the 500 total (the others had renal ence tumor progression prior to responding to clear cell cancer) reported 23% of patients alive at ipilimumab [Wolchok et  al. 2009] and only with least 5 years beyond treatment with high-dose IL-2 delayed follow up will demonstrate tumor regres- [Payne et al. 2014]. Unfortunately there is, to date, sion – a problem in both assessing the activity of no biomarker or group of parameters that can help the agent using traditional criteria and in the clin- to select patients for a higher therapeutic index ical management of such patients. With nivolumab (either more likely to benefit or less likely to experi- and pembrolizumab, most responses are apparent ence toxicities), although a recently completed 170 within 6–8 weeks, and most responding patients patient Cytokine Working Group protocol to iden- remain free of progression beyond 1 year; 13 of tify such factors is likely to provide important 18 responses to nivolumab were ongoing at 1 insights in 2015. http://tam.sagepub.com 185 Therapeutic Advances in Medical Oncology 7(3) Table 1. Update of current melanoma treatment options for adjuvant therapy and metastatic disease. Practice Trial design Endpoint RFS/PFS versus Capable of impacting consideration-control OS impacting long- arm term survival Adjuvant therapy High dose IFN Yes for Yes RFS and OS seen Yes stage III consistently in stage IIB–III PEG-IFN Yes for Yes RFS benefit maintains No stage III relevance considering prevention of morbidity from relapses in node positive patients Metastatic disease Ipilimumab Yes Yes, will be good Durable OS benefitPFS Yes control arm for benefit second line studies following approval of PD-1 High dose Yes Phase II combination Durable OS Yes IL-2 studies needed to benefitQuestionable PFS improve response benefit rate TIL (tumor Yes Not a good control PFS benefit modestDurable Single institution infiltrating arm, Further work OS benefit likely studies suggest lymphocytes) to decrease toxicity yes, accessibility necessary remains a problem PD-1 Yes Yes, should be new Significant PFS and OS Yes, significant, blockade control arm for benefit seen should become front line phase III the new standard trials for stage IV front-line therapy patients, and will for melanoma likely be impactful patients upon experimental arm in FDA approval Stage III patients Targeted Yes Yes, but must PFS and OS both positive Probably, but therapy establish whether longer term #vemurafenib this is best prior to or follow-up data #dabrafenib after immune therapy needed. #combination Carboplatin/ Yes No Unknown Unlikely paclitaxel DTIC/ Yes, but No Unknown Unlikely temozolomide more recent data less compelling DTIC, dacarbazine; FDA, US Food and Drug Administration; IFN, interferon; OS, overall survival; PD-1, programmed death 1; PEG-IFN, pegylated interferon; PFS, progression-free survival; RFS, relapse-free survival. Surgery for resectable melanoma locoregional disease eradication (Table 1). Surgery remains the most well established treat- Surgery alone for stage IV melanoma patients in ment for patients with melanoma up to stage III an era with few systemic options has been reported disease and may even be appropriate for selected to provide long-term survival in a substantial frac- patients with oligometastatic disease. No treat- tion of patients. Ollila reviewed the data from pre- ment presently available should replace surgical viously published single-institution series and resection as the first, curative-intent therapy for concluded that 5 year survival following resection 186 http://tam.sagepub.com KF Grossmann and K Margolin for stage IV melanoma could be achieved in subset from this series may turn out to be the last 5–38% of patients with skin, soft tissue and lymph and largest multicenter dataset available to inform node metastasis, 4.5–27% of patients with pul- understanding of the impact of surgery outside the monary metastasis, and 28-41% of patients with setting of modern effective systemic therapy. metastatic disease to the GI tract [Ollila, 2006]. Interpreting these data is difficult given the fol- Surgery as the first option for treatment of oligomet- lowing issues: (1) patient selection bias and for astatic melanoma is still worthy of consideration, the institutional variations in surgical procedures even with modern systemic therapies. In their review, and postsurgical surveillance methods and tim- Sondak and Gibney point out that the complete ing; (2) the lack of a method to control for non- response rate to surgery in stage IV cancer is 90% surgical treatments received prior to and after (the highest complete response rate in any stage IV surgery; and (3) no nonsurgical comparator series trial) [Sondak and Gibney, 2014]. However, the in which some patients were randomized to average PFS is only 5 months in the SWOG series, receive nonsurgical therapy, which in some eras which prospectively identified patients who on clini- could have ranged from best supportive care or cal grounds were felt most likely to achieve a status of single-agent chemotherapy to aggressive bio- NED following surgery. This observation was a fur- chemotherapy or high-dose IL-2, and in the pre- ther grim reminder that any pattern of metastasis in sent era could include any one or more of the stage IV melanoma patients is likely to be hematog- wide variety of systemic therapies detailed above. enously spread and rarely amenable to cure by resecting all detectable macroscopic metastases. The first efforts at controlling for at least some of these variables were demonstrated in the report of It seems likely that for those who have prolonged the multicenter controlled study SWOG 9430, in PFS following surgery, tumor biology is in their which 77 patients were entered prospectively and favor; they must have tumors that metastasize described in detail [Sosman et al. 2011]. Reported once, but do not maintain metastatic potential characteristics included presurgery performance beyond their final resting place. Debulking sur- status, use of systemic therapy and radiation, and gery may have OS impact but no PFS benefit if an standardized staging techniques. Patients enrolled alternate model of tumor spread is considered, in S9430 had a median OS of 21 months, and at i.e. metastasis begets more metastasis. In this 4 years, 31% of the patients were alive. These patient, removal of a perpetually seeding clone of results were achieved in a population which was tumor may offer long-term survival benefit. uniquely favorable in having predominantly non- visceral sites of metastasis (69%). Many scenarios now occur where front-line therapy for responding patients eradicates all but a few dis- Another retrospective study in the relatively recent ease sites. Furthermore, some patients experienced era reported the long-term survival of patients so-called mixed responses featuring different pro- originally participating in the Multicenter Sentinel gression in one or more sites while responding at all Lymph Node Trial-1, which randomized patients other sites of metastatic disease, making surgery to 3:2 to undergo sentinel lymph node biopsy or remove the resistant and relapsing clones an attrac- observation following primary melanoma excision tive option to consider. Proof of principle for this [Howard et al. 2012]. Among the 291 patients who practice may come from the data on longer term fol- relapsed at a distant site, approximately half (161) low up of completed [Koers et  al. 2013], ongoing, underwent surgical resection to no evidence of dis- and proposed neoadjuvant studies investigating ease (NED) status, with or without additional sys- modern systemic treatment where patients are temic therapy. This subset of patients enjoyed a resected to NED for advanced melanoma. Until significantly higher 4 year survival (21%) than these studies mature, surgery remains a highly valu- those who received only systemic therapy without able modality, although the precise clinical settings further surgery (7%). While the original study pop- in which oligometastatic disease should be consid- ulation had surgery in a prospectively randomized ered for resection remain without rigorous evidence- assignment, the decision to pursue surgery in this based guidelines. subsequent group of relapsers was based on oper- ability as well as a number of other clinical factors, Other important therapeutic considerations thus invalidating any direct comparison between and future directions the surgical and nonsurgical groups. However, the As our systemic therapies advance in their disease value of this report remains high since the surgical control rates, the late appearance of brain http://tam.sagepub.com 187 Therapeutic Advances in Medical Oncology 7(3) metastasis has become an increasing problem. treated with ipilimumab plus nivolumab [EudraCT Metastasis to the brain, and more rarely to the Number: 2012-004301-27]. leptomeninges, not uncommonly ends a remis- sion [Mitchell, 1989], and the biological mecha- Regarding the mechanisms for brain metastasis nisms for this CNS escape remain under control by agents not expected to cross the physi- investigation. Long-term survival for patients ologic blood–brain barrier, two principles are with brain metastasis is achievable but requires a likely at work. First, tumor directed lymphocytes multidisciplinary approach that may include radi- may transit from the circulation into the brain. ation (especially stereotactic forms of radiosur- Second, the blood–brain barrier may be focally gery) and surgery [Long and Margolin, 2013; disrupted at the site of the tumor, or be disrupted Ramakrishna and Margolin, 2013]. Although by the use of radiation allowing better access of many of the drugs and antibodies described in drugs into the brain–metastasis microenviron- this review may not cross an intact blood–brain ment. Better guidelines for managing this critical barrier with great efficiency, responses of mela- disease site require well-designed studies focused noma brain metastases have been reported with on patients with CNS disease. In addition to the both the BRAF inhibitors [Long et al. 2012] and encouraging results from the trials mentioned ipilimumab [Margolin et al. 2012] at frequencies above, several other studies are ongoing or in similar to their activity in extracranial disease. development that include further investigation of both the molecularly targeted agents and current For ipilimumab, several important studies are immunotherapeutic agents. reported: (1) an open-label phase II trial with two cohorts, one requiring steroids for symptom con- For treatment of patients who do not achieve trol (n = 21), the other not (n = 51); (2) a subset durable remission from any of the strategies out- analysis of the US expanded access study for lined earlier or from other investigational thera- patients with asymptomatic brain metastasis pies, it is unlikely that available, approved agents (n = 165) [Heller et  al. 2011]; and (3) a subset will provide long-term disease control. However, analysis of the Italian expanded access program one of the most promising strategies has been the for patients with asymptomatic brain metastasis use of adoptive cell therapies derived from tumor (n = 146) [Queirolo et  al. 2014]. For patients infiltrating lymphocytes (TIL), which have shown requiring no steroids at study entry, it is encour- gratifying activity in patients with melanoma aging to note that 1 and 2 year OS rates were 31% refractory to one or more of the standard or other and 26%, respectively. For patients on the US investigational therapies. Although this form of expanded access protocol, OS rate at 1 year was autologous adoptive T-cell therapy has been under 20%, which was similar to the Italian experience investigation since the 1980s [Lizee et  al. 2013; (1 year OS = 20%). Weber, 2014]), it was almost exclusively provided at the Surgery Branch of the US National Cancer Combining ipilimumab with drugs known to cross Institute and thus limited to a very small number the blood–brain barrier such as temozolomide of patients. However, improvements over the suc- [ClinicalTrials.gov identifier: NCT01119508; ceeding years and the recent development of simi- accrual complete, final results pending] or fotemus- lar programs at select other US centers (National tine [Di Giacomo et al. 2012] have also been stud- Institutes of Health, Moffitt and the MD ied in melanoma. Fotemustine plus ipilimumab Anderson Cancer Center),as well as in Israel and demonstrated a reasonable safety profile in the Denmark, have led to reports of objective 20-patient subset of the 86-patient Italian multi- responses in up to half of all patients receiving center trial NIBIT-M1, as well as showing at least treatment, and many of these responses are con- stable or reduced central nervous system (CNS) tinuing beyond one year of follow up [Weber, disease from baseline imaging (50%, 95% CI 27.2– 2014]. To take this technology to the next level 72.8) among 10 of the 20 patients with asympto- would require expansion of the treatment to more matic brain metastasis [Di Giacomo et  al. 2012]. investigative centers to perfect and extend the The ipilimumab and fotemustine combination is techniques or to utilize a commercial supplier for presently being further studied in a randomized TIL that are produced and quality controlled phase III trial for patients with brain metastasis centrally from a carefully handled portion of which was designed to compare fotemustine alone resected tumor and then shipped back to be with the combination of ipilimumab and fotemus- administered at a center closer to the patient’s tine, but has now added another treatment cohort home where the treating team has experience in 188 http://tam.sagepub.com KF Grossmann and K Margolin Atkins, M., Lotze, M., Dutcher, J., Fisher, R., Weiss, the management of high-dose chemotherapy, G., Margolin, K. et al. 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572284 TAM0010.1177/1758834015572284Therapeutic Advances in Medical OncologyKF Grossmann and K Margolin research-article2015 Therapeutic Advances in Medical Oncology Review Ther Adv Med Oncol Long-term survival as a treatment 2015, Vol. 7(3) 181 –191 DOI: 10.1177/ benchmark in melanoma: latest results and © The Author(s), 2015. Reprints and permissions: clinical implications http://www.sagepub.co.uk/ journalsPermissions.nav Kenneth F. Grossmann and Kim Margolin Abstract: Historically, stage III–IV melanoma patients have had few options to achieve long-term survival. For patients with stage III disease, surgery alone may be curative for approximately 50%. Adjuvant treatment with a slightly greater impact on relapse-free survival at the cost of substantial toxicity, and studies are ongoing to test the adjuvant benefit of other immunotherapies that appear more active and less toxic in advanced melanoma. Achieving long term survival for stage IV patients had been rare until recently and progress was painfully slow with traditional cytotoxic chemotherapy; review of multiple phase II studies showed universally poor results. Fortunately, since the approval by the US Food and Drug Administration of agents targeting the cytotoxic T lymphocyte antigen-4 (CTLA-4) receptor, as well as those targeting B-raf and mitogen-activated protein kinase kinase (MEK) in the mitogen-activated protein kinase (MAPK) pathway for patients whose melanoma is ‘driven’ by a BRAF mutation, long-term survival of stage IV melanoma is increasing substantially. Here we review the examples of studies documenting potentially curative approaches to melanoma and propose suggestions for the use of various treatments in achieving this important goal. Keywords: melanoma, immunotherapy, targeted therapy, b-raf, ipilimumab, nivolumab, pembrolizumab, vemurafenib, dabrafenib, trametinib Correspondence to: Historical background patients, but identifying patients prospectively for Kenneth F. Grossmann, Starting in the 1980s, highly selected patients enhanced surveillance based on risk factors with MD, PhD Division of Oncology, treated with high-dose interleukin-2 (IL-2) could the goal of early detection of metastatic lesions Department of Medicine, achieve durable remissions, and combinations of resectable for curative intent is another challenge University of Utah School of Medicine, Salt Lake City, IL-2, interferon-α (IFN-α) and cisplatin-based requiring further investigation. Furthermore, it Utah, USA combination chemotherapies showed high overall may eventually be possible to identify different kenneth.grossmann@hci. utah.edu response rates with some durable remissions markers of risk that lead to different approaches. Kim Margolin, MD [Atkins et  al. 1999; Bedikian et  al. 2008]. For example, frequent scanning to identify surgi- Division of Oncology, Unfortunately, the therapeutic index of both cally resectable disease versus the use of a circulat- Stanford University, Stanford, CA, USA approaches is poor, and in particular, biochemo- ing biomarker that identifies patients more likely therapy has proven less active than originally to benefit from adjuvant or systemic interventions reported [Atkins et  al. 2008]. While high-dose before the development of more overt signs of IL-2 is still used in some centers and current series metastatic disease. suggest selected clinical factors associated with more favorable outcomes [Payne et al. 2014], IL-2 as a single agent has for the most part been Adjuvant treatment may represent the best replaced by other forms of immunotherapy with a opportunity to cure patients after surgery more favorable therapeutic index. Multiple phase and to prevent morbidity from progression II studies have been conducted in search of other Following surgery for melanoma with a high risk active agents for melanoma during this era, but of relapse and death [many patients from stage produced disappointing results (Korn et al. 2008). IIB (>4 mm Breslow depth) and most from IIIA Surgery for oligometastatic stage IV disease does through IIIC], melanoma patients currently have provide durable disease control in a fraction of two treatment options approved by the US Food http://tam.sagepub.com 181 Therapeutic Advances in Medical Oncology 7(3) and Drug Administration: high-dose IFN-α With regard to which characteristics will identify (HDI) and pegylated IFN (PEG-IFN) (PEG- patients most likely to benefit from treatment, a IFN is approved for patients with nodal metasta- predictive biomarker is presently lacking for FDA sis only). The patterns of relapse in this population approved treatment options. High dose IFN-α is show that 51% of the relapses occur at distant the best studied treatment for patients with high sites [Romano et al. 2010], so treatment to delay risk resected melanoma with three completed relapse can be a significant benefit to patients, multicenter US intergroup trials: E 1684 even if the therapy does not increase long-term [Kirkwood et  al. 1996]; E1690 [Kirkwood et  al. overall survival (OS). Curing patients in this pop- 2000]; and E1694 [Kirkwood et al. 2001]. These ulation at high risk for relapse and death ideally studies showed a consistent benefit in relapse-free would require the pretreatment ability to identify survival (RFS), and two of the three studies which patients are destined for relapse (prognos- showed an OS benefit when compared with an tic information) and, among those at highest risk, inactive control (1684 versus observation, and who will benefit from a particular adjuvant inter- 1694 versus a ganglioside vaccine). Other dosing vention (predictive characteristics) which may regimens of IFN-α-2b have also been studied, relate to patient, tumor and therapy. and in a meta-analysis of data from over 10,000 patients who participated in studies of adjuvant To answer the first question, years of work have IFN-α with a ‘no treatment’ comparator cohort, a been devoted to evaluating clinical and pathologic RFS benefit [hazard ratio (HR) 0.83 (0.78–0.87)] risk factors related to the primary melanoma, and and OS benefit [HR 0.91 (0.85–0.97)] were the presence or absence of tumor in draining reported [Mocellin et al. 2013]. lymph nodes, which is the single most important determinant of survival. The current American Polyethylene glycol-conjugated PEG-IFN-α has Joint Committee on Cancer (AJCC) staging sys- also been studied in the adjuvant setting and tem recognizes the importance of ulceration of received FDA approval for stage III melanoma the primary tumor, mitotic rate, and the number following report of the European Organisation for and size of tumor bearing lymph nodes [Balch Research and Treatment of Cancer (EORTC) et al. 2009, 2010]. Further refinement of this sys- trial demonstrating a relapse free survival benefit tem is needed, because even with a full knowledge [HR = 0.82 (0.71–0.96) at 3.8 years follow up, of all of these factors, many patients defined as and HR = 0.87 (0.76–1.00) at 7.6 years follow high risk by AJCC criteria are likely cured by sur- up] without OS benefit [Eggermont et  al. 2008, gery and may be receiving adjuvant therapy for no 2012]. However, retrospective subset analysis benefit. revealed that patients who had ulcerated primary lesions and microscopic nodal disease derived the The potential for using molecular classifications to most benefit, including significantly improved define risk is best exemplified in uveal melanoma survival [Eggermont et  al. 2012], and a subse- based on gene expression profile data, where 459 quent study [ClinicalTrials.gov identifier: patients were followed prospectively after surgery. NCT01502696] was designed to confirm those Gene expression profiling segregated tumors into findings. Confirmation about whether ulceration class 1 with a very low 1.1% incidence of develop- is also useful as a predictive marker for high-dose ing distant metastasis at a mean follow up of IFN-α may come from the ongoing intergroup 18 months, compared with patients with a class study investigating IFN in comparison with ipili- 2 tumor who experienced a relapse rate of 25.9% mumab (E1609) [ClinicalTrials.gov identifier: over the same time interval [Onken et  al. 2012]. NCT01274338]. While retrospective subgroup Surveillance of these patients included blood test- analyses do not provide sufficiently robust data ing of liver functions every 6 months and liver for the identification of predictive biomarkers of imaging [usually computerized tomography (CT) benefit, they often provide hypothesis-generating with contrast] at 1 year intervals, but the contribu- data that can then be tested prospectively in con- tion of surveillance to OS is not clear, since ther- firmatory trials. apy for uveal melanoma with distant relapse has rarely been associated with prolonged survival. Other recent adjuvant trials for high risk mela- Several groups are further developing expression noma include the US cooperative group study of assays in cutaneous melanoma, which may soon biochemotherapy versus high-dose IFN-α prove to be useful tools in addition to the AJCC (S0008); an earlier US cooperative group trial risk stratification presently in use. (E4697) investigating the immunomodulatory 182 http://tam.sagepub.com KF Grossmann and K Margolin effects of granulocyte-monocyte colony-stimulat- Ipilimumab ing factor (GM-CSF); a melanoma antigen (gp- Ipilimumab is the first drug in the history of sys- 100)-derived peptide vaccine (this study included temic therapy for melanoma to demonstrate an patients with fully-resected oligometastatic mela- OS advantage in a randomized controlled trial in noma); and most recently, a placebo-controlled patients with metastatic melanoma [Hodi et  al. trial of a different melanoma antigen (MAGE-A3, 2010]. The toxicity of the drug, although signifi- GDK-2132231A) [ClinicalTrials.gov identifier: cant, has well-established management algo- NCT00796445]. The vaccine trials and the rithms, making it a generally safe and effective GM-CSF study have thus far failed to produce a front-line treatment for stage IV melanoma meaningful benefit. However, the biochemother- [Weber et  al. 2012]. Response rates to the drug apy study did show some intriguing results. have been modest (10–15%), but the achieve- Biochemotherapy was selected as a potentially ment of long-term progression-free survival better option for eradicating micrometastatic dis- (PFS) among patients whose best response is sta- ease owing to its higher response rate in stage IV ble disease rather than objective response has led cancer (30–50% versus 15% for HDI). The RFS to the concept of a ‘disease control rate’ based on advantage of 2 years median for biochemotherapy the sum of the rate of objective response plus sta- in comparison with HDI does corroborate that ble disease at the time of first post-therapy assess- extrapolation, but the lack of OS benefit similarly ment and beyond [Wolchok et  al. 2009]. mirrors the experience in advanced melanoma, Long-term follow-up data of the patients treated where the pooled data demonstrate that increas- in the phase II program of ipilimumab demon- ing the objective response rate fails to enhance strate that, in treatment-naïve patients treated survival [Atkins et al. 2008]. at the highest dose of ipilimumab (10 mg/kg), 37.7–49.5% of patients were living 4 years or The most recently reported data were from a longer [Wolchok et  al. 2013b]. Experience with global adjuvant trial of ipilimumab versus placebo the drug in 833 patients in the Italian expanded which remarkably mirrored the PEG-IFN-α data access program, which was less stringent in terms in demonstrating an overall RFS advantage and a of patient eligibility, showed that although the strong association of benefit with ulceration of the median PFS and OS were 3.7 and 7.2 months, primary melanoma [Eggermont et  al. 2014]. respectively [Ascierto et al. 2014b], a very encour- Further investigation of the immunologic corre- aging long RFS plateau around 20% was reported. lates of ulceration that explain this association This important benchmark appears to be a pla- with favorable adjuvant therapy outcomes may teau in the PFS curve, suggesting that patients lead to better patient selection for individual types who achieve PFS at the inflection point of 2.5–3.0 of adjuvant therapy and, importantly, for those years may not relapse and may effectively be who cannot benefit or who do not need adjuvant cured of their melanoma. While there remains a therapy. The potential for long-term OS benefit possibility that aftertherapies such as surgery for will also require both longer follow up and a care- residual oligometastases contributed to durable ful assessment of the effects of subsequent ther- control, the role of ipilimumab seems incontro- apy on patients who relapse. However, rapid vertible in the ultimate success of preventing these developments in the field of immune checkpoint patients’ death from advanced melanoma. blockade for melanoma have already permitted the development of the next important adjuvant Although clearly exciting, the low overall clinical trial, which will compare the PD-1 blocking anti- benefit rate and the notoriously slow or delayed body, pembrolizumab, with HDI for patients with regressions of metastatic melanoma in patients resected melanoma at high risk of relapse (S1404). treated with ipilumumab, together with the advent In parallel, the molecularly-targeted agents that of mutation-directed molecularly targeted agents, have shown important activity in advanced dis- have led to the development of combination regi- ease are also under evaluation in the adjuvant set- mens designed to exploit both immunologic and ting for patients with BRAF-mutated melanoma; molecularly directed mechanisms of antitumor due to their distinct mechanisms of action and activity. Unfortunately, the toxicity of ipilimumab toxicities, these agents are being compared to pla- has made it difficult to combine with the B-raf cebo rather than IFN (vemurafenib versus placebo inhibitor vemurafenib [Ribas et al. 2013] or with [ClinicalTrials.gov identifier: NCT01667418] the cytotoxic agent dacarbazine [Robert et  al. and dabrafenib plus trametinib versus placebo 2011]. In both cases, there was an increase in the [ClinicalTrials.gov identifier: NCT01682083]). frequency of high-grade hepatotoxicity, which is a http://tam.sagepub.com 183 Therapeutic Advances in Medical Oncology 7(3) very low frequency event with any of the single treatment, including the contribution of post pro- agents. Furthermore, the addition of dacarbazine gression therapies to long-term survival. did not appear to increase the activity of ipilumumab or downmodulate any of the other One concern about the use of single agent B-raf toxicities, making this an unattractive combina- blockade is the multitude of resistance mecha- tion. Combining molecularly targeted drugs with nisms that evolve on therapy [Bucheit and Davies, other immunomodulators for advanced disease 2014]. This leads to PFS times for vemurafenib continues to be an active area of investigation: and dabrafenib of approximately 6 months dabrafenib +/- trametinib plus ipilimumab [Chapman et  al. 2011; Hauschild et  al. 2012]. [ClinicalTrials.gov identifiers: NCT01767454, Combining B-raf and mitogen-activated protein NCT01940809, NCT02200562]; and vemu- kinase kinase (MEK) blockade, using the oral rafenib plus IL-2 [ClinicalTrials.gov identifiers: agent trametinib has led to improved PFS and OS NCT01683188, NCT01754376]. in a randomized trials; PFS 9.4 months with com- bination dabrafenib/trametinib, versus 5.8 months in the dabrafenib monotherapy group, and OS at Long-term survival on targeted therapy 12 months 72% combination versus 65% vemu- Approximately half of cutaneous melanomas rafenib alone (HR 0.69; 95% CI 0.53–0.89) (40–60%) harbor a B-raf mutation [Davies and [Flaherty et  al. 2012; Robert et  al. 2015a]). A Samuels, 2010]. In the first reports of clinical recently completed phase III placebo-controlled activity, response rates were impressive for both randomized trial also showed an improved PFS vemurafenib (FDA approved in 2011) [Flaherty (HR 0.75, p = 0.035) in favor of dabrafenib plus et al. 2010; Sosman et al. 2012], and dabrafenib trametinib in comparison with dabrafenib alone as (approved in 2013) [Ascierto et  al. 2013]. first-line therapy [Long et al. 2014]. The combina- Longer term follow-up data are maturing for tion of dabrafenib and trametinib were granted the randomized trial comparing vemurafenib accelerated approval for the use in patients with with dacarbazine in patients with unresectable advanced B-raf V600 mutated melanoma in stage IIIC or IV melanoma with a B-raf muta- January 2014. Similar results have been seen with tion. The first report of this trial showed signifi- vemurafenib and cobimetinib (a second MEK cant improvements for both OS and PFS inhibitor) combinations that have similar mecha- [Chapman et al. 2011]. Given the 44% crosso- nisms but a slightly different toxicity spectrum; ver from dacarbazine to vemurafenib, longer PFS 9.9 months combination versus 6.2 months term follow up was needed to estimate the vemurafenib; OS 9 month OS 81% versus 73% impact of this effect. Uncensored data show (HR = 0.65; 95% CI 0.42–1.00) [Larkin et  al. that the 18 month OS was 39% [95% confi- 2014]). There are also newer investigational agents dence interval (CI) 33–45] in the vemurafenib undergoing testing to overcome mechanisms of group and 34% (95% CI 29–40) in the dacar- resistance and the emergence of a successful regi- bazine group [McArthur et al. 2014]. Although men from these studies is likely to provide further the difference seen in this subset analysis small, survival benefits to selected patients. it is statistically significant (HR 0.76, 95% CI 0.63–0.93, p = 0.0068). PD-1 blockade This crossover impact suggests that patients can Patients treated with targeted drugs first, followed be rescued with highly active treatment following by immunotherapy upon disease progression, progression, but the lower OS associated with this appeared to benefit to a lesser extent and to experi- sequencing, together with the likely morbidity of ence greater toxicities than those receiving immu- progression events, toxicities and time to recover notherapy as their first treatment. The data from cytotoxic therapy before targeted therapy, demonstrating this phenomenon [Ackerman et  al. makes targeted therapy a better first choice in 2014; Ascierto et al. 2014a] may reflect a bias in the strategies to achieve long-term survival. What is assignment of patients with more aggressive disease very encouraging about the longer term follow up to initial targeted therapy due to its high response is that there appears to be a subset of patients who rate and rapid action. Immunotherapies that have are surviving out to 2 years (>20%). The charac- been available so far (high-dose IL-2 and ipilu- teristics of these long-term survivors are not mumab) benefit only a small fraction of patients known yet, but are under intense investigation and have a very unfavorable (IL-2) or moderately focused on characteristics of patient, tumor and unfavorable (ipilimumab) therapeutic index. 184 http://tam.sagepub.com KF Grossmann and K Margolin However, recent advances in the understanding year, while among the patients responding to of immune checkpoint blockade have led to the pembrolizumab, a median response duration had development of a class of fully human or human- not been reached at 11 months’ follow up. ized antibodies that interrupt a different, more Importantly, over half of the patients whose dis- tumor-specific checkpoint. So far, these agents, ease had progressed on prior ipilimumab experi- which block either programmed death-1 (PD-1) enced clinical benefit (objective response or mediated negative signaling on ‘exhausted’ T cells disease stabilization) with pembrolizumab (21/29 or its main ligand, PD-1 ligand (PD-L1) on tumor patients). Both reagents have similarly favorable and/or stroma, appear to have higher activity, toxicity profiles with <12% Gr3/4 adverse event lower toxicity and the potential for synergy with (AE) rates, which supports the safety and feasibil- cytotoxic T lymphocyte antigen-4 (CTLA4) ity of combining PD-1 blockade with other agents blocking antibodies. and suggests that these combinations will be safer and more effective than ipilimumab-based com- Nivolumab, targeting PD-1, has provided objec- binations. Results of combining ipilimumab with tive response rates of approximately 30% in stage nivolumab have shown high response rates (53%), IV melanoma [Topalian et  al. 2012]. When used but high-grade toxicities, generally inflammatory/ in the front-line setting, it has also shown an autoimmune in nature, have also emerged in improvement in OS in comparison with dacar- about half of the patients treated with the doses bazine in B-raf wildtype patients (HR 0.42, that provided the highest disease control rates p < 0.001) [Robert et al. 2015b]. A second PD-1 [Wolchok et  al. 2013a]. Longer follow up from antibody, pembrolizumab, has also shown similar large ongoing and other planned trials will better results with a response rate of 38% across all dose demonstrate the contribution of PD-1 blockade levels in a phase I study focusing on melanoma to long-term survival of melanoma patients and patients [Hamid et al. 2013]. It was data from this where this form of therapy best fits in the treat- large phase I study (n = 411) that led to the FDA ment algorithm. approval of pembrolizumab in patients with unre- sectable or metastatic melanoma and disease pro- gression following ipilimumab and, if B-raf V600 High-dose IL-2 mutation positive, a B-raf inhibitor. Recent High-dose IL-2 remains an important treatment updates have confirmed the response rate and option for patients with stage IV melanoma that durability of pembrolizumab with 1 year OS being has been available for many years to selected reached in 71% of all patients enrolled [Ribas patients at experienced centers. The most recently et  al. 2014]. Nivolumab shows similarly encour- published update on the activity of IL-2 from a aging longer term follow-up data with 2 and 3 multicenter experience showed that in melanoma, year OS rates of 48 and 41%, respectively [Hodi the response rate was about 16%, with long-term et  al. 2014]. Nivolumab was also granted FDA survival in approximately 10% of the patient popu- approval in December 2014 for the same indica- lation [Atkins et al. 1999]. Patients with melanoma tion as pembrolizumab (see above). and residual single lesions of unknown nature have often undergone excision, which may have contrib- In these landmark studies, the antitumor response uted to long-term RFS, and while a few patients also appears more quickly following initiation of relapse from radiologic complete response, there therapy than has been observed with CTLA4 are additional patients with radiologic partial blockade, which often takes 12–24 weeks before response who never relapse. A recently published tumor regression or confirmed stabilization is single institution experience with 314 melanoma achieved; furthermore some patients will experi- patients among the 500 total (the others had renal ence tumor progression prior to responding to clear cell cancer) reported 23% of patients alive at ipilimumab [Wolchok et  al. 2009] and only with least 5 years beyond treatment with high-dose IL-2 delayed follow up will demonstrate tumor regres- [Payne et al. 2014]. Unfortunately there is, to date, sion – a problem in both assessing the activity of no biomarker or group of parameters that can help the agent using traditional criteria and in the clin- to select patients for a higher therapeutic index ical management of such patients. With nivolumab (either more likely to benefit or less likely to experi- and pembrolizumab, most responses are apparent ence toxicities), although a recently completed 170 within 6–8 weeks, and most responding patients patient Cytokine Working Group protocol to iden- remain free of progression beyond 1 year; 13 of tify such factors is likely to provide important 18 responses to nivolumab were ongoing at 1 insights in 2015. http://tam.sagepub.com 185 Therapeutic Advances in Medical Oncology 7(3) Table 1. Update of current melanoma treatment options for adjuvant therapy and metastatic disease. Practice Trial design Endpoint RFS/PFS versus Capable of impacting consideration-control OS impacting long- arm term survival Adjuvant therapy High dose IFN Yes for Yes RFS and OS seen Yes stage III consistently in stage IIB–III PEG-IFN Yes for Yes RFS benefit maintains No stage III relevance considering prevention of morbidity from relapses in node positive patients Metastatic disease Ipilimumab Yes Yes, will be good Durable OS benefitPFS Yes control arm for benefit second line studies following approval of PD-1 High dose Yes Phase II combination Durable OS Yes IL-2 studies needed to benefitQuestionable PFS improve response benefit rate TIL (tumor Yes Not a good control PFS benefit modestDurable Single institution infiltrating arm, Further work OS benefit likely studies suggest lymphocytes) to decrease toxicity yes, accessibility necessary remains a problem PD-1 Yes Yes, should be new Significant PFS and OS Yes, significant, blockade control arm for benefit seen should become front line phase III the new standard trials for stage IV front-line therapy patients, and will for melanoma likely be impactful patients upon experimental arm in FDA approval Stage III patients Targeted Yes Yes, but must PFS and OS both positive Probably, but therapy establish whether longer term #vemurafenib this is best prior to or follow-up data #dabrafenib after immune therapy needed. #combination Carboplatin/ Yes No Unknown Unlikely paclitaxel DTIC/ Yes, but No Unknown Unlikely temozolomide more recent data less compelling DTIC, dacarbazine; FDA, US Food and Drug Administration; IFN, interferon; OS, overall survival; PD-1, programmed death 1; PEG-IFN, pegylated interferon; PFS, progression-free survival; RFS, relapse-free survival. Surgery for resectable melanoma locoregional disease eradication (Table 1). Surgery remains the most well established treat- Surgery alone for stage IV melanoma patients in ment for patients with melanoma up to stage III an era with few systemic options has been reported disease and may even be appropriate for selected to provide long-term survival in a substantial frac- patients with oligometastatic disease. No treat- tion of patients. Ollila reviewed the data from pre- ment presently available should replace surgical viously published single-institution series and resection as the first, curative-intent therapy for concluded that 5 year survival following resection 186 http://tam.sagepub.com KF Grossmann and K Margolin for stage IV melanoma could be achieved in subset from this series may turn out to be the last 5–38% of patients with skin, soft tissue and lymph and largest multicenter dataset available to inform node metastasis, 4.5–27% of patients with pul- understanding of the impact of surgery outside the monary metastasis, and 28-41% of patients with setting of modern effective systemic therapy. metastatic disease to the GI tract [Ollila, 2006]. Interpreting these data is difficult given the fol- Surgery as the first option for treatment of oligomet- lowing issues: (1) patient selection bias and for astatic melanoma is still worthy of consideration, the institutional variations in surgical procedures even with modern systemic therapies. In their review, and postsurgical surveillance methods and tim- Sondak and Gibney point out that the complete ing; (2) the lack of a method to control for non- response rate to surgery in stage IV cancer is 90% surgical treatments received prior to and after (the highest complete response rate in any stage IV surgery; and (3) no nonsurgical comparator series trial) [Sondak and Gibney, 2014]. However, the in which some patients were randomized to average PFS is only 5 months in the SWOG series, receive nonsurgical therapy, which in some eras which prospectively identified patients who on clini- could have ranged from best supportive care or cal grounds were felt most likely to achieve a status of single-agent chemotherapy to aggressive bio- NED following surgery. This observation was a fur- chemotherapy or high-dose IL-2, and in the pre- ther grim reminder that any pattern of metastasis in sent era could include any one or more of the stage IV melanoma patients is likely to be hematog- wide variety of systemic therapies detailed above. enously spread and rarely amenable to cure by resecting all detectable macroscopic metastases. The first efforts at controlling for at least some of these variables were demonstrated in the report of It seems likely that for those who have prolonged the multicenter controlled study SWOG 9430, in PFS following surgery, tumor biology is in their which 77 patients were entered prospectively and favor; they must have tumors that metastasize described in detail [Sosman et al. 2011]. Reported once, but do not maintain metastatic potential characteristics included presurgery performance beyond their final resting place. Debulking sur- status, use of systemic therapy and radiation, and gery may have OS impact but no PFS benefit if an standardized staging techniques. Patients enrolled alternate model of tumor spread is considered, in S9430 had a median OS of 21 months, and at i.e. metastasis begets more metastasis. In this 4 years, 31% of the patients were alive. These patient, removal of a perpetually seeding clone of results were achieved in a population which was tumor may offer long-term survival benefit. uniquely favorable in having predominantly non- visceral sites of metastasis (69%). Many scenarios now occur where front-line therapy for responding patients eradicates all but a few dis- Another retrospective study in the relatively recent ease sites. Furthermore, some patients experienced era reported the long-term survival of patients so-called mixed responses featuring different pro- originally participating in the Multicenter Sentinel gression in one or more sites while responding at all Lymph Node Trial-1, which randomized patients other sites of metastatic disease, making surgery to 3:2 to undergo sentinel lymph node biopsy or remove the resistant and relapsing clones an attrac- observation following primary melanoma excision tive option to consider. Proof of principle for this [Howard et al. 2012]. Among the 291 patients who practice may come from the data on longer term fol- relapsed at a distant site, approximately half (161) low up of completed [Koers et  al. 2013], ongoing, underwent surgical resection to no evidence of dis- and proposed neoadjuvant studies investigating ease (NED) status, with or without additional sys- modern systemic treatment where patients are temic therapy. This subset of patients enjoyed a resected to NED for advanced melanoma. Until significantly higher 4 year survival (21%) than these studies mature, surgery remains a highly valu- those who received only systemic therapy without able modality, although the precise clinical settings further surgery (7%). While the original study pop- in which oligometastatic disease should be consid- ulation had surgery in a prospectively randomized ered for resection remain without rigorous evidence- assignment, the decision to pursue surgery in this based guidelines. subsequent group of relapsers was based on oper- ability as well as a number of other clinical factors, Other important therapeutic considerations thus invalidating any direct comparison between and future directions the surgical and nonsurgical groups. However, the As our systemic therapies advance in their disease value of this report remains high since the surgical control rates, the late appearance of brain http://tam.sagepub.com 187 Therapeutic Advances in Medical Oncology 7(3) metastasis has become an increasing problem. treated with ipilimumab plus nivolumab [EudraCT Metastasis to the brain, and more rarely to the Number: 2012-004301-27]. leptomeninges, not uncommonly ends a remis- sion [Mitchell, 1989], and the biological mecha- Regarding the mechanisms for brain metastasis nisms for this CNS escape remain under control by agents not expected to cross the physi- investigation. Long-term survival for patients ologic blood–brain barrier, two principles are with brain metastasis is achievable but requires a likely at work. First, tumor directed lymphocytes multidisciplinary approach that may include radi- may transit from the circulation into the brain. ation (especially stereotactic forms of radiosur- Second, the blood–brain barrier may be focally gery) and surgery [Long and Margolin, 2013; disrupted at the site of the tumor, or be disrupted Ramakrishna and Margolin, 2013]. Although by the use of radiation allowing better access of many of the drugs and antibodies described in drugs into the brain–metastasis microenviron- this review may not cross an intact blood–brain ment. Better guidelines for managing this critical barrier with great efficiency, responses of mela- disease site require well-designed studies focused noma brain metastases have been reported with on patients with CNS disease. In addition to the both the BRAF inhibitors [Long et al. 2012] and encouraging results from the trials mentioned ipilimumab [Margolin et al. 2012] at frequencies above, several other studies are ongoing or in similar to their activity in extracranial disease. development that include further investigation of both the molecularly targeted agents and current For ipilimumab, several important studies are immunotherapeutic agents. reported: (1) an open-label phase II trial with two cohorts, one requiring steroids for symptom con- For treatment of patients who do not achieve trol (n = 21), the other not (n = 51); (2) a subset durable remission from any of the strategies out- analysis of the US expanded access study for lined earlier or from other investigational thera- patients with asymptomatic brain metastasis pies, it is unlikely that available, approved agents (n = 165) [Heller et  al. 2011]; and (3) a subset will provide long-term disease control. However, analysis of the Italian expanded access program one of the most promising strategies has been the for patients with asymptomatic brain metastasis use of adoptive cell therapies derived from tumor (n = 146) [Queirolo et  al. 2014]. For patients infiltrating lymphocytes (TIL), which have shown requiring no steroids at study entry, it is encour- gratifying activity in patients with melanoma aging to note that 1 and 2 year OS rates were 31% refractory to one or more of the standard or other and 26%, respectively. For patients on the US investigational therapies. Although this form of expanded access protocol, OS rate at 1 year was autologous adoptive T-cell therapy has been under 20%, which was similar to the Italian experience investigation since the 1980s [Lizee et  al. 2013; (1 year OS = 20%). Weber, 2014]), it was almost exclusively provided at the Surgery Branch of the US National Cancer Combining ipilimumab with drugs known to cross Institute and thus limited to a very small number the blood–brain barrier such as temozolomide of patients. However, improvements over the suc- [ClinicalTrials.gov identifier: NCT01119508; ceeding years and the recent development of simi- accrual complete, final results pending] or fotemus- lar programs at select other US centers (National tine [Di Giacomo et al. 2012] have also been stud- Institutes of Health, Moffitt and the MD ied in melanoma. Fotemustine plus ipilimumab Anderson Cancer Center),as well as in Israel and demonstrated a reasonable safety profile in the Denmark, have led to reports of objective 20-patient subset of the 86-patient Italian multi- responses in up to half of all patients receiving center trial NIBIT-M1, as well as showing at least treatment, and many of these responses are con- stable or reduced central nervous system (CNS) tinuing beyond one year of follow up [Weber, disease from baseline imaging (50%, 95% CI 27.2– 2014]. To take this technology to the next level 72.8) among 10 of the 20 patients with asympto- would require expansion of the treatment to more matic brain metastasis [Di Giacomo et  al. 2012]. investigative centers to perfect and extend the The ipilimumab and fotemustine combination is techniques or to utilize a commercial supplier for presently being further studied in a randomized TIL that are produced and quality controlled phase III trial for patients with brain metastasis centrally from a carefully handled portion of which was designed to compare fotemustine alone resected tumor and then shipped back to be with the combination of ipilimumab and fotemus- administered at a center closer to the patient’s tine, but has now added another treatment cohort home where the treating team has experience in 188 http://tam.sagepub.com KF Grossmann and K Margolin Atkins, M., Lotze, M., Dutcher, J., Fisher, R., Weiss, the management of high-dose chemotherapy, G., Margolin, K. et al. 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Journal

Therapeutic Advances in Medical OncologySAGE

Published: Feb 24, 2015

Keywords: melanoma; immunotherapy; targeted therapy; b-raf; ipilimumab; nivolumab; pembrolizumab; vemurafenib; dabrafenib; trametinib

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