American Journal of Clinical Oncology:
Melanoma: From Darkness to Promise
Blesa, Joan Manel Gasent MD, PhD*; Pulido, Enrique Grande MD†; Candel, Vicente Alberola MD, PhD‡; Pulla, Mariano Provencio MD, PhD§
From the *Medical Oncology Service, Hospital Marina Alta de Dénia, Alacant, Spain; †Medical Oncology Department, Hospital Ramón y Cajal, Madrid, Spain; ‡Medical Oncology Service, Hospital Arnau de Vilanova, València, Spain; and §Medical Oncology Service, Hospital Puerta de Hierro, Madrid, Spain.
Reprints: Joan Manel Gasent Blesa, MD, PhD, Medical Oncology Department, Hospital de Denia, Marina Salud, Partidade Beniadlas/n03700, Denia, Alacant, Spain. E-mail: firstname.lastname@example.org.
Metastatic melanoma is one of the most resistant tumors to standard chemotherapy approaches. The median overall survival of patients diagnosed with metastatic melanoma is lower than 9 months. Current approved treatments offer only marginal survival advantages. New immunotherapeutic targets have appeared recently trying to modulate the host immune response against the tumor. New targeted agents have changed the standard of care of other solid tumor types like breast cancer. Here, we discuss the new advances and achievements in the treatment of this highly resistant disease.
Metastatic melanoma is highly resistant to chemotherapy, radiation therapy, hormonal therapy, and current immunotherapeutic approaches. There are several promising phase II studies suggesting long-term benefits with immunotherapeutic approaches like interleukin 2 (IL-2), bevazicumab, everolimus ipilimumab or tremelimumab; however, no large-scale phase III randomized trial has demonstrated any superiority versus chemotherapy alone as of yet.
Here we will review the current data regarding the agents most use, as well as the promising data derived from the new targeted therapies and new immunotherapeutic agents under clinical development.
SINGLE AGENT THERAPY
Dacarbazine and Temozolomide
Single-agent chemotherapy produces objective response rates of less than 20%. However, a small subset of patients, mainly those with metastases to the lungs, good performance status, and normal blood lactate dehydrogenase enzyme levels, can achieve long-term disease control with a good quality of life, and some of them may even achieve a complete remission, with potential to cure.1
Dacarbazine (DTIC) induces response rates ranging from 15% to 25% in single-institution trials with median response durations of 5 to 6 months, but less than 5% of these responses are complete in historical series.2
Long-term follow-up of patients treated with DTIC alone shows that less than 2% can be expected to survive for 6 years. In modern designed phase III trials that used strict response assessment criteria, the response rates with DTIC did not exceed 12%.3–5 It has been demonstrated that single doses of DTIC (850–1000 mg/m2) are well tolerated, and should be the reference standard for randomized trials comparing new therapies with DTIC.6
DTIC remains the only cytotoxic drug approved by the US Food and Drug Administration for the treatment of metastatic melanoma. Despite its low single-agent activity, it has remained the basis for many combination chemotherapy regimens.
A DTIC related agent is temozolomide (TMZ), an oral formulation prodrug of DTIC with demonstrated improved brain penetration. Based on this, TMZ may represent a viable alternative to DTIC, which is ineffective against central nervous system metastases.7
Single-agent activity of TMZ in metastatic melanoma has been detected in phase I/II studies.8 In a randomized trial conducted on 305 patients with advanced melanoma, TMZ showed equivalence to DTIC in terms of objective response rate, time to progression, disease-free survival and overall survival (OS).4 The median survival was 7.7 months for patients who received TMZ and 6.4 months for patients who received DTIC. The median progression-free survival (PFS) was 1.9 months in the TMZ-treated group and 1.5 months in the DTIC-treated group. Overall, TMZ had a good tolerance, and appeared to have advantages in terms of improved quality of life. This trial excluded patients who had brain metastases. The Food and Drug Administration did not accept the results of this trial for approving a melanoma indication for TMZ, because the trial design was intended to demonstrate the superiority of TMZ over DTIC, not its equivalence.
It has been suggested that the administration of TMZ in multiple doses per day or as a prolonged daily administration may overcome some chemotherapy drug-resistance mechanisms. The rationale for the use of these doses of TMZ is based on an evaluation of recent data on the drug's mechanism of action. Five-(3-methyltriazen-1-year) imidazole-4-carboximide, which is the active metabolite of DTIC and the end product of spontaneous metabolism of TMZ, methylates guanine residues in DNA at the O6 position.9 Increased levels of O6-alkylguanine-DNA alkyltransferase (ATase) are associated with resistance to agents that produce O6 methylation (DTIC, TMZ, and nitrosoureas). Administration of TMZ results in decreased ATase activity within 4 hours of an oral dose that persists in peripheral blood mononuclear cells for at least 24 hours.9 Daily administration resulted in the progressive depletion of ATase activity over the 5 days of treatment. Thus, on each day of treatment, there is increased sensitivity to the cytotoxic effects of TMZ resulting from the decrease in ATase activity induced by the prior day's chemotherapy. Currently, there is an ongoing trial conducted by the European Organization for Research and Treatment of Cancer comparing DTIC with prolonged daily administration of TMZ. The extended dose of TMZ (75 mg/m2 per day) administered for 6 weeks followed by a 2-week rest is well tolerated and may be used in patients who have a borderline performance status. Other agents that lower ATase are Lomeguatrib (Patrin, PM), which is an orally bioavailable, highly potent O6-MeG analog and poly polymerase inhibitor that is well tolerated as a singe agent.10,11
Nitrosoureas induce objective responses ranging from 13% to 18% of patients. It is supposed that these drugs cross the blood-brain barrier. However, when given at conventional doses, little or no activity was observed against melanoma brain metastases.12 Furthermore, nitrosoureas induce prolonged myelosuppression. Despite this, they have frequently been included in multiagent chemotherapy regimens, presumably because of their ability to penetrate into the central nervous system. Fotemustine is probably the most active nitrosourea in metastatic melanoma. It has been tested in 5 phase II trials on 351 patients with response rates of 20% to 25% and complete response rates of 5% to 8%.13–15 Fotemustine was the first drug to show significant efficacy in brain metastases. In the first published phase II trial, 169 patients with histologic evidence of disseminated malignant melanoma, including patients with cerebral metastases, were treated with a regimen based on 100 mg/m2 1 hour IV infusion every week for 3 consecutive weeks, followed by a 4- to 5-week rest period (induction therapy) of fotemustine. One hundred fifty-three patients were evaluable for response. Three complete responses and 34 partial responses were observed, leading to an objective response rate of 24.2% (95% confidence interval: 17.4%–31.0%). Responses were also documented on cerebral (25.0%), visceral (19.2%), or nonvisceral (31.8%) metastatic sites. The median duration of response was 22 weeks (range, 7–80 weeks). The objective response rate in previously untreated patients was 30.7% (19 of the 62 patients). The main toxicity was hematologic with delayed and reversible leukopenia and/or thrombopenia.13
Cisplatin as a single-agent therapy has induced a 15% response rate with a median duration of 3 months.16 Doses up to 150 mg/m2 in combination with amifostine produced tumor responses in 53% of patients.17 Some of the responses were complete, and the median response duration was 4 months.18
A response rate of 19% was reported in 26 chemotherapy-naive patients with metastatic melanoma who received carboplatin. In those patients, there were 5 partial responses, and thrombocytopenia was the dose-limiting toxicity.19
In vitro studies have suggested that oxaliplatin can be more active than cisplatin or carboplatin in the treatment of melanoma, but oxaliplatin has yet to be tested extensively in patients with melanoma.20 A small phase II trial in 10 patients who had received and failed before chemotherapy did not show any objective responses.21
Vinca Alkaloids and Taxanes
Vinca alkaloids, particularly vindesine and vinblastine, have been studied, and responses were found in approximately 14% of patients.22 Taxanes have produced responses ranging from 16 to 17% of patients.23–25
A potentially active new drug is ABI-007 (abraxane), which is an albumin-bound nanoparticle formulation of paclitaxel with an improved therapeutic index. It has been tested in a phase II trial in 37 previously treated and chemotherapy-naive patients with metastatic melanoma and showed an overall response rate (ORR) of around 30%. ABI-007 will be explored in a randomized phase III trial.26
Single-agent chemotherapy regimens have demonstrated only modest activity in the treatment of metastatic melanoma. Many combination regimens have been tested in clinical trials with a view to improving these results.
Initially, 2-agent combinations were used. DTIC was combined with either a nitrosourea, a vinca alkaloid, or a platinum compound. In the majority of those trials, response rates ranging from 10% to 20% were observed, and there was low evidence to suggest superiority to single-agent DTIC.27–31
After those disappointing results, trials with more aggressive, multiagent regimens were conducted. Phase II studies of 3- and 4-drug combinations generally produced response rates that ranged from 30% to 50% in single-institution studies.
The 4-drug combination, named the Dartmouth regimen, based on cisplatin, DTIC, carmustine, and tamoxifen (CBDT), produced responses in 46% of 141 patients (16 complete responses and 49 partial responses). The median response duration was 7 months.32 The authors suggested that the inclusion of tamoxifen was essential, with only 10% of response rates for the 3 cytotoxic drugs in the same doses when tamoxifen was omitted.33
A randomized phase III trial conducted by the National Cancer Institute of Canada that compared cisplatin, DTIC, carmustine, and tamoxifen (CDBT) with cisplatin, DTIC, and carmustine (CDB) produced a response rate of 30% for the CDBT arm compared with 21% for the CDB arm (P = 0.187). Six percent of the patients who received Tamoxifen achieved a complete response, compared with 3% of the patients who did not receive Tamoxifen, although this difference was not statistically significant (P = 0.33).
In this study, more patients in the tamoxifen group achieved a partial remission (27% vs. 14%). This difference was of borderline significance (P = 0.05). Gender did not seem to be a predictive factor of response. The response rate and the median survival for women in the tamoxifen group did not differ statistically compared with those for women in the chemotherapy-alone group. Similarly, there was no difference between men in the treatment groups. PFS and OS did not differ significantly between the 2 arms (P = 0.86 and P = 0.52).34 In another randomized phase III trial, the CDBT combination was compared with single-agent DTIC. Two hundred forty patients were recruited for this trial. The response rate was 10.2% for the DTIC regimen compared with 18.5% for the CDBT regimen (P = 0.09). The median survival was 7 months, with no significant difference between the 2 treatment arms. Toxicity was substantially greater for the combination regimen than with DTIC.35
The 3-drug combination, cisplatin, vinblastine, and dacarbazine (CVD) was developed by Legha et al at M.D. Anderson Cancer Center and induced responses in 40% of 50 evaluable patients in a phase II trial. Complete response rate was achieved in the 4% of the patients with a median duration of response of 9 months.36 Nevertheless, in a randomized trial comparing CVD with single-agent DTIC, the CVD arm produced a 19% response rate compared with 14% for the DTIC arm, and there were no differences in either response duration or survival.37
A very small phase II trial of carboplatin and paclitaxel as a first line therapy published in 2002 reported 20% partial response and 47% stable disease,38 while a randomized phase II study of weekly paclitaxel versus carboplatin and paclitaxel as a second line therapy in 2003 produced an ORR of less than 10% in both arms.39 In this regard, Rao et al40 recently added a retrospective review of 31 pretreated patients to the carboplatin and paclitaxel literature documenting a 26% ORR. An Eastern Cooperative Oncology Group (ECOG) phase III trial of carboplatin and paclitaxel with and without sorafenib is ongoing.
COMBINATIONS OF CHEMOTHERAPY WITH IMMUNOMODULATORY OR HORMONAL AGENTS
Tamoxifen and Interferon α
Combinations of cytotoxic drugs that have minimal efficacy with immunomodulatory or hormonal agents have been investigated. The results of adding tamoxifen to CDB chemotherapy were discussed above; however, tamoxifen also has been added to single-agent DTIC in several studies. Results from a small, randomized trial of DTIC with or without tamoxifen indicated that combination therapy may be more effective.41 A response rate of 28% and a median survival of 41 weeks were reported for patients who received DTIC plus tamoxifen compared with a response rate of only 12% and a median survival of 23 weeks for patients who received DTIC alone.
Similar results were reported with the combination of DTIC plus interferon α (IFN-α). In a small, randomized trial that compared DTIC with or without IFN-α2b, the combination therapy produced 12 complete responses and 4 partial responses in 30 patients compared with only 2 complete responses and 4 partial responses among 30 patients who received DTIC.42 The median response and survival were prolonged significantly for the DTIC plus IFN-α2b arm in that trial. To further evaluate the potential benefits of combining DTIC with either tamoxifen or IFN-α, or both, the ECOG conducted a 4-arm, 2 × 2, design, phase III trial that failed to confirm the initial results (ECOG 3690).3 The ORR in that trial was 18%, and the median time to treatment failure was 2.6 months. The median survival was identical (9.1 months) for all 4 arms tested. In that trial, there was no advantage in terms of response or survival with the addition of IFN-α2b, tamoxifen, or both agents to DTIC.
In a recent meta-analysis of 6 published, randomized trials involving a total of 912 patients who were randomized to receive either chemotherapy or biochemotherapy with or without tamoxifen, no improvements in the rates of overall response, complete response, or survival were demonstrated.43
The combination of TMZ plus thalidomide is one of the most promising of those reported thus far. Thalidomide is an antiangiogenic agent with immune modulatory properties. An ORR of 32% was reported in a phase II study in 38 patients44 without brain metastasis and a 15% ORR in 60 patients in a phase II trial including patients with brain metastasis.45 The overall objective response rate of 32% was higher than that achieved with TMZ alone. One patient presented deep vein thrombosis and no thrombotic events were reported in the second one.
In a more recent trial, 26 patients with brain metastasis achieved an objective response rate of 11% in the brain lesions.46 However, the combination of TMZ plus thalidomide should not be accepted as a standard therapy until and unless it demonstrates superiority in phase III trials or at least until the high response rate can be confirmed in larger, multi-institutional phase II trials using strict response assessment criteria. In addition, it should be noted that, in a phase II study of TMZ, thalidomide, and whole-brain radiation therapy in patients with brain metastases from melanoma that was conducted by the Cytokine Working Group in 40 patients, no patient exhibited a systemic response.47
In the last decade, several trials have evaluated the role of combination chemotherapy with other agents, such as IFN-α and IL-2. Many investigators have combined IL-2 with both IFN-α and chemotherapy in an attempt to improve both the response rate and the percentage of durable complete remissions. A large body of data exists signifying that such biochemotherapy combinations can produce response rates ranging from 40% to 60%, with a complete response rate of approximately 10%.48–50 Durable remissions exceeding 5 years were achieved by approximately 5% to 10% of patients. Recurrences beyond the 2-year time point were uncommon, thus suggesting that those patients who exhibited durable responses may have achieved a cure.50,51 However, many of the most active biochemotherapy regimens are associated with moderate to severe toxicity, which has limited their broader use and acceptance.
Many trials have been performed in an attempt to identify biochemotherapy regimens that may be administered in an outpatient setting, with less toxicity, and using lower doses of intravenous or subcutaneous IL-2.52 Unfortunately, biochemotherapy regimens that involved low-dose, subcutaneous IL-2 administration appeared to produce lower response rates than were observed generally with regimens involving intravenous IL-2.52
Two meta-analyses of patients with metastatic melanoma who were included in studies with various combinations of chemotherapy, biotherapy, or biochemotherapy demonstrated an improvement in response rates, but not in survival, with the use of biochemotherapy. In a report by Keilholz et al,52 patients with metastatic melanoma who were treated with IL-2/IFN-α/chemotherapy, IL-2/IFN-α without chemotherapy, and IL-2/chemotherapy without IFN-α regimens, had response rates of 45%, 21%, and 15%, respectively. However, in this trial, survival did not differ significantly between the groups (10.5 months), with 20% and 10% survival rates at 2 years and 5 years, respectively that did not differ among the groups. In a second meta-analysis of combined studies that involved 7711 patients with advanced melanoma from 168 published trials, treatment with an IL-2/IFN-α/chemotherapy combination resulted in a significantly improved response rate compared with treatment that used chemotherapy or IL-2-based biotherapy.53
Different prospective, randomized studies in the United States and Europe evaluated aggressive biochemotherapeutic regimens that contained IL-2 and IFN-α.
In a prospective European trial, 138 patients with metastatic melanoma were randomized to receive IFN and decreasing doses of IL-2 with or without cisplatin.54 The results demonstrated a significant increase in the response rate (from 18% to 33%) in the group that received biochemotherapy compared with the group that received biotherapy, and an increase in PFS from 53 days to 92 days without any statistical differences in terms of survival.
A second trial by the European Organization for Research and Treatment of Cancer involving 363 patients evaluated cisplatin, DTIC, and IFN-α with or without IL-2.53 No statistical improvement in response rate was shown with the addition of IL-2 (22.8% vs. 20.8%, respectively) and in PFS (median 3.0 months vs. 3.9 months, respectively). The median survival was 9 months in both arms, and the 2-year survival rate was 12.9% and 17.6%, respectively (P = 0.32).
Another study that was conducted by Rosenberg and his colleagues55 at the National Cancer Institute-Surgery Branch randomized 102 patients with stage IV melanoma to receive either chemotherapy (DTIC, cisplatin, and tamoxifen) or biochemotherapy (IL-2, IFN-α, DTIC, cisplatin, and tamoxifen). Although the response rate in the biochemotherapy arm (44%) was almost twice that obtained in the chemotherapy arm (27%), the difference was not statistically significant (P = 0.07). Furthermore, there was a survival advantage in the chemotherapy arm compared with the biochemotherapy arm (median survival 5.8 months in the biochemotherapy arm vs. 10.7 months in the chemotherapy arm; P = 0.05). One of the reasons for this survival finding may be due to the administration of high-dose IL-2 as salvage therapy to a significant proportion of the patients who failed to respond to chemotherapy alone.
A large-scale phase III trial that enrolled 482 patients and compared CVD chemotherapy with CVD plus intravenous IL-2 and subcutaneous IFN-α was the ECOG E3695. Important aspects of the E3695 protocol were that it was large enough to distinguish clinically meaningful differences in survival and durable responses, and that it involved a population with a relatively large percentage of patients who had prior IFN exposure in the adjuvant setting. There were no statistically significant differences between the chemotherapy and biochemotherapy arms in response rate, PFS, OS. It should be noted that there were many inevaluable patients, many patients were not treated according to the protocol, and more patients were randomized to the biochemotherapy arm.56 Nonetheless, the conclusion from this and all randomized biochemotherapy trials performed to date was that biochemotherapy should not be used routinely outside of a clinical trial.
The study conducted by Eton et al comparing CVD versus CVD plus intravenous IL-2 and subcutaneous IFN-α in 183 evaluable patients was the only one that showed a statistically significant advantage of biochemotherapy over chemotherapy alone in terms of response rate (48% vs. 25%, respectively), complete response rate (7% vs. 2%, respectively), and median time to recurrence (4.9 vs. 2.4 months). A modest but statistically significant increase in median OS (11.9 vs. 9.2 months, respectively) was also observed.57
More recently the E369558 published its phase II trial comparing chemotherapy with CVD versus CVD concurrent with IL-2 and interferon alfa-2b (BCT every 21 days, for a maximum of 4, in 415 enrolled patients, with 395 patients assessable. The response rate was 19.5% for BCT and 13.8% for CVD, non significant. Median PFS was significantly longer for BCT than for CVD (4.8 vs. 2.9 months (P = 0.015), although this did not translate into an advantage in either median OS (9.0 vs. 8.7 months) or the percentage of patients alive at 1 year (41% vs. 36.9%). The side effects were also more relevant in the biochemotherapy group.
Granulocyte-Macrophage Colony-Stimulating Factor
A phase I study to investigate the feasibility and safety of immunoembolization with granulocyte-macrophage colony-stimulating factor (GM-CSF; sargramostim) for malignant liver tumors, predominantly hepatic metastases from patients with primary uveal melanoma, was published by the group of Sato et al.59 This group treated a total of 39 patients with surgically unresectable malignant liver tumors, including 34 patients with primary uveal melanoma. Hepatic artery embolization accompanied an infusion of dose-escalated GM-CSF given every 4 weeks.
The maximum tolerated dose was not reached up to the dose level of 2000 μg, and there were no treatment-related deaths.
Thirty-one assessable patients with uveal melanoma were included. Of these patients, 2 complete responses were observed, 8 partial responses, and 10 stable diseases in their hepatic metastases. The median OS of intent-to-treat patients who had metastatic uveal melanoma was 14.4 months. The multivariate analyses indicated that female sex, high doses of GM-CSF (≥1500 μg), and regression of hepatic metastases were correlated to longer OS. Moreover, high doses of GM-CSF were associated with prolonged PFS in extrahepatic sites.
COMBINATIONS OF CHEMOTHERAPY WITH TARGETED THERAPIES
The intrinsic resistance of melanoma to conventional chemotherapy has led investigators to evaluate new approaches such as protein kinase inhibitors (eg, sorafenib), agents that act on cytotoxic T-lymphocyte antigen 4 (CTLA-4) or on apoptotic mechanisms (eg, oblimersen sodium; previously referred to as G3139), and antiangiogenic agents (eg, bevacizumab, axitinib, MEDI-522, PI-88).
Sorafenib Plus Chemotherapy
Sorafenib targets the adenosine triphosphate-binding site of the BRAF kinase and inhibits both wild-type and mutant BRAF in vitro. In addition, the spectrum of kinases inhibited by sorafenib includes RAF proto-oncogene serine/threonine-protein kinase (CRAF), vascular endothelial growth factor receptor 2, platelet-derived growth factor receptor β, flt-3, and c-kit.60 Preclinical studies demonstrated a significant retardation in the growth of human melanoma tumor xenografts with sorafenib.61 In a phase I study, the maximum tolerated dose of sorafenib as a single agent was established at 400 mg twice daily, and the most common toxicities were gastrointestinal (mainly diarrhea), dermatologic (skin rash, hand-foot syndrome), and fatigue.62 In a phase II trial involving 20 patients with refractory metastatic melanoma, sorafenib showed modest activity, with 1 partial response and 3 patients who achieved stable disease.63 In another phase II, randomized, discontinuation trial, no objective responses were reported, and 19% of patients achieved stable disease.64 However, in a phase I/II study that combined carboplatin and paclitaxel with escalating doses of sorafenib in 35 patients, a promising response rate of 31% was observed, and another 54% of patients experienced stable disease that lasted more than 3 months.65 This study was recently updated to include 105 patients, and the current response rate is 27%. It is noteworthy that responses to sorafenib have not been correlated to date with BRAF mutation status.66 Responses were observed in previously treated patients and in at least 1 patient with a noncutaneous primary melanoma.
Two phase III trials have been launched to assess the efficacy of carboplatin and paclitaxel plus sorafenib versus placebo in chemotherapy-naive patients, sponsored by the ECOG 2603 and in previously treated patients. Relatively little is known about the inherent activity of carboplatin and paclitaxel as systemic therapy for patients with stage IV melanoma, particularly at the doses employed in the phase II trial and, now, in the phase III trial.
The ECOG 2603 communicated that, after the randomization of 800 patients, it would not meet the primary end point of improved OS.
In a report on previously treated patients, no responses were observed among 19 patients who received the 2-drug combination,41 whereas a second trial in chemotherapy-naive patients resulted in 3 partial responders and 7 patients with stable disease among 15 evaluable patients.40 Thus, it is likely that the combination of carboplatin and paclitaxel, by itself, has inherent activity in metastatic melanoma. The results of the phase III trials will define the real impact of adding sorafenib to this regimen in patients with metastatic melanoma.
A randomized phase II trial of 2 schedules of TMZ plus sorafenib is also underway, and the preliminary results have been considered encouraging.66
Heat Shock Protein HSCC-96 STA 4783 and Elescomol
An alternative approach to improve the response to chemotherapy is to up-regulate the production of HSPs with the administration of STA—4783 or Elescomol an inducer of HSP70 is a bis-thiobenzoylhydrazide compound. S leads to up-regulation of HSP70 in tumor cell lines. Xenograft models of solid tumors showed synergistic antitumor activity in combination with paclitaxel. Berkenblit et al,67 used Elescomol in a cohort of patients with refractory metastatic solid tumors. The combination of Elesomol with Paclitaxel, did not affect the esperated toxicity with the use of paclitaxel in monotherapy and 2 partial responses were achieved.
A randomized phase II trial in patients with metastatic melanoma, presented in 200768 suggested that the combination prolonged PFS, the primary end point of the study. In this study the median PFS was established in 3.68 months, and in 8.28 months for chemonaive patients. Adverse effects were low, and led to treatment discontinuation for the 10% of patients treated with paclitaxel plus elescomol, and in 14% of patients with paclitaxel monotherapy.
A confirmatory phase III trial of paclitaxel plus elesclomol versus paclitaxel plus placebo has been initiated.
Twenty-six patients were enrolled in a multicenter phase II trial of another oral kinase inhibitor, imatinib.69 No objective clinical responses were noted among the 25 evaluable patients. The median time to progression was 54 days and the median OS was 200 days. No patient was free of disease progression at 6 months. The immunostaining of the tumors described 3 tumors with moderate and 5 tumors with weak staining for c-kit.
Anti-CTLA-4 Antibodies and Chemotherapy
Two human anti-CTLA-4 monoclonal antibodies have been tested in clinical trials: ipilimumab (formerly MDX-010) and tremelimumab (formerly CP-675,206). Responses have been observed with both antibodies administered as single-agent therapy in patients with metastatic melanoma,70,71 providing a rationale for combinations with chemotherapy. In a phase II study, the activity of ipilimumab alone or in combination with DTIC was assessed. There were 2 partial responses in the antibody alone arm and 1 complete response and 4 partial responses in the antibody plus DTIC arm, suggesting more activity for the combination.72 In the long-term follow-up of this study, 1 additional complete response was observed in the combination arm, and durable clinical responses were noted.73 These results are intriguing, but it remains unclear whether the activity of the combination is simply additive or truly synergistic, and further study is probably warranted in preclinical models.
Data from a phase I/II study (MDX010–15), in 88 metastatic melanoma patients, that received ipilimumab, were communicated during the 44th American Society of Clinical Oncology by the group of Weber et al.74 This trial reported a complete response, 3 partial responses and 20 stabilizations in 88 r. The patients with responses or stabilizations, presented with immune related adverse effects, like pruritus, diarrhea, or colitis. In 27 patients these adverse effects were considered severe.
The most relevant published studies about the use of ipilimumab in the treatment of metastatic melanoma have been the 008,75 022,76 and 007.77 These studies treated patients with 10 mg/kg of ipilimumab (induction and maintenance) and show a consistent 1-year survival rate between 47% and 51%. Patients progressing just after finishing the treatment (study 008) had a 1-year survival rate of 47%. The 022 study, recruited previously treated patients, patients that relapsed or did not respond to experimental treatment, or patients who were not tolerating current standard therapies, observed a 48% of 1-year survival. The 007 study reported a 51% 1-year survival in patients treated previously with therapy other than ipilimumab (Study 007).
The follow-up for survival was up to 24.8, 21.88, and 26.32 months in studies 008, 022 and 007, respectively.
Safety results from the 3 studies were consistent with previously reported clinical trials of ipilimumab. The most common immune-related adverse events were rash, diarrhea, and hepatitis. Grade 3 and 4 immune-related adverse event rates occurred in approximately 20% to 28% and 0% to 12% of the patients, respectively, in patients who received 10 mg/kg of ipilimumab. Adverse events were generally manageable and reversible within days or weeks with the use of supportive care and systemic steroids using established treatment guidelines in the majority of patients.
Additional data on efficacy and survival with an active control group will come from an ongoing phase III, randomized, double-blind study (024) assessing ipilimumab (10 mg/kg) in combination with DTIC versus DTIC alone in patients with untreated unresectable stage III or stage IV metastatic melanoma. A phase III study (029) of ipilimumab administered as adjuvant therapy in patients with high-risk stage III metastatic melanoma is also currently being conducted.
Tremelimumab is a fully human IgG2 monoclonal antibody directed against the CTLA-4 receptor of the T cells. Tremelimumab owns an extremely long half life of 22 days that allows its intravenous administration every 3 months. In a phase I/II study conducted in 119 patients with pretreated advanced melanoma, tremelimumab showed an objective response rate of 7% but with a median OS of 11.5 months in those patients treated with the every 3 months dosing. The key element of this trial was the amazing duration of response, ranging from 11 to more than 36 months. Based on this promising activity, a prospective randomized phase III trial in naive advanced melanoma patients was recently reported. A total of 655 patients were randomized to receive either tremelimumab or chemotherapy (DTIC or TMZ as single agent). Unfortunately, tremelimumab failed to demonstrate a better OS versus chemotherapy (11.7 vs. 10.7 months; P = 0.73). No differences in either response rate or PFS were observed. The duration of responses was clearly longer for those patients treated with tremelimumab.71,78
An active search for both tumor and host biomarkers that could predict for response to these anti-CTLA4 agents is needed and the future role of these drugs is not yet established.
Auto-immune hypophysitis was recently reported to occur in 5% of patients treated with anti-CTLA-4 antibodies.79 Symptoms included extreme fatigue, headaches, memory loss, and loss of libido. In most cases diagnosis could be confirmed by enlargement of the pituitary on magnetic resonance imaging. Patients treated emergently with high dose steroids appeared to have better recovery of pituitary function, although all patients continued to require some hormone replacement at the time of publication. The authors recommend that baseline hormone levels and magnetic resonance imaging measurement of the pituitary be obtained prior to treatment, and that complaints of headache, fatigue, and visual changes be carefully evaluated. While auto immune side effects are dangerous, they are associated with clinical response, thereby suggesting that the immune system is effectively activated by anti-CTLA-4.
Anti-BCL2 Antisense Oligonucleotide
Oblimersen sodium, an anti-BCL2 antisense oligonucleotide, was originally tested in a phase I/II trial in combination with DTIC that was followed by a randomized phase III trial in 771 patients. The primary end point of the trial was OS, which was not statistically significantly different between the 2 arms (9.1 months for the combination arm vs. 7.9 months for DTIC alone arm), although overall and complete response rates were significantly better for the combination arm (overall response 11.7% vs. 6.8%, respectively; P = 0.019) and PFS was also improved with the combination (74 vs. 49 days; P = 0.0003). In an updated analysis, for the subgroup of patients with lactate dehydrogenase values ≤2 times the institutional upper limit of normality, there was a statistically significant survival benefit for combination therapy (10.2 vs. 8.7 months; P = 0.02).80 These data support the idea that oblimersen has at least modest activity when combined with DTIC, justifying further studies of this compound and similar strategies to overcome drug resistance in melanoma.81
MEDI-522 is a humanized monoclonal antibody directed against the αVβ3 integrin. αVβ3 is essential for endothelial cell proliferation, maturation, and survival; and, when it is blocked, proliferating endothelial cells undergo apoptosis and regress. In addition, αVβ3 is highly expressed in melanomas and is associated with tumor growth.82 In preclinical studies using αVβ3 antagonists, inhibition of melanoma tumor growth independent of its antiangiogenic effects was reported.78 In the Phase II trial, 57 patients received MEDI-522 alone, and 55 patients received MEDI-522 plus DTIC. MEDI-522 with or without DTIC was well tolerated and was active in patients with metastatic melanoma. The median survival was 12.6 months for the group that received MEDI-522 with DTIC and 9.4 months for the group that received MEDI-522 without DTIC.83
Bevacizumab is a potent antibody against the vascular endothelial growth factor (VEGF). Recently, high effectiveness of bevacizumab in combination with paclitaxel was reported in a single metastatic melanoma case of a 68-year-old man with a vitreous melanoma metastasis of the left eye, treated with a revitrectomy combined with intravitreal bevacizumab application because of iris neovascularization and progressive epiretinal tumor plaques. The melanoma-associated neovascularization completely disappeared 4 days after the treatment, but it recurred after 6 weeks. Although repetitive administration of local bevacizumab produced the same antiangiogenetic effect, progression of the epiretinal tumor plaques could not be stopped with the local bevacizumab treatment.84
A recent phase II trial was presented during American Society of Clinical Oncology 2007 annual meeting.85 In this phase II trial, data from 20 patients were presented. In this trial, patients were treated with the combination of paclitaxel (80 mg/m2 IV on days 1, 8, and 15 of a 28-day cycle), carboplatin (area under the curve [AUC] = 6 IV on day 1), and bevacizumab (10 mg/kg IV on days 1 and 15). The primary end point of the study was the 8-week PFS. The 8-week PFS rate was 70%. The median time to progression was 163 days. One partial response was observed. There were 3 disease-related deaths. The most common toxicities were neutropenia (95%; 45% = grade 3), anemia (95%; 15% = grade 3), fatigue (90%; 5% = grade 3), leukopenia (85%; 25% = grade 3), and thrombocytopenia (75%; 5% = grade 3).
Axitinib is a new and potent oral multitargeted tyrosine kinase inhibitor against the vascular endothelial growth factor receptor (VEGFR)-1, VEGFR-2, VEGFR-3, and platelet derived growth factor receptor (PDGFR). Fruehauf et al conducted a small phase II trial in 32 previously treated advanced melanoma patients. Six of 32 (19%) patients achieved an objective radiologic response according to response evaluation criteria in solid tumors criteria in this highly pretreated subpopulation. One complete response was also confirmed. The median duration of response was 7.9 months (95% confidence interval: 2.3-NA). The median PFS for the whole sample was 2.3 months. Axitinib was well tolerated, with fatigue and hypertension being the most common toxicities found. Further investigation of this new targeted agent is warranted in advanced melanoma patients.86
EVEROLIMUS. THE INHIBITON OF MTOR IN MELANOMA
Everolimus (RAD-001), an orally administered inhibitor of mTOR, is well tolerated at a dose of 30 mg/wk. The group of Rao et al87 presented a phase II trial, to asses PFS in 24 patients with metastatic melanoma. Fifteen of these patients had received previous treatments for the disease, and 9 were chemo-naive. The interim analysis of the first 20 included patients, showed a PF of 16 weeks, and no grade 3 toxicities were registered. The most relevant grade 2 side effects were fatigue (17%), diarrhea (8%), and anemia (8%). Patients had a clinically relevant benefit, with the median PFS for all 24 patients of 3 months. Median OS was not reached when the data were communicated.
Peyton et al88 presented a phase II trial with the combination of Bevacizumab 15 mg/mg every 21 days and daily Everolimus 10 mg orally, in 56 unresectable metastatic melanoma that had received up to 2 previous treatment regimens. One patient of 28 evaluable presented a partial response. Nineteen additional patients showed stable disease, for a disease control rate of 72%. With a medial follow-up of 5 months, the median PS was established in 3.5 months.
ADOPTIVE CELL TRANSFER
Adoptive T cell transfer has previously shown efficacy in melanoma, with an ORR of 51% reported by Rosenberg and colleagues in a phase I study of 35 patients.89 To circumvent the requirement that patients have preexisting antitumor T cells which can be expanded in vitro, Morgan and colleagues90 isolated peripheral blood mononuclear cells from patients, cultured them with IL-2 and anti-CD3, and transduced them with a retroviral vector containing the gene for T cell receptor (TCR) a and b chains reactive against the melanoma antigen MART-1. Seventeen patients with refractory disease received fludarabine and cyclophosphamide as part of a lymphodepleting regimen, followed by transduced T cells, followed by IL-2. Transduced TCRs were shown to persist by polymerase chain reaction (PCR) of DNA from peripheral blood mononuclear cells and 2 out of 17 patients had complete responses. This is the first published clinical study of treatment with T cell receptor-transduced T cells, and it is hoped that it will lead to future therapeutic advances.
The group led by Steven Rosenberg91 performed 2 additional sequential trials of Adoptive Cell Transfer with autologous tumor-infiltrating lymphocytes in patients with metastatic melanoma refractory to standard therapies. They used a host preparative lymphodepletion consisting of cyclophosphamide and fludarabine with either 2 (25 patients) or 12 Gy (25 patients) of total-body irradiation administered before cell transfer. The nonmyeloablative chemotherapy alone showed a response rate of 49%. When 2 or 12 Gy of total-body irradiation were added, the response rates were 52% and 72%, respectively. Responses were seen in all visceral sites including the brain. There was one treatment-related death in the 93 patients. Objective responses were correlated with the telomere length of the transferred cells.
POTENTIAL NEW TARGETS
Available information regarding genetic lesions in melanomas is expanding. Two stereotypical tumor suppressor mutations in melanoma are p16 and phosphatase and tensin homolog (PTEN). P16, or CDKN2a, is a locus on chromosome 9 encoding both INK4a and alternate reading frame (ARF). PTEN, meanwhile, on chromosome 10, regulates phosphatidylinositol signaling, thereby modulating protein kinase B (AKT) and antiapoptotic factor bcl-2. Bcl-2 is overexpressed in melanoma. Other genes of more recent interest are microphthalmia-associated transcription factor (MITF), a melanocyte differentiation factor which may function as an oncogene, and genes of the WNT signaling pathway including b-catenin.92 Of particular clinical relevance is the RAS-RAF-MEK-ERK (rat-sarcoma [RAS]-raf [Raf proto-oncogene serine/threonine-protein kinase]-mitogen-activated protein kinase [MEK]-erk [extracellular signal-regulated kinase]) signaling pathway. This pathway is constitutively activated in human tumors with somatic missense mutations in (raf [RAF proto-oncogene serine/threonine protein kinase]) B-RAF reported in 66% of melanomas.93 A further 15% of melanomas have mutated N-Ras (neuroblastoma Rat sarcoma gene) proteins. Intriguingly, these mutations appear to be mutually exclusive, suggesting that activation at one stage of the pathway is sufficient, with B-RAF (raf [RAF proto-oncogene serine/threonine-protein kinase]) mutations predicting in vitro sensitivity to mitogen-activated protein kinase (MEK) inhibitors.94 A better understanding of specific genetic lesions in melanoma should lead to improved targeted therapies. In this regard, a recent analysis of 126 melanomas published by Curtin and colleagues95 categorized tumors into 4 groups based on clinical profiling, and found that these groups could be distinguished based on genetic profiling with 70% accuracy. Acral and mucosal abnormality had more frequent chromosomal abnormalities in this study, while B-RAF (raf [RAF proto-oncogene serine/threonine-protein kinase]) mutations were found most commonly in melanomas developing on skin without sun damage. CD117 (KIT), a tyrosine kinase receptor which inhibits the mitogen activated kinase (MAP) kinase pathway, was recently found to be selectively activated on mucosal, acral, and sun-associated melanomas, but not in those melanomas growing on skin without sun damage.96
When compared with standard chemotherapy based on DTIC, no other drug has shown benefits in terms of survival up to now. Adding more chemotherapeutic agents to DTIC or combining chemotherapy with classic immunotherapeutic drugs like IL-2 or interferon has failed to improve survival in this setting. It seems that the current chemo- and biotherapy armamentarium will not significantly provide a significant benefit in survival to our patients.
However, a deeper knowledge not only of the molecular biology of the tumor but also of the immune system allows the design of new molecular targeted drugs directed against the tumor or inducing patient immunity against the melanoma.
Melanoma remains a challenging disease and represents a niche to explore new targeted agents and immunotherapeutic approaches.
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angiogenesis; targeted; melanoma; treatment
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