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European Post-Chicago Melanoma/Skin Cancer Meeting 2016
The European Post-Chicago Melanoma/Skin Cancer meetings, under the auspices of the European Association of Dermato–Oncology, aim to provide a comprehensive overview on new developments in melanoma diagnostics and therapy, and to offer insights for choosing the right treatment for the right patient. This year’s sixth annual meeting, held in Munich, Germany, from June 30 to July 1, attracted approximately 600 medical professionals.
Melanoma Brain Metastases
Dr. Meier began by reviewing a trial examining the effects of adjuvant whole-brain radiotherapy (WBRT) in stereotactic radiosurgery (SRS). SRS has high efficacy for treating brain metastases (90%), but when applied by itself, it is associated with a high rate of new brain metastases development. Research by Paul Brown, MD, Professor of Radiation Oncology at the University of Texas MD Anderson Cancer Center in Houston, examined the survival benefit and acute and late toxicities of WBRT.4 It showed no impact on survival, but a negative effect on cognitive function. His review of three SRS trials of adjuvant WBRT revealed improvement in local control (81–100% versus 67–73% for SRS alone) and distant brain metastasis control (67–73% versus 36–52% for SRS alone), but no boost in overall survival (OS) (5.7–10.9 months versus 8.0–15.2 months for SRS alone).
Dr. Brown’s adjuvant WBRT-N0574 trial showed equivalent OS between SRS and SRS with WBRT after brain tumor resection, but a –22% score after three months for SRS with WBRT in functional well being. The N107C trial of SRS to the surgical bed or WBRT in patients with more than three brain metastases after resection is ongoing. The potential advantages of SRS are less acute toxicity, less delay in systemic therapy, and likely less cognitive impact. The disadvantages of SRS are that it does not address micrometastases and is labor intensive.
The QUARTZ trial of palliative WBRT, which tested WBRT plus supportive care versus supportive care alone in 538 poor-prognosis patients with brain metastases not suitable for resection or SRS, found no WBRT benefit.
Is it possible to decrease WBRT toxicity? The RTOG 0614 trial of WBRT with or without 20-mg once-daily dosing of memantine, an Alzheimer’s disease drug, in patients with brain metastases demonstrated a 22% reduction in risk of cognitive deterioration (P = 0.01).
Dr. Brown’s phase 2 trial (RTOG 0933) of conformal avoidance of the hippocampus revealed memory deficits were reduced from 30% to 7%. A phase 3 trial of WBRT plus memantine versus hippocampal avoidance WBRT plus memantine in 518 patients with brain metastases is ongoing (time to cognitive failure is the outcome measure).
“The role for radiosurgery is growing; the role for WBRT is diminishing,” Dr. Meier concluded.
Turning to clinical trials of targeted therapies in 40 or more patients with melanoma brain metastases, Dr. Meier cited phase 2 trials of dabrafenib and vemurafenib, with the former showing intracranial response rates (RRs) of 39.2% and 30.8% in asymptomatic patients with new and recurrent disease, respectively. RRs in symptomatic patients with recurrent and new disease were 18% and 20%, respectively. Progression-free survival was approximately four months in all groups of both trials, and median OS ranged from 6.9 to 8.2 months. Current trials are assessing dabrafenib, dabrafenib and trametinib, vemurafenib and cobimetinib, and buparlisib.
The Eastern Cooperative Oncology Group consensus guidelines warn of potential intracranial neurotoxicity from radiotherapy combined with BRAF inhibitors, but note that rates of radionecrosis, hemorrhage from WBRT or SRS, or both do not appear to be increased with concurrent or sequential administration of BRAF inhibitors, Dr. Meier said. The guidelines recommend refraining from BRAF inhibitors three days before and after fractionated radiotherapy, and for one day before and after SRS.
Phase 2 research on the use of immune checkpoint inhibitors (anti-programmed cell death protein-1 [PD-1]) included a trial of pembrolizumab in 18 melanoma patients with brain metastases. The RR (complete plus partial response) was 22%. A further brain metastasis trial comparing ipilimumab and anti-PD-1 therapy reported a median OS of 6.64 months for ipilimumab and 11.27 months for anti-PD-1 therapy. Subgroup analysis showed disease control rates (DCRs) with ipilimumab of 32% in asymptomatic patients and 37% in symptomatic patients. With anti-PD-1 therapy, DCRs were 48% in asymptomatic patients and 25% in symptomatic patients.
Dr. Meier commented that ipilimumab efficacy was higher than in published data, explained perhaps by post-ipilimumab treatment with anti-PD-1 therapy in 67% of patients.
Finally, reviewing a trial of SRS with the gamma knife (GK) plus systemic therapy in BRAF-mutated patients showed a median OS of approximately three months for GK alone and approximately seven to 13 months for GK plus targeted therapy or immunotherapy.5 For BRAF wild-type patients, the median OS was about two months for GK alone and approximately nine to 14 months for GK plus targeted therapy or immunotherapy. The conclusion was that in patients with melanoma brain metastases, GK followed by new targeted therapies or immunotherapies (especially anti-PD-1) produced limited recurrence, controlled extracerebral disease, and favored prolonged survival.
Dr. Meier suggested future directions, including local therapies (stereotactic radiation, SRS, perhaps WBRT and/or systemic therapy with targeted therapies or immunotherapies) for macroscopic disease; systemic therapy or perhaps WBRT for microscopic disease; and systemic therapies for systemic disease. “With a multidisciplinary approach,” she said, “we can make a difference in the lives of our patients.”
Highlights of American Society of Clinical Oncology (ASCO) Immunotherapy Findings in Melanoma
The progression-free survival (PFS) benefit achieved by adding nivolumab to ipilimumab or with nivolumab alone as compared with ipilimumab alone in patients with treatment-naïve advanced melanoma continued in follow-up out to a median of 18 months. The data were presented in updated Checkmate 067 trial results by Jed D. Wolchok, MD, PhD, of Memorial Sloan Kettering Cancer Center in New York, at the 2016 ASCO annual meeting.6 The combination therapy reduced patients’ risk for progression by 58% compared with ipilimumab alone (hazard ratio [HR], 0.42; 99.5% confidence interval [CI], 0.31–0.57; P < 0.00001), and nivolumab monotherapy reduced the risk for progression by 45% (HR, 0.55; 99.5% CI, 0.43–0.76; P < 0.00001). An exploratory endpoint analysis showed that combination therapy reduced progression risk by 24% compared with nivolumab alone (HR, 0.76; 95% CI, 0.60–0.92).
According to Dr. Postow, what stood out as the highest absolute difference in objective response rate (ORR) between the ipilimumab/nivolumab combination versus nivolumab monotherapy was the one between the two in BRAF-mutant patients, with an ORR of 66.7% for the combination and 36.7% for nivolumab alone (Δ30%). In BRAF wild-type patients, the difference was only 7% (53.3% for the combination versus 46.8% for nivolumab alone). The import of the 66.7% ORR in BRAF-mutant patients, Dr. Postow underscored, is that “we shouldn’t just be thinking about targeted therapies for these patients; we should also be thinking about immune therapy. ... The ORR for single-agent nivolumab was very high, as well.”
Longer median PFS for nivolumab and the nivolumab/ipilimumab combination continued versus ipilimumab monotherapy at 18 months (nivolumab, 6.9 months; combination, 11.5 months; ipilimumab, 2.9 months), with hazard ratios for the combination of 0.55 versus nivolumab and 0.42 versus ipilimumab. PFS was 44% for the combination, 39% for nivolumab monotherapy, and 14% for ipilimumab monotherapy.
While overall survival (OS) analysis is not available yet in the phase 3 trial, Dr. Postow’s presentation of the phase 1 Checkmate 069 data at the American Association for Cancer Research annual meeting had shown a 26% median OS benefit for nivolumab plus ipilimumab versus ipilimumab alone in an exploratory analysis, with a 10% advantage in probability of survival (64% versus 54%) at two years in BRAF wild-type and BRAF-mutant patients.7
The OS finding is consistent with the KEYNOTE-006 trial phase 3 finding of 55% OS at two years for both pembrolizumab regimens (every two weeks and every three weeks) and 43% for ipilimumab (HR, 0.68; 95% CI, 0.53–0.87; P = 0.00085 for pembrolizumab every two weeks) (HR, 0.68; 95% CI, 0.53–0.86; P = 0.00083 for pembrolizumab every three weeks).
While cautioning about cross-trial comparisons, Dr. Postow reviewed several other trials, which all showed programmed cell death protein-1 (PD-1) inhibitor two-year OS in the mid- to upper-mid 50% range (and a phase 1 trial with three-year survival at 68%).
The further concern, he said, is to reduce the side effects of the combination. In the presentation of the phase 1 KEYNOTE-029 data by Georgina Long, MD, with an ipilimumab dose lowered from the standard 3 mg/kg to 1 mg/kg with pembrolizumab (2 mg/kg), the ORR in an expansion cohort was 57% with a six-month PFS of 70% in advanced melanoma.8 Grade 3 or 4 treatment-emergent adverse events were reported in 42% of patients. Randomized trials are needed, Dr. Postow said, noting that a trial looking at grade 3–5 adverse events comparing ipilimumab 3 mg/kg plus nivolumab 1 mg/kg with ipilimumab 1 mg/kg plus nivolumab 3 mg/kg is upcoming.
The observation of patients who have quickly discontinued ipilimumab dosing because of adverse events and have still had impressive response rates and PFS begs the question of whether it may be feasible to evaluate patients via computerized tomography (CT) scan at week 6 after two doses of ipilimumab/nivolumab, and if they are already responding switch them to nivolumab monotherapy, he said. Furthermore, in Dr. Caroline Robert’s presentation of KEYNOTE-001 data on the 61 complete responders who stopped pembrolizumab for observation, only two patients experienced progression.
Summarizing, Dr. Postow said that combination therapy has the highest PFS, response rates, and toxicity. Overall survival data are not yet mature, but combinations with less ipilimumab or none (combining PD-1 with different agents) are of interest. While stopping PD-1 in patients with complete responses has proven successful, stopping PD-1 in patients with partial responses or long-term stability, the role of CT or positron emission tomography scans or biopsy to assess responses, and the efficacy of PD-1 reinduction stand out as themes for future research.
Current Clinical Trials: Soft Tissue And Skin Metastases
“Why would anyone be interested in local treatment of a systemic disease?” Dr. Agarwala began. While the new systemic immunotherapies and targeted therapies are exciting and have raised the bar quite high, “we are hitting a toxicity limit. Secondly, let’s not forget that melanoma is not just a systemic disease.” Three percent to 10% of primary melanomas develop local/in-transit recurrences with a greater than 50% risk of distant disease and death. In addition, the soft tissue and skin metastases that occur frequently in melanoma may be associated with considerable morbidity, which can itself lead to mortality, or the patient can suffer for a long time with local disease that can be very hard to control with the available treatments, including surgery. Furthermore, a significant portion of patients may not be candidates for the aggressive systemic therapies.
Oncolytic immunotherapies can work either directly through cell lysis or indirectly through “bystander responses” through induction of either innate or adaptive immune responses. By making the tumor more visible to the immune system, these oncolytic immunotherapies “make the tumor your friend, your ally.”
While the list of intralesional therapies is growing rapidly, those closest to approval employ electrochemotherapy (cisplatin, bleomycin), chemical ablation (rose bengal disodium 10% [PV-10]), and oncolytic viruses (herpes simplex virus [HSV], coxsackievirus, and reovirus), with talimogene laherparepvec (T-VEC [Imlygic, Amgen]) among them already approved in the U.S. and Europe. Single-agent clinical trials are ongoing with PV-10 (phase 3), electroporation of interleukin (IL)-12, and coxsackievirus type A21 (CVA21)(Cavatak, Viralytics, Ltd.), and combination trials are ongoing with T-VEC, PV-10, and HF10 (an attenuated, replication-competent HSV).
PV-10, a small-molecule fluorescein derivative, causes primary tumor lysis by entering lysosomes, with necrotic tumor cells facilitating antigen presentation leading to regression of distant tumors. The 80-patient phase 2 trial revealed a 51% response rate (26% complete responses [CRs]) in target lesions, and a 33% response rate in nontarget lesions (26% CRs). Progression-free survival was 11.4 months in responders and 4.1 months in nonresponders. Responses were “robust” in stage III subjects, and adverse reactions were mild to moderate.
In the phase 3 trial, 225 patients with locally advanced cutaneous melanoma are receiving PV-10 every four weeks, chemotherapy (dacarbazine or temozolomide) every four weeks, or T-VEC every two weeks.
In electroporation, better tumor cell entry by IL-2, “a fairly strong immune-based cytokine,” is induced by application of an electric current to the tumor. It is a commonly used modality in Europe, Dr. Agarwala said. Objective response rates (ORRs) in interim analysis of a 28-patient phase 2 study have been in the 30% to 50% range, with responses in 59% of untreated “bystander” lesions.
In Robert Andtbacka’s phase 2 CALM trial of CVA21 in 57 patients with advanced melanoma, the response rate was 36.8% with a disease control rate of 75.4%.
The first trial of an intralesional therapy combined with a systemic therapy was a phase 1b trial of T-VEC or ipilimumab (3 mg/kg) in 18 patients with stage IIIB/C–IVM1c melanoma not suitable for surgical resection, which had ORR as a secondary endpoint. Investigator-assessed responses were observed in 56%, with CRs in 33% of patients.
An evaluation of responses in a phase 1b trial of T-VEC plus pembrolizumab in unresected stage III or IV melanoma found that in 50 injected lesions, there was a 100% reduction in tumor area from baseline in 70% (n = 35). The same 100% reduction was found in 40% of 20 noninjected nonvisceral lesions (n = 8) and in 10.3% of 29 noninjected visceral lesions (n = 3). “Despite the small number of patients, the first combination trials seem to imply a synergy, with the combinations producing a higher response rate than the sums of the rates for the individual agents. But phase 3 trials will be the true test,” he said.
The MASTERKEY-265 phase 3 trial of T-VEC and pembrolizumab versus pembrolizumab and a T-VEC placebo will be the first placebo-controlled, randomized trial in melanoma. Further combination trials in melanoma are testing neoadjuvant T-VEC treatment with surgery versus surgery alone, PV-10 with pembrolizumab (1b), and HF10 with ipilimumab (1b/2). The phase 2 portion of the HF10/ipilimumab trial has already reported an ORR of 49% after 24 weeks.
“It is interesting,” Dr. Agarwala said, “that we can now combine two agents with different, nonoverlapping toxicities to produce a benefit.” The intralesional therapies combined with ipilimumab or pembrolizumab have produced response rates in the 49% to 56% range with grade 3 or higher adverse events in the 24% to 32% range. Combining the available oncolytic therapies in clinical trials with the newer programmed cell death protein-1 (PD-1) inhibitors will potentially avoid the additive adverse effects seen when the PD-1s are combined with the anti-CTLA-4 inhibitor ipilimumab. “The important thing is that you have reasonably good response rates, but the adverse event rates stay the same as with the systemic therapies because adverse events with the intralesional therapies are few and local. So these combination therapies including the intralesional agents are likely to be the future and may be the best way to integrate them into practice.”
- Brown PD. Use of stereotactic radiosurgery in treating brain metastases: Is there a role for WBRT? Presentation at American Society of Clinical Oncology Annual Meeting, Chicago, Illinois, June 3–7, 2016. Available at: http://meetinglibrary.asco.org/content/50917?media=vm. Accessed August 4, 2016.
- Grob JJ, Dussouil A-S, Carron R, et al. New systemic treatments to improve survival in melanoma patients whose brain metastases are controlled by an on-demand gamma-knife radiosurgical strategy. Presentation at American Society of Clinical Oncology Annual Meeting, Chicago, Illinois, June 3–7, 2016. Abstract published in J Clin Oncol 2016;34(15)(suppl):9573. Available at: http://meeting.ascopubs.org/cgi/content/short/34/15_suppl/9573?rss=1. Accessed August 4, 2016.
- Wolchok JD, Chiarion-Sileni V, Gonzalez R, et al. Updated results from a phase III trial of nivolumab combined with ipilimumab in treatment-naive patients with advanced melanoma (CheckMate 067). Presentation at American Society of Clinical Oncology Annual Meeting, Chicago, Illinois, June 3–7, 2016. Abstract published in J Clin Oncol 2016;34(15)(suppl):9505. Available at: http://meetinglibrary.asco.org/content/165588-176. Accessed August 4, 2016.
- Postow M, Chesney J, Pavlick A, et al. Initial report of overall survival rates from a randomized phase II trial evaluating the combination of nivolumab and ipilimumab in patients with advanced melanoma. Presentation at American Association for Cancer Research Annual Meeting, New Orleans, Louisiana, April 16–20, 2016. Available at: http://tinyurl.com/AACR16-AbstCT002. Accessed August 4, 2016.
- Long GV, Atkinson V, Cebon JS, et al. Pembrolizumab plus ipilimumab for advanced melanoma: results of the KEYNOTE-029 expansion cohort. Presentation at American Society of Clinical Oncology Annual Meeting, Chicago, Illinois, June 3–7, 2016. Abstract published in J Clin Oncol 2016;34(15)(suppl):9506. Available at: http://meetinglibrary.asco.org/content/167092-176. Accessed August 4, 2016.