Retrospective comparison of a weight-based dose every 2 weeks with a fixed dose every month: a real-life analysis of nivolumab in the treatment of advanced melanoma.

Nivolumab was first authorized at a weight-based dose (WBD) of 3 mg/kg every two weeks (Q2W). Since 2017, a fixed dose (FD) regimen [first 240 mg Q2W and then 480 mg per month (Q4W)] was allowed. The objective of the study was to compare a WBD regimen and an FD regimen with regard to effectiveness and safety. We conducted a single-center, retrospective, real-life study of consecutive adult patients who had received a WBD of nivolumab or an FD of 480 mg Q4W. The primary endpoint was the occurrence of grade ≥3 immune-related adverse events (irAEs). The secondary endpoints were overall survival and cost of the treatment. In all, 342 patients were included: 71 in the WBD cohort and 271 in the FD cohort. Of these patients, 201 patients (59.6%) experienced an irAE, and 24 of these events were graded as ≥3. At 12 months, there was no significant difference in irAE occurrence between the two cohorts [hazard ratio (95% confidence interval): 0.54 (0.21-1.36), P  = 0.19]. The 12-month overall survival rate was significantly lower in the WBD cohort ( P  < 0.001). Switching from a fortnightly weight dose to a fixed monthly dose halves the cost of hospitalization. Our results did not show a significant difference between WBD and FD cohort in the occurrence of severe irAEs. However overall survival appeared to be significantly higher in FD group. Some clinical trials are investigating a hybrid dosing regimen in which a WBD is capped by an FD. The present results need to be confirmed in prospective studies.

Sequential combination of Sonic Hedgehog inhibitors followed by consolidation radiotherapy in locally advanced basal cell carcinoma.

BACKGROUND: Sonic Hedgehog inhibitors (SHHis) are an effective treatment in locally advanced basal cell carcinoma (laBCC), but the use of these drugs is limited by adverse events and relapse at discontinuation in around half of patients. A few cases of patients treated concomitantly by radiotherapy (RT) and SHHis have been reported in the literature, suggesting that the combination results in an improved overall response. Maintaining complete response after stopping treatment is a concern, especially since resuming treatment in the case of relapse does not guarantee a new therapeutic response. The optimal combination and sequence of treatment to improve local control of laBCCs are not yet defined. OBJECTIVE: We hypothesized that consolidation RT after complete response to SHHis could reduce the risk of relapse at discontinuation. METHODS: We present a case series of patients with laBCCs who achieved complete response (CR) after SHHi treatment and were treated with consolidation RT. Patients were evaluated by a skin cancer board. The closure RT technique and dosage were refined by a radiotherapist. RESULTS: Eleven patients were included. SHHis were prescribed for 5 months (range 4-11). Consolidation RT was performed after CR to SHHis and discontinuation. RT was delivered at a median dose of 45 Gy (range 40.5-66) in 10 fractions (range 9-33). With a median follow-up of 23 months, all patients maintained complete clinical response. This strategy was well tolerated with no grade 3 adverse events. CONCLUSION: SHHi treatment followed by RT consolidation after drug discontinuation seems effective and safe. Further studies are needed to develop a precise strategy for the management of laBCCs.

Dramatic response of refractory metastatic squamous cell carcinoma of the skin with cetuximab/pembrolizumab.

Cutaneous squamous cell carcinoma (cSCC) accounts for 20% of skin cancers. At an advanced stage the prognosis is poor, making cSCC the second leading cause of death from skin cancer. In cases of metastatic or unresectable disease, anti-programmed cell death 1 (anti-PD1) treatment has shown promising results in a recent phase II study. Although anti-PD1 treatment now offers higher response rates, the responses remain inconsistent and may lead to therapeutic impasses. Preclinical data have suggested synergy between anti-epidermal growth factor receptor (anti-EGFR) and immunotherapy. We report the case of a patient with metastatic cSCC that proved refractory first to anti-EGFR/carboplatin and then to immunotherapy, but who showed a complete and durable response with cetuximab/pembrolizumab combination. This response could reflect synergy of the two treatments.

Severe skin toxicity with organ damage under the combination of targeted therapy following immunotherapy in metastatic melanoma.

Targeted therapy combination (TTC: antiRAF+antiMEK) is known to improve metastatic melanoma survival. Few severe skin toxicities (grade ≥3) are described with first-line TTC (17% for vemurafenib+cobimetinib and none for dabrafenib+trametinib) in a phase III trial. Among our 42 patients treated by TTC between January 2014 and March 2017, 4.8% (2/42) of those treated in the first line presented severe skin rash versus 19% (8/42) of patients treated in the second line after previous immunotherapy. In particular, we observed one case of Stevens-Johnson syndrome and four cases of severe drug reaction with eosinophilia and systemic symptoms syndrome under TTC in patients who had received immunotherapy previously. Thus, previous immunotherapy appears to play an important role in the skin rash onset and severity induced by TTC.

BRAF inhibitor discontinuation and rechallenge in advanced melanoma patients with a complete initial treatment response.

BRAF inhibitors (BRAFi), a targeted therapy, are used to treat metastatic late-stage melanomas harbouring the BRAF-V600 mutation (found in about 50% of melanomas). The targeted therapy is generally maintained until tumour progression or major toxicity occurs, although responses are often limited in time. It is unknown whether melanoma patients achieving a complete response with targeted therapy can safely discontinue treatment. We retrospectively observed the clinical course of patients with metastatic melanoma who discontinued BRAFi therapy after achieving a complete response and those with an incomplete response combined with surgical removal of the remaining tumours. We also evaluated the effectiveness of BRAFi in these patients after recurrence. In 11 patients, the best response was diagnosed after a median BRAFi treatment duration of 105 (29-341) days. The median follow-up after BRAFi initiation was 769 (435-1765) days. Recurrence was observed in all 11 patients (100%), median: 82 (27-322) days. Five patients achieved a complete response, with a median progression-free survival after cessation of 136.5 (34-322) days versus 82 (27-144) days for six patients with an incomplete response combined with surgical removal of remaining tumours. Baseline characteristics and time to best response and to discontinuation did not influence the rate of relapse. Subsequently, eight patients were rechallenged with a BRAFi. The median progression-free survival time after BRAFi rechallenge was 222.5 (15-425) days. The three remaining patients received treatments other than BRAFi. Our findings may be valuable with respect to ongoing clinical trials of combinations of targeted therapies and immunomodulatory antibodies.

Cerebrospinal fluid concentrations of vemurafenib in patients treated for brain metastatic BRAF-V600 mutated melanoma.

Anti-BRAF agents, including vemurafenib, have modified the prognosis for patients with melanoma. However, a difference can still be observed between extracerebral and cerebral responses. The aim of this study was to investigate the diffusion of vemurafenib in cerebrospinal fluid (CSF) from patients treated for brain metastatic BRAF-V600 mutated melanoma. Six patients treated with vemurafenib 960 mg twice daily were included. These patients had undergone a lumbar puncture because of suspicions of leptomeningeal metastasis, along with simultaneous blood sampling to measure vemurafenib level. The concentrations of vemurafenib in the CSF and the plasma were measured by high-performance liquid chromatography. The mean plasma and CSF concentrations of vemurafenib were 53.4±26.2 and 0.47±0.37 mg/l, respectively. The mean ratio of the CSF : plasma concentration was 0.98±0.84%. No relationship was found between plasma and CSF concentrations (P=0.8). In conclusion, our preliminary results highlight for the first time a low CSF vemurafenib penetration rate associated with a large interindividual variability in patients treated for metastatic BRAF-V600 mutated melanoma and brain metastases. Further investigations with larger cohorts are required to study the relationship between CSF vemurafenib concentrations and cerebral response.

[Diagnosis of melanoma]. / Diagnostic du mélanome.

Melanoma is a rare cancer but it is the cancer with the biggest increase of incidence, especially in caucasian populations. UV exposure and genetic predisposition are the two main risk factors. The diagnosis is often clinically suspected with the "ABCDE" rule. However, there are some diagnostic traps. Histological exam of the whole lesion will confirm diagnosis and guide the management. In case of localised melanoma, Breslow index is the best prognostic index. In case of metastatic melanoma, prognostic is dark. The AJCC classification stages patients in 4 groups according to their global survival.

Leptomeningeal metastasis in melanoma: a prospective clinical study of nine patients.

BACKGROUND: Melanoma has the highest rate of spread to the leptomeninges and the incidence of melanoma has been steadily rising. This article describes recent experience at the Lille University Hospital, between 2007 and 2011 and discusses the possibilities for treatment of leptomeningeal metastasis. PATIENTS AND METHODS: Nine patients were diagnosed with leptomeningeal metastasis of melanoma. The standard criteria were used for the diagnosis. The treatment consisted of a combination of intrathecal chemotherapy, systemic chemotherapy and best supportive care. RESULTS: The overall median survival from the time of leptomeningeal metastasis diagnosis was eight weeks (range=1-168 weeks). In two cases, the median overall survival was 104 weeks. For these patients, there was a clear benefit in intrathecal chemotherapy combined with systemic treatment. No complication was observed. CONCLUSION: Despite a poor prognosis, treatment of melanoma leptomeningeal metastasis is needed in order to improve the quality of life, neurological progression-free survival and overall survival of patients.

Topical treatment of cutaneous metastases of malignant melanoma using combined imiquimod and 5-fluorouracil.

BACKGROUND: Despite multiple available options, the treatment of cutaneous melanoma metastases is often unsuccessful. Based on the hypothesis that imiquimod and 5-fluorouracil have synergistic antitumor properties, we used this topical combination to treat several patients. AIM: Our objective was to investigate the treatment combination in a small cohort of patients with surgically non-resectable melanoma metastases. METHODS: The lesions of 5 patients with multiple cutaneous metastases were treated topically, 5 days per week, with 5-fluorouracil in the morning and imiquimod at night. RESULTS: 45 lesions were treated. A clinical response was seen in 44 lesions, with a complete response in 19 lesions and a partial response in 25. Stable disease was confirmed in the 1 remaining lesion. No patients developed new lesions during treatment. However, one patient had a recurrence 6 months after treatment discontinuation, followed by a partial response when rechallenged. CONCLUSIONS: The imiquimod and 5-fluorouracil combination is effective. That patients did not develop new, distant lesions suggests the achievement of locoregional control, probably by the induction of antitumor immune response.

Oral metronomic cyclophosphamide in elderly with metastatic melanoma.

INTRODUCTION: In Western countries, the number of frail elderly people with metastatic melanoma (MM) keeps increasing. Conventional chemotherapy frequently induces imbalance in frail physiological cases. We propose to treat these patients with oral metronomic cyclophosphamide. PATIENTS AND METHODS: This retrospective study analyses the data of patients with unresectable MM who received 50 to 100 mg of cyclophosphamide a day, 3 weeks out of 4. Main evaluation criterion was safety. Secondary evaluation criteria were objective response rate and overall survival. RESULTS: Thirteen patients were included (median age: 80, 5 AJCC stage III and 8 AJCC stage IV). Clinical and biological safety were good, leading to long home staying and rare treatment discontinuations. Main toxicity observed was lymphopenia; no opportunist infection occurred. The control rate was 46%: one partial response and five stable diseases (median: 10 months). Survival after beginning of treatment ranged from 4 to 37 months (median: 8 months). DISCUSSION: Literature about MM in frail elderly is limited. Still, specific treatment is necessary. Cyclophosphamide in metronomic schema was well tolerated. The response rate was difficult to assess (small population) but several patients presented with long lasting stabilisation. The mechanisms of action of this treatment are original, associating antiangiogenic action and immunomodulation. CONCLUSION: Cyclophosphamide in metronomic schema showed good safety results for this frail population. Oral treatment enabled patients to stay at home longer and limited hospitalisation time. A larger controlled study will be necessary to confirm these encouraging results in elderly with MM, a classical chemoresistant tumor.