ESMO 2017-CANCER PATIENTS CAN NOT UNDERSTAND CLINICAL TRIALS

Cancer patients struggle to understand what is involved in a clinical trial, even when they have participated in them. In a survey of 1090 adult cancer patients, more than half did not understand the concepts of clinical equipoise or randomization.

In the survey, 63% of patients thought that "my doctor would make sure that I got the better treatment in a clinical trial," and 55% said that "my doctor would know which treatment in a clinical trial was better."

The concept of randomization was also not understood. The survey involved 1090 patients who were attending 14 cancer centers in Ireland. About a third (30%) had already taken part in a clinical trial, but more than half of these patients did not understand that randomization means that the treatment would be allocated by chance. Among the cancer patients who had not participated in a clinical trial, the proportion was even higher ― 73% did not think that the choice of treatment was made on the basis of chance.

"This shows poor understanding of randomization, and we know this is a difficult concept for patients," commented lead author Catherine Kelly, MD, associate professor of medical oncology at the Mater Misericordiae University Hospital and University College in Dublin, Ireland.

"There is also the concept of clinical equipoise, that the reason you are doing the clinical trial is because there is uncertainty over which is the best option," she said in an interview. The results here were rather surprising, she said, because even patients who had been in a clinical trial still felt that the treating physician would choose the best treatment and, even more worrying, that the physician would make sure that they were getting the best treatment.

These responses show that patients "very much trust their cancer doctors, with the expectation that the doctor will know what is the best treatment and will ensure that they get it," Dr Kelly said.

The findings suggest that oncologists and their research teams need to explain more clearly these concepts and suggest a need for more training of communication skills, Dr Kelly suggested.

"Doctors have a responsibility to properly inform their patients in this regard, because they are the ones patients trust the most," Dr Kelly said.

"To provide informed consent when participating in a trial, patients need to understand these key concepts ― and doctors explaining them well is essential to alleviating any fears that might prevent patients from participating. For example, many didn't realize that clinical trials are not just an option for when standard treatment has failed," she observed.

Reacting to the findings, Dr Bettina Ryll, chair of the ESMO Patient Advocates Working Group, commented: "The question of whether patients understand clinical trial methodology is a very valid one, and what makes this study so interesting is that more than a quarter of the patients questioned had actually been on clinical trials before," she said.

"However, I was surprised at the median age of the cohort: 60 years. It would be interesting to compare the data collected here with younger patient groups, who access information in a very different way," Dr Ryll observed. "I would also expect to see differences across tumor groups: among breast cancer patients, for instance, who make up almost a third of the study cohort and for most of whom there is a well-established standard of care, clinical trials are likely to be of less interest than among lung cancer patients, for whom the standard treatment is less effective."

Dr Ryll further cautioned: "When we talk about understanding, it is important to consider that patients and physicians approach clinical trials from different perspectives. For example, the concept of randomization is one that many patients question from a moral standpoint. Equipoise, by contrast, may be a laudable moral concept, but it is difficult to uphold if the results of earlier trials are already known: finding out whether a treatment is, say, 51% better or only 49% may matter to an HTA [health technology assessment] assessor but not to a patient. This undermines the conclusion that patients simply do not understand equipoise."

European Society for Medical Oncology (ESMO) 2017 Congress. Abstract 1465P_PR, presented September 10, 2017.

ESMO 2017-TARGETED THERAPY FOR BRAF+ NSCLC

Activating mutations in the BRAF gene, which are generally mutually exclusive from EGFR mutations or ALK rearrangements, act as an alternative oncogenic driver in metastatic non-small cell lung cancer (NSCLC). The most common of these mutations, BRAFV600E, is observed in 1–2% of lung adenocarcinomas. Combined BRAF and MEK inhibition has shown superior efficacy compared with BRAF inhibitor monotherapy in patients with BRAF-mutated metastatic melanoma, potentially contributing to sustained pathway inhibition and delay or prevention of resistance.

Three-fourths of patients with previously untreated BRAF V600E–mutated NSCLC, receiving a combination of a BRAF inhibitor dabrafenib plus a MEK inhibitor trametinib, achieved complete or partial response or stable disease by investigator assessment and independent review, according to findings from a phase II trial presented at ESMO 2017, the Annual Congress of the European Society for Medical Oncology in Madrid, Spain.

David Planchard, Department of Medical Oncology, Institute Gustave Roussy in Villejuif, France presented the results of the third (cohort C) of three sequentially enrolled cohorts in the phase II study of patients with BRAF V600E–mutated metastatic NSCLC (NCT01336634). In this cohort, 36 patients with BRAF V600E–mutated metastatic NSCLC received first-line treatment with 150 mg twice daily of dabrafenib and 2 mg once daily of trametinib. The patients had not received prior systemic therapy for metastatic disease.

Dr. Planchard pointed out that substantial clinical activity has been previously demonstrated by the combination in patients with previously treated BRAF V600E–mutated metastatic NSCLC (cohort B), who showed an investigator-assessed confirmed overall response rate (ORR) of 67%, median progression-free survival (PFS) of 10.2 months, and median overall survival (OS) of 18.2 months.

In the findings presented at ESMO 2017, the patients had a median age of 67 (range 44 to 91) years, 61% were female (61%), 83% were white, and 72% of patients were current or former smokers.

Investigator-assessed ORR was the primary endpoint and secondary endpoints included duration of response (DOR), PFS, overall OS, and safety.

Durable responses observed with dabrafenib and trametinib

At data cut-off on 8 April 2017, 11 (31%) patients remained on treatment.

After a median follow-up of 15.9 months, the investigator assessed ORR was 64% (95% confidence interval [CI] 46%, 79%). Two (6%) patients receiving the combination experienced a complete response (CR), and 21 (58%) patients demonstrated partial response (PR). Overall, 4 (11%) patients had stable disease (SD) lasting ≥ 12 weeks as their best response, thus the disease control rate (DCR = CR+PR+SD) was 75% (95% CI 58%, 88%). 

Investigator-assessed maximum change in target lesion by best response.

© David Planchard.

The independent review committee assessment supported these results.

The investigator-assessed median DOR was 10.4 (95% CI 8.3, 17.9) months. The median PFS was 10.9 (95% CI 7.0,16.6) months and median OS was 24.6 (95% CI 12.3, not estimable) months.

All (100%) of the patients experienced ≥ 1 adverse event (AE), and 69% had ≥ 1 grade 3/4 AE. Serious AEs (SAEs) occurring in > 2 patients included alanine aminotransferase increase in 14%, pyrexia in 11%, aspartate aminotransferase increase in 8%, and ejection fraction decrease was reported in 8% of patients.

A total of 24 patients progressed or died; of these 17 patients died. One patient death was due to due to a SAE of cardiorespiratory arrest that was determined to be unrelated to study treatment.

Regulatory agencies approvals

The US Food and Drug Administration (FDA) first approved the combination of dabrafenib and trametinib for patients with metastatic melanoma in January 2014. The European Commission approved the dabrafenib/trametinib combination for adults with unresectable or metastatic melanoma with a BRAF V600 mutation a year later.

In April 2017, the European Commission approved the combination of dabrafenib and trametinib for patients with BRAF V600-positive advanced or metastatic NSCLC.

On 22 June, 2017, the US FDA granted regular approvals to dabrafenib and trametinib administered in combination for patients with metastatic NSCLC with BRAF V600E mutation as detected by an FDA-approved test.

Conclusions

The investigators concluded that combined dabrafenib and trametinib represents a new targeted therapy with clinically meaningful antitumour activity and a manageable safety profile in patients with previously untreated BRAF V600E–mutated metastatic NSCLC, and noted that these results supported the recent approvals by the European Commission and US FDA.

ESMO 2017-NEW IMMUNOTHERAPY FOR RENAL CANCER

Promising clinical benefit was demonstrated in the trial of rocapuldencel-T plus standard-of-care therapy (SOC) versus SOC therapy alone in patients with newly diagnosed metastatic renal cell carcinoma (mRCC), according to findings from an analysis presented at ESMO 2017, the Annual Congress of the European Society for Medical Oncology in Madrid, Spain.

In addition, a statistically significant association between overall survival (OS) and an increase in the number of rocapuldencel-T induced memory T cells was reported.

These promising long-term data come from the phase III ADAPT trial, which is ongoing after trial discontinuation was advised. In February, 2017 the ADAPT trial’s Independent Data Monitoring Committee recommended that the study be halted following a planned interim data review that showed 75% of the targeted number of 290 events (deaths) had been reached and the OS hazard ratio in the rocapuldencel-T/SOC treatment arm was greater than the pre-defined futility boundary of 0.98 for the 3^rd interim assessment.

The trial’s sponsor discussed the preliminary trial data with the US Food and Drug Administration (FDA) and the decision was made to keep the ADAPT trial open, based upon the safety profile, maturing survival data, and the mechanism of action of rocapuldencel-T, which involves the induction of long-term memory immune responses. Rocapuldencel-T is an individualised immunotherapy formulated with RNA isolated from each patient's tumour to activate autologous dendritic cells with tumour-specific antigens to induce an immune response including tumour-specific memory T-cells targeting each patient's specific tumour antigens.

Robert Figlin of the Division of Hematology Oncology, Cedars-Sinai Medical Center in Los Angeles, USA presented findings from the ADAPT trial of rocapuldencel-T plus SOC versus SOC in patients with newly diagnosed mRCC.

The trial recruited adults with synchronous, clear cell mRCC who were eligible for nephrectomy. The ADAPT is an ongoing phase III trial that is being conducted at 107 sites across North America, Europe, and Israel.

A total of 462 patients were randomised 2:1 to receive either three 0.2 mL intradermal injections of rocapuldencel-T plus SOC or SOC alone.

Treatment with SOC/rocapuldencel-T showed a potential survival benefit in patients with mRCC

At a median follow-up of 20 months, the majority of patients in both treatment groups were still alive.

A review of data from 154 of the first third of patients randomised having the longest duration of follow-up and least censored data (44%), suggest a potential survival benefit for the combination.

The researchers also observed a statistically significant correlation between OS and an increase in the number of rocapuldencel-T induced memory T cells (CD8+/CD28+/CD45RA-) in the 114 patients who had received 7 doses of rocapuldencel-T and had data that had been analysed.

Rocapuldencel-T was well-tolerated and demonstrated a safety profile that was consistent with that shown in an earlier phase II trial.

Conclusions

The ADAPT trial is ongoing to further evaluate the long-term effects of this well-tolerated individualised immunotherapy. The finding of a potential survival benefit is worthy of further assessment.

Helen Gogas, Professor in Medical Oncology at First Department of Medicine, National and Kapodistrian University of Athens, Greece who discussed the study results has agreed that censoring may impact assessment of both median survival and potential tail-of-the curve effect which is supported by phase II results. However, she doubts this will be a positive trial as >50% of subjects are censored in both treatment groups at interim analysis. The IDMC recommended to discontinue the study for futility and to the best of her knowledge when IDMC recommendation is termination for futility no trial has turned to be positive. Trials may be positive or may be negative. This is clinical research. She pointed out that we have to accept it and it is the reason we conduct phase III randomised clinical trials.

ESMO 2017-ATEZOLIZUMAB FOR HEAD-NECK CANCER

Monotherapy with the checkpoint inhibitor atezolizumab demonstrated promising efficacy in patients with advanced head and neck cancer that was independent of both PD-L1 expression status on immune cells and the presence of human papilloma virus (HPV) infection, according to findings presented during ESMO 2017, the Annual Congress of the European Society for Medical Oncology in Madrid, Spain.

Atezolizumab is an anti–PD-L1 checkpoint inhibitor that restores tumour-specific T-cell immunity by blocking the binding of PD-L1 to both PD-1 and B7.1.

Rastislav Bahleda of the Early Drug Development Department, Gustave Roussy in Villejuif, France presented data from this phase Ia study (NCT01375842) evaluating the safety and clinical activity of single-agent atezolizumab in patients with advanced head and neck cancer.

The first 10 patients were non-selectively enrolled; however, upon identification of PD-L1 as a potential biomarker, subsequent enrolment was based on PD-L1 status of > 5% expression on immune cells (IC2/3) as detected by immunohistochemistry using the VENTANA SP142 antibody. Determination of HPV status was made by PCR.

Of the 32 enrolled patients, 84% were male with a median age of 62 years (range 32 to 78 years), 66% of patients were ECOG performance status 1, and the majority (66%) of patients reported current or previous tobacco use. All patients had been heavily pre-treated, with 53% of patients receiving ≥ 2 prior lines of therapy. Most (56%) patients had a primary tumour in the oropharynx and other common primary tumour sites included the oral cavity in 22%, and nasopharynx in 13% of patients.

Atezolizumab was initially administered intravenously every 3 weeks for 16 cycles or up to 1 year but patients were subsequently treated until loss of clinical benefit was observed.

Atezolizumab monotherapy was safe in patients with head and neck cancer

The primary endpoint of this study was safety.

The duration of follow-up was 14 months or more and the median treatment duration was 3.4 months.

Most (66%) patients experienced a treatment-related adverse event (TRAE). Grade 3 TRAEs of tumour lysis syndrome, hyponatremia, pruritus, and colitis occurred in 3 (9%) patients. One (3%) patient had grade 4 treatment-related cardiac tamponade.

No grade 5 TRAEs were seen.

Atezolizumab showed activity in the overall population and in subgroups of patients with low to no and higher PD-L1 expression status

© Rastislav Bahleda. 

© Rastislav Bahleda. 

PD-L1 expression in immune cells was <5 7="" and="" in="" patients="">5% (IC2/3) in 25 patients. In all patients, regardless of PD-L1 expression, the confirmed objective response rate (ORR) by RECIST v1.1. was 22%; median progression-free survival (PFS) was 2.6 months (range 0.5 to 48.4 months) and median overall survival (OS) was 6.0 months (range 0.5 to 51.6+ months).

The subgroup of 25 IC2/3 patients with higher PD-L1 expression demonstrated an ORR of 24% that consisted entirely of partial responses, and the disease control rate (DCR) was 28%. In responding patients, the median duration of response (DoR) was 26.2 (range 2.8 to 45.8) months.

In the subgroup of 7 patients with low PD-L1 expression, the ORR was 14%, which represented one partial response. The DCR was 43% and the DOR was 7.4 months in responding patients.

Conclusions

The authors concluded that atezolizumab was well-tolerated in patients with advanced head and neck cancer. Encouraging responses and long-term survival were observed. These findings warrant further investigation.

ESMO 2017-NIVOLUMAB FOR HEAD-NECK CANCER

Antitumour activity was observed when nivolumab was continued post-progression in patients with recurrent/metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) who progressed on nivolumab after experiencing prior recurrence within 6 months of platinum-based chemotherapy, according to findings presented during ESMO 2017, the Annual Congress of the European Society for Medical Oncology in Madrid, Spain.

Robert Haddad of the Department of Medical Oncology, Dana-Farber/Harvard Cancer Center, in Boston, USA, and colleagues quantitated the treatment responses to nivolumab after initial radiologic evidence of progression per RECIST v1.1. was observed among participants in the CheckMate 141 (NCT02105636) trial.

The investigators conducted a biomarker analysis and updated the clinical outcomes in patients in the CheckMate 141 nivolumab arm who met protocol defined criteria, which excluded patients without progression or tumour assessment. Immune cell phenotyping was conducted by flow cytometry and it was associated to clinical response in patients having samples available for both treatment days 1 and 43.

Nivolumab prolonged overall survival compared to standard single-agent therapy

CheckMate 141 was a randomised phase III study in patients with R/M HNSCC that compared nivolumab to investigator’s choice of single-agent systemic therapy in 361 patients with progressive disease occurring within 6 months after platinum-based chemotherapy. Nivolumab was administered at a dose of 3 mg per kilogram every 2 weeks. Overall survival (OS) was determined significantly longer with nivolumab compared to standard single-agent therapy (hazard ratio [HR] 0.70 (97.73% confidence interval [CI] 0.51, 0.96).

At ESMO 2017, findings from an analysis based upon a September, 2016 database lock with a minimum follow-up of 11.4 months were presented. Disease progression was detected in 146 (61%) of 240 patients randomised to nivolumab in CheckMate 141. One or more doses of nivolumab was delivered to 62 (42%) of these patients following progression (TBP group), and 84 (58%) patients were not treated beyond progression (NTBP group).

Updated findings show antitumour activity with nivolumab post-progression in recurrent/metastatic HNSCC

Updated findings showed that median OS was 12.7 months (95% CI 9.7, 14.6) with nivolumab in the TBP group.

Caption line for image 1: Overall survival, patients treated beyond progression.

© Robert Haddad. 

Caption line for image 2: Overall survival.

© Robert Haddad. 

After the initial progression, 15 (24%) TBP patients had a reduction in the target lesion size, and 3 patients had a greater than 30% reduction. Of the 15 responding patients, 8 were human papilloma virus (HPV)-positive, 5 had PD-L1 tumour expression ≥1%, and 5 patients had shown a greater than 20% increase in target lesion at the first progression.

Caption line for image 3: Tumor reduction in patients treated beyond progression.

© Robert Haddad. 

Tumor reduction in patients treated beyond progression.

© Robert Haddad. 

Nivolumab showed a safety profile that was in accord with previous reports. The rates of grade 3/4 treatment-related adverse events (TRAEs) were similar in the TBP and NTBP groups.

At day 1, the percentage of PD-1-positive CD8-positive effector T cells was lower in responders and TBP patients . Additionally, on day 1 a  lower percentage of PD-1-positive T-regulatory cells was detected in TBP patients, that was similar to the percentage detected in responders.

Conclusions

Nivolumab-treated patients who experienced tumor reduction with treatment beyond progression had some circulating cellular immune profiles that were similar to conventional responders. Nivolumab treatment beyond progression was sooiciated with tumor size reductions, is well tolerated and can be considered  in some patients with R/M HNSCC, according to the CheckMate 141 investigators .

ESMO 2017-DURVALUMAB FOR HEAD-NECK CANCER

Patients with recurrent/metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) with high PD-L1 expression who have progressed on platinum-based chemotherapy mounted a strong response to the anti-PD-L1 immunotherapy durvalumab, according to findings presented during ESMO 2017, the Annual Congress of the European Society for Medical Oncology, in Madrid, Spain.

Reports that programmed cell death 1 (PD-1) and its ligand 1 (PD-L1) are frequently upregulated in HNSCC, among other tumour types, prompted Dan P. Zandberg, Hematology/Oncology, University of Maryland Greenebaum Comprehensive Cancer Center in Baltimore, Maryland, USA, to investigate durvalumab as monotherapy in patients with R/M HNSCC in the global, single-arm, phase II HAWK study (NCT02207530).

HAWK enrolled immunotherapy-naïve adult patients with high PD-L1 expression, defined as ≥25% staining of tumour cells using the VENTANA SP263 Assay, who had progression or recurrence during or after 1 platinum-based regimen for R/M HNSCC. Durvalumab at 10 mg/kg was administered intravenously to 112 patients for up to 12 months or until progression, the initiation of another anticancer therapy, consent withdrawal, or unacceptable toxicity occurred. The recruited patients, from 12 countries, had a median age of 60 years, 71.4% were male, 34.3% were human papillomavirus (HPV)-positive, and 61.6% of patients were either current or former smokers.

The primary endpoint of the study was objective response rate (ORR) by blinded independent central review according to RECIST v1.1. Progression-free survival (PFS) and overall survival (OS) were secondary endpoints.

Durvalumab shows promise in poor prognosis patients with recurrent/metastatic HNSCC and limited therapeutic options

At data cut-off (DCO) on 31 March 2017 the median duration of treatment was 3.45 months and median follow-up was 6.13 months. Among the 111 patients with evaluable data, the ORR was 16.2% (95% confidence interval [CI], 9.9–24.4). Of the 18 responding patients, 10 (55%) had an ongoing response at DCO.

The disease control rate at 24 weeks (patients with a complete response or partial response plus those with stable disease at 24 weeks) was 23.4%. 

In the overall cohort, median PFS was 2.1 months (95% CI, 1.9–3.7) median OS was 7.1 months (95% CI, 4.9–9.9) and the 12-month survival rate was 33.6% (95% CI, 24.8–42.7).

Caption line for figure: Overall survival.

© Dan P. Zandberg. 

Higher response rates were observed in HPV-positive patients with HNSCC

When the response was evaluated in an exploratory analysis according to HPV status, patients who were positive for HPV demonstrated an ORR of 29.4%, compared with ORR 10.8% in those who were negative for HPV.

Durvalumab demonstrated a manageable safety profile consistent with previous reports. The incidence of grade ≥3 treatment-related adverse events (AEs) was 8.0%. Only 1 patient discontinued durvalumab because of a treatment-related AE. There were no deaths due to a treatment-related AE.

Conclusions

The authors concluded that promising antitumour activity was demonstrated with durvalumab, together with an acceptable safety profile, in patients with R/M HNSCC and high PD-L1 expression. These data support the potential use of durvalumab in this patient population.

Phase III studies of durvalumab with or without tremelimumab (anti-CTLA-4) in recurrent or metastatic HNSCC are currently ongoing (EAGLE NCT02369874 and KESTREL NCT02551159).

ESMO 2017-ADJUVANT DABRAFENIB-TRAMETINIB FOR BRAF+ MELANOMA

Combined dabrafenib plus trametinib as an adjuvant treatment for patients with high-risk BRAF V600-mutated melanoma after surgical resection significantly decreased the risk of death or recurrent disease, according to findings from the phase III COMBI-AD study presented at ESMO 2017, the Annual Congress of the European Society for Medical Oncology in Madrid, Spain.

Axel Hauschild, University Hospital Schleswig-Holstein, Kiel, Germany and colleagues conducted this trial to develop an adjuvant regimen for patients with melanoma and regional nodal involvement (stage III disease), who are still at a high risk for relapse and death after a complete lymphadenectomy.

The randomised double-blind, placebo-controlled, phase III COMBI-AD trial (NCT01682083) investigated dabrafenib plus trametinib as an adjuvant treatment for patients with high-risk stage III BRAF V600E/K-mutated melanoma following complete surgical resection. The trial stratified 870 patients according to BRAF mutation (V600E versus V600K) and stage (IIIA versus IIIB versus IIIC); 18% of patients were stage IIIA, 41% IIIB, 40% were IIIC, and 1% of patients had unknown stage disease.

In this study, 438 patients were randomised to receive dabrafenib at 150 mg twice daily plus trametinib at 2 mg once daily, and 432 patients to receive matching placebo for 12 months. The primary endpoint was relapse-free survival (RFS), with secondary endpoints of overall survival (OS), distant metastasis-free survival (DMFS), freedom from relapse (FFR), and safety.

The primary endpoint of relapse-free survival was met

After a median follow up of 2.8 years, the risk of disease recurrence or death was reduced by adjuvant dabrafenib plus trametinib by 53% compared to placebo, hazard ratio [HR] 0.47; 95% confidence interval [CI] 0.39, 0.58.

The median RFS was not reached versus 16.6 months, respectively, with dabrafenib plus trametinib versus placebo (p < 0.001). This RFS benefit was consistent across all patient subgroups.

Secondary endpoint also showed a benefit; the hazard ratio for OS was 0.57 in favour of the combination (95% CI, 0.42, 0.79), for DMFS the HR was 0.51 (95% CI 0.40, 0.65), and FFR was HR 0.47 (95% CI 0.39, 0.57).

Forty-one percent of patients had grade 3/4 adverse events (AEs) in the combination arm compared to 14% of patients on placebo. Additionally, 26% of patients in the dabrafenib plus trametinib arm discontinued the trial due to an AE compared to 3% of patients in the placebo arm. The type and severity of treatment-related AEs did not differ from already known toxicities observed in randomised trials for advanced unresectable metastatic melanoma leading to the approval for this stage of melanoma in 2015.

Conclusions

In COMBI-AD, adjuvant therapy with dabrafenib and trametinib was associated with improvements in RFS, OS, DMFS, and FFR, and demonstrated manageable safety in patients with high-risk, resected, stage III, BRAF V600E/K–mutated melanoma.

The authors concluded that a combined dabrafenib and trametinib regimen represents a new adjuvant treatment option in this setting.

Alexander Eggermont of the Gustave Roussy Cancer Campus, Villejuif, France who discussed the study results said that dabrafenib/trametinib is convenient oral adjuvant treatment for resected BRAF-mutant melanoma. 

ESMO 2017-ADJUVANT NIVOLUMAB BETTER THAN IPILIMUMAB FOR MELANOMA

Patients with stage IIIb/IIIc or stage IV melanoma at high risk of recurrence following complete surgical resection had greater recurrence-free survival (RFS) with adjuvant nivolumab compared to adjuvant ipilimumab, according to results from the phase III CheckMate 238 study reported at ESMO 2017, the Annual Congress of the European Society for Medical Oncology in Madrid, Spain.

Jeffrey Weber of the Perlmutter Cancer Center, NYU Langone Health in New York, USA presented the first results on behalf of an international research team from the CheckMate 238 trial (NCT02388906), which directly compared nivolumab to ipilimumab in patients with resected stage IIIb/c/IV melanoma at high risk of recurrence.

CheckMate 238 is an ongoing phase III, randomised, double-blind study of nivolumab versus ipilimumab in patients greater than 15 years of age who have undergone complete resection of stage IIIb/IIIc or stage IV melanoma. The trial randomised 906 patients, 453 patients per treatment arm, to receive either nivolumab at 3 mg/kg i.v. every two weeks or ipilimumab at 10 mg/kg i.v. every 3 weeks for four doses and every 12 weeks thereafter until documented disease progression or unacceptable toxicity, up to a maximum treatment duration of one year.

The primary endpoint of recurrence-free survival was met in the ongoing study

The primary endpoint in the study was RFS, defined as the time between randomisation and the date of first recurrence or death.

Overall, stage IIIb, IIIc, and IV disease was reported for 34%, 47%, and 19% of patients, respectively. Thirty-two percent of patients had ulcerated primary disease, 48% had macroscopic lymph node involvement, and 42% of patients were positive for the BRAF mutation.

RFS was significantly improved with nivolumab over ipilimumab at a median follow-up of 18.5 months; the 18-month RFS rates were 66.4% versus 52.7%, respectively, hazard ratio [HR] 0.65; 97.56% confidence interval [CI] 0.51, 0.83 (p < 0.0001).

CheckMate 238 primary endpoint: RFS.

© Jeffrey Weber. 

Median RFS was not reached in either treatment arm.

Findings from prespecified subgroup analyses demonstrated consistent hazard ratios favouring nivolumab

Safety results also favour nivolumab

Fewer grade 3/4 treatment-related adverse events (TRAEs) were observed with nivolumab. Grade 3/4 TRAEs occurred in 14% of patients treated with nivolumab and 46% of patients on ipilimumab.

Study discontinuation due to an adverse event of any grade was reported in 10% of nivolumab and 43% of ipilimumab patients.

The incidence of grade 3/4 immune-related TRAEs for the following organ systems with nivolumab and ipilimumab was: gastrointestinal 2.0% versus 16.8%, hepatic 1.8% versus 10.8%, and skin 1.1% versus 6.0%.

No deaths due to study drug toxicity were reported for nivolumab; however, two (0.4%) patient deaths due to colitis and medullary aplasia occurred in patients more than 100 days after last ipilimumab dose.

Both drugs are currently approved for treatment of advanced melanoma

Nivolumab and ipilimumab are immune checkpoint inhibitors that restore immune anti-tumour activity by different mechanisms. Nivolumab blocks the programmed death 1 (PD-1) receptor and ipilimumab targets the cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) molecule on T cells.

Both drugs have demonstrated significant benefit and have been approved for advanced melanoma. Ipilimumab has also been approved in the adjuvant setting for patients with resected stage III melanoma in the United States since 2015, based on results from the phase III international, double-blind EORTC 18071 trial. This trial showed that ipilimumab at a 10 mg/kg dose reduced the risk of recurrence by 25% versus placebo (HR 0.75; 95% CI, 0.64-0.90; p < 0.002).¹

Despite surgical intervention and possible adjuvant treatment, most patients with stage IIIb/IIIc melanoma experience disease recurrence and many progress to advanced disease. By five years, 68% of patients with stage IIIb and 89% of patients with stage IIIc melanoma experience disease recurrence, making development of successful adjuvant therapy a priority in melanoma.

Conclusions

Nivolumab administered as adjuvant therapy significantly improved RFS compared to ipilimumab for patients with stage IIIb/c/IV melanoma at high risk of recurrence.

ESMO 2017-ADJUVANT VEMURAFENIB FOR MELANOMA

Adjuvant vemurafenib provided substantial benefit to patients with completely resected stage IIC-IIIB BRAF^V600 positive melanoma at high recurrence risk, where fewer disease-free survival (DFS) events and distant metastasis-free survival (DMFS) events were observed with vemurafenib compared to placebo, researchers reported during the ESMO 2017, the Annual Congress of the European Society for Medical Oncology in Madrid, Spain.

However, this benefit was not significant in patients with resected stage IIIC melanoma, where a trend towards improved DFS was seen.

Karl Lewis, an associate professor of medicine, Division of Medical Oncology, at the University of Colorado Denver School of Medicine, in Aurora, USA presented results of the BRIM8 trial, which compared adjuvant vemurafenib to placebo in patients with completely resected V600E BRAF-mutated melanoma who had a high risk of recurrence.

BRIM8 was a randomised, double-blind, placebo-controlled, 2-cohort study that placed 498 adult patients with fully resected stage IIC, IIIA, or IIIB melanoma into cohort 1 and patients with stage IIIC melanoma to cohort 2. Both cohorts were randomly assigned to vemurafenib at 960 mg twice daily or placebo for 52 weeks. In cohort 1, patients were also stratified by geographic region and disease stage.

The primary endpoint of BRIM8 was DFS. Secondary objectives included safety, DMFS, and overall survival (OS). A hierarchical analysis of cohort 2 data prior to cohort 1 was prespecified.

Greater DFS seen with vemurafenib at nearly three years of follow-up

As of the clinical cut-off date for the primary analysis, cohorts 2 and 1 had a median follow-up of 34 and 31 months, respectively.

Cohort 2 contained 184 patients with resected stage IIIC melanoma, including 93 patients on adjuvant vemurafenib and 91 patients on placebo. Analysis of the data revealed a trend towards improved DFS with adjuvant vemurafenib compared to placebo; DFS events occurred in 52 (55.9%) versus 53 (58.2%) of patients, respectively, hazard ratio [HR] 0.80; 95% confidence interval [CI] 0.54, 1.18 (p = 0.2598). The DMFS was similar between treatment arms in cohort 2, HR 0.91 (p = 0.6815).

However, in cohort 1, which included patients with resected stages IIC, IIIA, or IIIB melanoma, adjuvant vemurafenib substantially improved DFS versus placebo. Of the 157 patients in each treatment arm, 45 (28.7%) versus 72 (45.9%) patients receiving vemurafenib versus placebo experienced a DFS event and the median time to event was ‘not estimated’ versus 36.9 months (95% CI 21, NE), respectively, HR 0.54; 95% CI 0.37, 0.78 (p = 0.0010).

Cohort 1 data for DMFS reflected that of DFS: DMFS events occurred in 21.7% of vemurafenib patients versus 33.1% of placebo treated patients and the median time to DMFS event was not estimated for both groups, HR 0.58 (p = 0.0133).

Subgroup analyses were conducted in cohort 1 by common disease and demographic covariates that showed results that were consistent with the overall analysis.

The OS data are immature for both cohorts.  

Both cohorts had a similar exposure to study drug with a median duration of 364.0 days and the median dose intensity was approximately 80% overall.

Patients receiving vemurafenib in cohorts 1 and 2 had a similar incidence of serious adverse events (AEs) of 16.2% and 16.1%, respectively. Cohort 1 showed a slightly higher rate of treatment discontinuation due to a treatment related AEs of 22.7% compared to 15.1% in cohort 2.

Vemurafenib is currently indicated in first line BRAFV⁶⁰⁰ positive advanced melanoma

Current indications for vemurafenib include approval by the European Medicines Agency as a monotherapy or in combination with cobimetinib for the treatment of adult patients with BRAF V600E mutation-positive unresectable or metastatic melanoma and US Food and Drug Administration (FDA) approval for the treatment of patients with unresectable or metastatic melanoma with the BRAF V600E mutation as detected by an FDA-approved test. 

Conclusions

Although the study did not meet the primary DFS endpoint in patients with stage IIIC disease, adjuvant vemurafenib appeared to be well tolerated and effective in patients with resected stage IIC–IIIB BRAF^V600 positive melanoma.

Overall, the safety profile of adjuvant vemurafenib was consistent with previous data and no new safety signals were observed.