ESMO 2018-MALE BREAST CANCER

Despite the fact that male breast cancer patients are, on average, older than their female counterparts and that the disease profiles of male breast cancer and female breast cancer differ at diagnosis, male breast cancer patients appear to respond just as well to the same treatments as those given to women, suggest data from several new studies.

The new analyses were presented as posters here at the European Society of Medical Oncology (ESMO) 2018 Congress. They were welcomed by experts, who pointed out that male breast cancer is a rare disease for which there is a paucity of data both on incidence and treatment outcomes.

In the first study, Mohamed A. Gouda, MD, Department of Clinical Oncology, Menoufia University, Shebin El Kom, Egypt, examined data from the National Cancer Institute's Surveillance, Epidemiology, and End Results Program on all cases of breast cancer reported in the United States during 15-year period (2000-2015).

His team identified 6790 men who were diagnosed during the study period, at an incidence rate of 10.2 per 100,000,000 men.

The incidence rate increased significantly during the study period, at an annual percentage change of 1.9% (P < .05).

The majority (81.3%) of cases occurred in white men (median age, 68 years). The cancer was more likely to occur on the left side, at a rate of 52.3%. Most cases were either regional (43.8%) or localized (46.4%) at the time of diagnosis.

Of note, breast cancer was the only primary in 66.3% of patients; it was the first of two primaries in 11.6% of patients; and it was a secondary or later primary in 22.1% of patients.

Calculating median survival using the Ederer II method, Gouda found that median observed survival for male breast cancer was 70.6% at 5 years and 48.8% at 10 years.

Five-year relative survival was estimated at 84.0%, and 10-year relative survival was 71.1%.

Speaking to Medscape Medical News, Gouda said that it is not clear why breast cancer in men should be found more often on the left hand side, but he speculated that it may be related to the disease occurring as a second primary in around a fifth of cases, rather than a phenomenon associated with case reporting.

He added that it "may be a further sequelae of prior treatment."

Gouda underlined that, despite the differences in baseline characteristics between male and female patients, male breast cancer "is treated in the same way that we treat female breast cancer." He added, "To our knowledge, it has a slightly different course."

These findings were echoed by a large study from in France. In that study, the average age and treatment profile were similar for male and female patients.

Jean-Sébastien Frénel, MD, from the Institut de Cancerologie de l'Ouest, Nantes, France, and colleagues collected data from the Epidemiological Metastatic Breast Cancer platform, which includes 18 French comprehensive cancer centers, for 2008 to 2014.

They identified 149 men (0.89%) of a total of 16,701 evaluable breast cancer patients.

Similar to the Gouda study, the mean age of male patients was 68.1 years, which was significantly older than that for women, at 60.6 years (P < .0001).

Men were also significantly more likely than women to have hormone receptor–positive (HR+) and human epidermal growth factor receptor–2 negative (HER2-) disease, at 78.4% vs 65.6% (P = .0019).

Among the HR+/HER2- male breast cancer patients, 42.9% received first-line hormonal therapy, which included tamoxifen (multiple brands) or an aromatase inhibitor with or without a luteinizing hormone–releasing hormone (LNRH) analogue.

Median progression-free survival (PFS) among these patients was 9.8 months, which was comparable to that seen in a group of women matched for age, breast cancer histology, breast cancer grade, metastasis location, and adjuvant therapy, at 13.0 months (P = .8).

For the 27.6% of HR+/HER2- male breast cancer patients who were treated with first-line chemotherapy, median progression-free survival was 6.9 months, which again was similar to the 6.3 months seen in a group of matched women.

Median overall survival was comparable between men and women, at 41.8 months and 34.9 months, respectively (P = .745).

"We found that men with HR+/HER2-disease had similar survival outcomes as women with the same form of breast cancer," Frénel said in a statement.

"Most of the patients receiving hormonal therapy were treated with tamoxifen, and the remainder received aromatase inhibitors," he continued. "But few patients received aromatase inhibitors plus LHRH analogues, despite some guidelines recommending that they should be given in combination."

Commenting for ESMO, Agnes Jager, MD, PhD, from Erasmus Medical University Cancer Institute, Rotterdam, the Netherlands, said that such a large study in men with primary breast cancer "was missing until now."

This justifies our current clinical practice. Dr Agnes Jager

"This new study shows the prognosis of men and women is similar, which is of great value, as this justifies our current clinical practice," she said. "We currently treat men with breast cancer in a similar way to women, which is now supported by these data."

She noted, however, that the study was small and that there was a lack of data on the extent of advanced disease, BRCA mutation status, and the type of chemotherapy used.

"More detailed information and longer-term follow-up will indicate whether there are characteristics or prognostic factors that are specific for men, which will allow us to change practice in the future, " she added.

First Randomized Trial

In the Male-GBG54 study, which is the first prospective randomized trial to examine different hormonal treatments in men with breast cancer, Mattea Reinisch, MD, PhD, from Kliniken Essen-Mitte, Essen, Germany, and colleagues compared tamoxifen with or without a gonadotrophin-releasing hormone analogue (GnRHa) with an aromatase inhibitor plus a GnRHa.

For the study, 55 male breast cancer patients with HR+ disease were randomly assigned to receive one of three regimens for 6 months:

• tamoxifen 20 mg per day;
• tamoxifen plus GnRHa given subcutaneously every 3 months; or
• exemestane (Aromasin, Pharmacia and Upjohn) 25 mg/day plusa GnRHa.

Among the 46 men for whom full data were available, those treated with tamoxifen alone experienced an increase in estradiol levels of 67% at 3 months and 41% at 6 months.

In contrast, in the two arms in which men received hormonal treatment with a GnRH analogue, estradiol levels fell and continued to remain low. The group taking tamoxifen plus GnRHa experienced an 85% decrease at 3 months, whereas those given exemestane plus GnRHa experienced a 73% decrease. This continued for 6 months, with decreases of 59% and 63%, respectively.

Tamoxifen therapy had little effect on health-related quality of life or erectile function. However, both of those measures were severely affected in patients treated with exemestane + GnRHa, the researchers noted.

"The suppression of peripheral estradiol is a necessary condition for a therapeutic benefit of endocrine therapy in men with breast cancer when receiving an aromatase inhibitor plus GnRH analogue," Reinisch said in a press statement.

"Within the tamoxifen monotherapy arm, the estradiol values increased. These changes are known from female breast cancer patients and were expected," Reinisch said.

She concluded that "tamoxifen monotherapy should be kept as standard hormonal therapy for men with breast cancer. The side effects are moderate, hardly impairing sexual behavior.

"The combination with GnRH influenced patients' well-being and erectile function profoundly," she noted.

ESMO expert Jager commented that the researchers "are to be congratulated" for having conducted a randomized trial "in such a rare study population, which must have been a real effort.

"However, it is regrettable that the estradiol suppression at 3 months was the primary endpoint," she said.

"Although it is relevant to know whether and to what extent estradiol levels change over time during different endocrine treatment strategies, as far as I know, estradiol suppression at 3 months is neither a validated nor a clinically useful surrogate endpoint for the efficacy of endocrine treatment," she said.

She added that the finding that tamoxifen allowed an increase in estradiol levels at 3 and 6 months "is not new, although the degree of the increase is somewhat unexpected."

Overall, Jager emphasized that the endpoint used in the study means that the question of whether an LNRH agonist should be added to tamoxifen remains unanswered.

"Due to the severe side effects of LHRH agonists in men and the negative impact on quality of life, clarity about this is of great clinical importance," she said.

Also commenting for ESMO, Stefan Zimmerman, MD, Centre Hospitalier Universitaire Vaudois, Switzerland, said that, taken together, the studies show that "male breast cancer patients seem to benefit from endocrine therapy to a similar degree as women.

"These research results add to the current literature suggesting that the addition of GnRH analogues might improve on tamoxifen alone, but studies with clinical endpoints are needed," he said in a statement.

Zimmerman nevertheless stressed that it "is urgent that strategies that have proven effective in deferring resistance to endocrine therapy in women are explored in men with advanced breast cancer as well, including CDK4/6 inhibitors."

The Male-GBG54 study was funded by the Claudia von Schilling Foundation and was conducted in collaboration with Pfizer. Dr Gouda, Dr Frénel, and Dr Reinisch have disclosed no relevant financial relationships. 

European Society for Medical Oncology (ESMO) 2018 Congress. Abstracts 259P, 294PD, and 273PD, presented October 22, 2018.

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ESMO 2016-DABRAFENIB-TRAMETINIB-PANITUMUMAB FOR BRAF MUTATIONS

Patients with metastatic colorectal cancer and tumors harboring the BRAF V600E mutation who received triple therapy with dabrafenib (Tafinlar), trametinib (Mekinist), and panitumumab (Vectibix) showed an improved best overall response and prolonged progression-free survival compared to panitumumab plus either drabrafenib or trametinib, according to results reported by Corcoran et al at the 2016 European Society for Medical Oncology (ESMO) Congress in Copenhagen (Abstract 455O).

Dabrafenib acts by inhibiting BRAF and trametinib by inhibiting MEK1 and MEK2; both agents block the MAPK pathway. Both drugs have demonstrated activity and have been approved for BRAF V600E–mutated melanoma, for use either as single agents or in combination. BRAF V600E mutations have also been reported in 5% to 10% of metastatic colorectal cancer cases; however, BRAF- and MEK-inhibiting monotherapies have been shown to have little activity in metastatic colorectal cancer, where the presence of a BRAF V600E mutation often signals a poorer prognosis.

Lead author Ryan B. Corcoran, MD, PhD, Translational Research Director for the Gastrointestinal Cancer Center at Massachusetts General Hospital and a Damon Runyon Clinical Investigator, presented findings from a study testing whether combined inhibition of the EGFR pathway with panitumumab and dual inhibition of the MAPK pathway could provide clinical benefit in BRAF-mutated metastatic colorectal cancer. This study evaluated the efficacy and safety of panitumumab plus dabrafenib or trametinib, and in triple combination with both.

The trial enrolled 134 patients with BRAF-mutated metastatic colorectal cancer who were randomized to receive panitumumab plus dabrafenib (n = 20), panitumumab plus trametinib (n = 31), or triple combination with panitumumab, dabrafenib, and trametinib (n = 83). Each agent in the combination could be administered at up to the full monotherapy dose.

The trial included integrated biomarker analyses. Tumor biopsies were taken prior to and during treatment and evaluated by immunohistochemistry for phosphorylated ERK. Serial circulating tumor DNA samples were obtained and profiled for mutations in the BRAF, KRAS, NRAS, and PIK3CA genes.

The majority of study participants, 120 patients, had received prior chemotherapy for metastatic colorectal cancer, and 14 were treatment-naive.

Improved Progression-Free Survival

In the dabrafenib/panitumumab treatment arm, the confirmed complete/partial response rate was 10%, and 80% of patients achieved stable disease. With trametinib/panitumumab, no patients attained complete/partial response, but 53% showed stable disease. However, the 2 agents combined with panitumumab yielded an 18% complete/partial response rate, and 67% of patients showed stable disease.

Median progression-free survival for combined dabrafenib/trametinib/panitumumab has not yet been reached compared with median progression-free survival of 3.4 and 2.8 months demonstrated with dabrafenib/panitumumab and trametinib/panitumumab, respectively.

The safety analysis showed that the most commonly reported adverse events overall were dermatitis acneiform, diarrhea, fatigue, nausea, and rash.

Integrated Biomarker Analysis

Immunohistochemistry done in on-treatment and pretreatment biopsies revealed a reduction in phosphorylated ERK in on-treatment vs pretreatment biopsies. The median phosphorylated ERK reductions were 23% for dabrafenib/panitumumab, 50% for trametinib/panitumumab, and 54% for the triple combination.

Serial circulating tumor DNA analysis also showed reductions in the BRAF V600E–mutant fraction of more than 70% as early as week 4 of treatment in 12 of 14 (86%) patients in the dabrafenib/trametinib/panitumumab arm. This finding corresponds with the partial response achieved by 6 of these 12 patients by week 6.

Conversely, circulating tumor DNA analysis also demonstrated an increased BRAF V600E–mutant fraction in 10 patients upon progression.

Other mutations that were not present at baseline were detected in circulating tumor DNA upon progression. Of the 12 patients showing a best response of complete/partial response or stable disease, 7 (58%) patients had RAS mutations in circulating tumor DNA upon progression that were not detectable at baseline; 3 of these patients developed multiple RAS mutations. In addition, BRAF V600E and RASmutations were coexpressed in 2 patients at baseline.

Conclusions

Combined dabrafenib/trametinib/panitumumab demonstrated acceptable tolerability and activity in BRAF-mutated metastatic colorectal cancer, according to the authors, who further concluded that integrated biomarker analysis by immunohistochemistry provided evidence of downstream target inhibition. The circulating tumor DNA data suggested that changes in BRAF V600E–mutation frequency may serve as a biomarker and allow for monitoring of both treatment response and disease progression. The investigators explained that preexisting and emergent RAS mutations may represent potential mechanisms of resistance to combination treatment.

ESMO 2016-12 WEEK INTERVAL BETWEEN CHEMORADIOTHERAPY AND SURGERY FOR RECTAL CANCER

A longer waiting interval from the end of preoperative chemoradiotherapy to surgery increases the rate of pathologic complete response and yields a higher proportion of patients achieving tumor downstaging in patients with locally advanced rectal cancer, according to new findings from a prospective, randomized trial presented by Evans et al at the 2016 European Society for Medical Oncology (ESMO) Congress in Copenhagen (Abstract 452O).

Greater tumor downstaging and regression could impact the rates of sphincter preservation and achieve improved local control, according to Jessica Evans, MBBS, MRCS, of the Colorectal Surgery Department at the Royal Marsden Hospital NHS Foundation Trust. Dr. Evans and colleagues conducted this prospective, randomized, multicenter trial designed to determine whether a 6- or 12-week interval between neoadjuvant chemoradiotherapy and surgery is optimal in patients with locally advanced rectal cancer to allow greater rectal cancer downstaging and tumor regression.

This study enrolled 237 patients with locally advanced rectal cancer to receive chemoradiotherapy followed by surgery. Following chemoradiotherapy, 122 patients were randomized to a cohort with a planned 6-week interval, and 115 patients were randomized to another cohort with a 12-week interval between chemoradiotherapy and surgery.

12-Week Cohort and Tumor Downstaging

Differences were observed between the two cohorts in the proportion of patients achieving downstaging of their tumors and in the pathologic complete response rates. A greater proportion (58%) of patients in the 12-week interval cohort had tumor downstaging compared with 43% of patients in the 6-week interval cohort (P = .019).

An improved rate of pathologic complete response was also observed with a longer interval; the pathologic complete response rate was 20% in the 12-week vs 9% for the 6-week cohort (P < .05). Additionally, more patients in the 12-week interval cohort achieved magnetic resonance imaging (MRI) tumor regression grade of 1 or 2 (52% in the 12-week arm vs 34% in the 6-week arm; P < .05).

Conclusions

The authors advised that a longer (12-week) interval after chemoradiotherapy prior to surgery results in significantly greater tumor downstaging, improved pathologic complete response rates, and greater MRI tumor regression grade. Since obtaining a pathologic complete response and improved MRI tumor regression grade after the neoadjuvant treatment is an accepted surrogate measure of disease-free survival, undertaking surgery before maximal regression may be disadvantageous in patients with locally advanced rectal cancer. The authors recommend that the adoption of a change in the standard from surgery at 6 to 8 weeks to surgery at 12 to 14 weeks can only be safely undertaken if MRI evaluation of response or progression is still undertaken at 4 to 6 weeks.

ESMO 2016-VEMURAFENIB FOR BRAF V600 MUTATED TUMORS

Findings from a phase II trial of vemurafenib in previously treated patients with advanced disease and BRAF-mutated tumors indicate that the drug is effective in patients with diverse BRAF V600­–mutated tumors but not in patients with BRAF non-V600 mutations. After a mean treatment duration of  1.9 months (range = 0.2–11.0 months), antitumor activity of vemurafenib was found in non–small cell lung cancer (NSCLC), hairy cell leukemia (HCL), and a miscellaneous cohort of BRAF V600–mutated tumors, while non-V600–mutated tumors derived no benefit.

Vemurafenib is approved for BRAF-mutated melanoma and has shown activity in other nonmelanoma tumors that harbor BRAF V600E mutations, which have been reported to be present at low (< 5%) frequency.

Jean-Yves Blay, MD, PhD, medical oncologist at the Centre Léon Bérard, in Lyon, France, presented results from the phase II ACSE study at the 2016 European Society for Medical Oncology (ESMO) Congress in Copenhagen (Abstract 55PD). Dr. Blay explained that this study is part of an effort undertaken by the French National Cancer Institute (INCa) that attempts to avoid off-label use and to allow patients to have safe and controlled access to targeted therapies outside of the labeled indication.

ACSE Trial

The ACSE trial enrolled patients for whom standard treatment for different types of advanced cancers had failed. All patients had a BRAF mutation that was identified using INCa molecular genetic platforms. Of the more than 1,500 patients screened for mutations at 96 centers throughout France, 78 patients with BRAFV600 and BRAF non-V600 mutations were enrolled and treated with vemurafenib at 960 mg twice daily.

The dedicated treatment cohort comprised diverse BRAF V600–positive cancer types including lung, ovarian, bladder, thyroid, and prostate cancers; cholangiocarcinoma; sarcoma/gastrointestinal stromal tumor (GIST); multiple myeloma; chronic lymphocytic leukemia (CLL); and HCL. The specific miscellaneous cohort comprised patients with non-V600 BRAF (exon 11, 15)–mutated tumors or other BRAF alterations.

The efficacy endpoint was objective response rate (ORR), which was evaluated every 8 weeks by RECIST (Responce Evaluation Criteria in Solid Tumors) version 1.1 criteria for solid tumors and by specific criteria for myeloma, CLL, and HCL. Treatment could be halted early when an inefficacy boundary for objective response of 10% that was determined by a Bayesian approach was demonstrated.

The median age of the patients was 67 (range = 18–84) years, and 51% of patients were female. Data from 56 patients were analyzed for response and reported by mutation status and cancer subtype.

Response Demonstrated Across Tumor Types

In the cohort of patients with BRAF V600–positive cancers, 31 patients with NSCLC demonstrated an ORR of 43%; 13 patients achieved partial response, 6 showed stable disease, 7 patients experienced progressive disease, 4 patients died, and the data were missing for 1 patient.

In patients with HCL, 4 of 4 patients having evaluable data showed an ORR of 100%; 2 patients demonstrated a partial response, and 2 patients had stable disease.

The one patient with sarcoma died.

Of the 2 patients with cholangiocarcinoma, one patient also died and one patient demonstrated SD.

Of the 3 patients with thyroid cancer, 1 patient demonstrated stable disease and 2 had progressive disease.

In the miscellaneous cohort, 5 of 6 patients with BRAF V600 mutations had evaluable data: partial response was achieved by 3 of these patients, and 2 patients showed stable disease, resulting in an ORR of 60%. All 6 patients with BRAF non-V600–mutated tumors experienced progressive disease.

The most frequently reported treatment-related adverse events of grade 3 or greater were skin and gastrointestinal toxicities.

Conclusions

The authors concluded that the nationwide screening program for BRAF mutation allowed patients with BRAF-mutated disease to have faster access to treatment in this trial. Although vemurafenib demonstrated important antitumor activity in NSCLC, HCL, and miscellaneous V600 mutation–positive tumors, patients with BRAF non-V600–mutated tumors derived no benefit.

ESMO 2016-LURBINECTEDIN FOR BRCA+ BREAST CANCER

Lurbinectedin showed promising clinical benefit in pretreated patients with metastatic breast cancer and BRCA1or BRCA2 mutations, including patients previously treated with platinum, according to phase II trial results presented by Balmaña et al at the 2016 European Society for Medical Oncology (ESMO) Congress in Copenhagen (Abstract 223O).

Lurbinectedin (PM01183) blocks transactivated transcription by binding to the minor groove of DNA. Activity has been demonstrated in patients with diverse tumor types, and in those that are resistant to platinum-based chemotherapy. Observations that lurbinectedin was active against homologous recombination–deficient cell lines led investigators to test it in patients with metastatic breast cancer having deleterious germline BRCA mutations, said lead investigator Judith Balmaña, MD, PhD, of the Department of Medical Oncology, Hospital Vall d’Hebron and Vall d’Hebron Institute of Oncology in Barcelona.

Trial Details

This phase II trial enrolled patients with BRCA mutation–positive, measurable metastatic breast cancer per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1, with performance status ≤ 1. Patients were required to have adequate major organ function. L

urbinectedin was initially to be administered to all patients at a 7-mg fixed dose intravenously every 3 weeks, but the dose was changed by protocol amendment to 3.5 mg/m2 for improved safety. In all, 35 patients received 7 mg of lurbinectedin, and 19 patients were treated with 3.5 mg/m2. The primary endpoint of the trial was confirmed overall response rate (ORR) by RECIST v1.1.

The patients’ median age was 43 years. Thirty patients had performance status 0, and 33 patients had more than 2 metastatic sites. The patients had a median of one prior chemotherapy treatment for advanced disease. Additionally, 45 patients had received prior anthracyclines, 47 received taxanes, 27 received platinum, and 9 had been treated with PARP inhibitors. BRCA1 mutations were documented in 30 patients, and 31 patients had triple-negative breast cancer.

Primary Endpoint Met

Lurbinectedin had been administered to 54 patients as of May 2016, with patients receiving a median of 6 (range: 1–24) treatment cycles.

Of 54 patients with evaluable data, the ORR was 39% (95% confidence interval [CI] = 26%–54%) in patients receiving the fixed dose and 44% in patients dosed at 3.5 mg/m2, with an overall response rate of 40.7% (95% CI = 27%–55%). The best overall response with lurbinectedin included complete response in 1 patient (2%), partial response in 21 (39%), and stable disease in 23 (43%). Just 9 patients (17%) with advanced metastatic breast cancer experienced progressive disease. The median duration of response was 6.7 months (95% CI = 3.0–11.3), and progression-free survival was 4.1+ months (95% CI = 2.8–5.9).

Platinum-pretreated patients demonstrated an ORR of 26% (95% CI = 11%–26%).

In patients receiving the fixed dose of lurbinectedin, the most commonly reported grades 3/4 adverse events included neutropenia in 71% of patients and grade 4 neutropenia, which was seen in 51%. Febrile neutropenia occurred in 29%; thrombocytopenia and transaminase increase were each seen in 26% of patients. Grade 4 throbocytopenia, and transaminase increase occured in 20% and 3% of patients, respectively. Grade 3 fatigue and nausea occurred in 17% and 9% of patients, respectively.

Conclusions

At the reduced dose, adverse events included neutropenia in 50% of patients, febrile neutropenia and thrombocytopenia in 6% each, transaminase increase occurred in 11%, and grade 3 fatigue and nausea occurred in 17% and 6%, respectively. Grade 4 neutropenia was seen in 5% of patients but no other grade 4 adverse events occurred in this cohort.

The investigators concluded that the trial met the primary endpoint and lurbinectedin showed activity in primary BRCA–positive metastatic breast cancer, including patients who had previously received platinum therapy.

They noted that tolerance to lurbinectedin improved at the 3.5 mg/m2 dose without compromising efficacy.

Based on these results and on predefined criteria of 17 or more confirmed responses in the cohort of evaluable patients, the investigators concluded that further development of lurbinectedin in patients with BRCA mutation and metastatic breast cancer is warranted.

ESMO 2016-ESMO BENEFIT SCALE FOR RARE TUMOURS

COPENHAGEN, Denmark — The European Society for Clinical Oncology (ESMO) Magnitude of Clinical Benefit Scale (MCBS) was found to be a helpful tool for clinical practice in rare tumors, according to findings of the first study to analyze the tool in this setting.

The authors analyzed the feasibility of using the MCBS for rare tumors and assessed data on neuroendocrine tumors (NETs); glioblastomas; sarcomas; and thyroid, pancreatic, ovarian, head/neck, and urothelial cancers.

Overall, the ESMO-MCBS was an effective adjunct for clinicians and supported treatment decisions based on the expected clinical benefit.

That said, lead author Barbara Kiesewetter, MD, from the Medical University of Vienna, Austria, noted that its practicability was also somewhat limited in cases where there was a lack of randomized trial data, such as for sarcoma and glioblastoma.

"However, the ESMO-MCBS was applicable in most situations where controlled trials were available, such as the data on salvage treatment with pazopanib for soft tissue sarcoma achieving a score of 3 based on a significant progression-free survival gain of 3 months in comparison to 1.6 months in the placebo arm," she said in a statement.

The findings were presented here at the ESMO Congress 2016.

Tool to "Stratify" Drug's Benefit 

Released last year, the ESMO-MCBS was developed to offer a rational, structured, and consistent approach to "stratify" a drug's clinically meaningful benefit.

The scale was developed and field tested on 77 cancer drugs across 10 cancer types, and it takes into account several measures of efficacy as well as the prognosis of the condition and the toxicity of the drug. These factors are taken together to assess the magnitude of clinical benefit.

The treatment is then analyzed with respect to the duration of response or survival in the control arm, and this results in a clinical benefit ranking.

Cost was not included in the assessment tool because of the variation in prices across different European countries.

In the current study, Dr Kiesewetter and colleagues note that while they have already evaluated the practicability of using the ESMO-MCBS in daily practice for treating common tumor types at their center, it has not yet been used for rare tumors.

To analyze the feasibility of using the tool for rare tumors, they developed a three-step approach.

First, data were retrospectively collected to gain an overview of which treatments were in regular use. Next, they scored the data by using the ESMO-MCBS. Third, they evaluated the results with the corresponding program directorships to assess feasibility in a real-life setting.

For NETs and thyroid cancer, the authors found that recently published trials for these cancers were similar in design and efficacy and the ESMO-MCBS scores were consistent with the clinical benefit seen in practice.

"However, the MCBS added little information on the question of optimal sequencing except for differentiated thyroid cancer where prior treatment (TKI [tyrosine kinase inhibitor] or not) suggests an algorithm," they write.

With pancreatic cancer, only two major trials evaluating first-line treatment were available, and thus making any direct comparisons was difficult.

ESMO-MCBS was useful for gastrointestinal stromal tumor (GIST) and non-GIST sarcoma, but MCBS practicability was limited for rare subtypes because of a lack of controlled trials.

"For sarcomas, practicability of ESMO-MCBS was limited due to a lack of trials in many indications," said Dr Kiesewetter. "However, the ESMO-MCBS was useful whenever randomized data were available. For example, the ESMO-MCBS score of 4 clearly underlines the clinical benefit achieved by adding dacarbazine to gemcitabine in pretreated soft tissue sarcoma."

"This is in line with our clinical experience and supports further use of the ESMO Magnitude of Clinical Benefit Scale," she noted.

The authors did find that the MCBS supported the use of bevacizumab in high-risk patients with ovarian cancer, but for the remaining cancers in their study — glioblastoma, head/neck, and urothelial cancers — only minimal data were available.

The study was funded by the Department of Medicine at the University of Vienna. Dr Kiesewetter has disclosed no relevant financial relationships; several of the coauthors report relationships with industry.

European Society for Medical Oncology (ESMO) 2016 Congress. Abstract 1364O_PR. Presented October 10, 2016.

ESMO 2016-WHY ONCOLOGISTS USE CHEMOTHERAPY AT THE END OF LIFE

Despite the effort of major organizations, including the Institute of Medicine and the American Society of Clinical Oncology (ASCO), to put more emphasis on palliative care for cancer patients, data suggest that chemotherapy use in the last 2 weeks of life may actually be increasing in the United States.^[1]

At ESMO 2016 in Copenhagen, Paolo Bossi, MD, a medical oncologist in the Head and Neck Cancer Department at the Fondazione IRCCS Istituto Nazionale dei Tumori in Milan, Italy, provided his perspective on a new study analyzing chemotherapy at the end of life on Medscape's ESMO 2016 Live Blog, which is excerpted below.

For a review of the most important ESMO 2016 sessions across all tumor types, visit Medscape's ESMO 2016 Live Blog.

The supportive and palliative care session at ESMO 2016 featured a very interesting study^[2] presented by Philippe Rochigneux, MD, from the Institut Paoli-Calmettes Cancer Center in Marseille, France, on the use of chemotherapy near the end of life.

The study analyzed different factors associated with administering chemotherapy in the last months of life, such as young patient age, oncologist as treating physician, chemosensitivity of the tumor, and access to palliative care, among other factors.

The main analysis was performed with data from a national French hospital-based registry, including about 280,000 patients, that were used to calculate the rates of chemotherapy and targeted therapies in the last 3 months of life. Seventy percent of the patients were over 60 years of age; in 30% of the cases there was a palliative care unit in the facility.

The results deserve attention: About 40% of patients received chemotherapy in the last 3 months of life, 20% in the last month of life, and 11% in the last 2 weeks of life. About 7% of the patients started or resumed a therapy in the last month of life.

The following characteristics were associated with an increase in chemotherapy rates in the last month of life:

• Patient-related factors, including male sex, young age, and fewer comorbidities;
• Tumor location, specifically head and neck, lung, breast, and gynecologic cancers; and
• Institutional factors, including higher overall volumes of chemotherapy given and private facilities.

During the abstract discussion, Stein Kaasa, MD, PhD, a professor of palliative medicine at the Institute of Cancer Research and Molecular Medicine at the Norwegian University of Science and Technology in Trondheim, asked what would be an ideal goal: 0% in the last month of life and 10% in the last 3 months?

This may be ideal, certainly, but what conclusions can be drawn from the current study?

Guidelines for oncologic care near the end of life are urgently needed, using prognostic scores to assess the possible benefit, or not, in choosing to continue (or to start) chemotherapy. Moreover, promoting end-of-life discussions with patients and caregivers is essential and should be started early in the course of patient care.

ESMO 2016-HIGHLIGHTS OF MEETING

Lung Cancer 

The Presidential Symposia featured two important trials on immunotherapy in lung cancer, including a landmark trial of pembrolizumab alone as first-line therapy and new data on pembrolizumab plus chemotherapy, also in the first-line setting.

The data on first-line pembrolizumab in non–small-cell lung cancer (NSCLC) come from the first 305 patients enrolled in the phase 3 KEYNOTE-024 study,^[1] presented by Martin Reck, MD, PhD, and published simultaneously in the New England Journal of Medicine.

This study was conducted in patients whose lung cancer biopsies showed no EGFR or ALK mutations and showed high expression of programmed death-ligand 1 (PD-L1) (defined as expression in 50% of tumor cells).

In this patient population, pembrolizumab alone gave superior results to platinum-containing doublet chemotherapy—median progression-free survival (PFS) was 10.3 vs 6 months (hazard ratio [HR], 0.50). The secondary endpoint of overall survival (OS) was also significantly improved: The OS rate at 6 months was 80% vs 72% (HR, 0.60) and the 1-year OS rates were 70% vs 54%. Toxicity was lower with immunotherapy compared with chemotherapy as well (grade 3/4 adverse events, 27% vs 53%).

The other data on pembrolizumab plus chemotherapy in the first-line setting come from a small phase 2 trial of 123 patients in the KEYNOTE-021 study,^[2] presented by Corey Langer, MD, from the University of Pennsylvania.

This study was conducted in patients with squamous NSCLC who were not selected on the basis of PD-L1 expression, so it is a bigger patient population than the pembrolizumab-alone study—but again, patients with EGFR and ALK mutations were excluded. Pembrolizumab was added onto the chemotherapy doublet of carboplatin plus pemetrexed, and compared with chemotherapy.

The addition of pembrolizumab improved PFS to 13.0 vs 8.9 months (HR, 0.53; P = .0102), but it also added to toxicity (grade 3 or higher, 39% vs 26%).

In KEYNOTE-024, a randomized trial of pembrolizumab vs platinum-based chemotherapy in patients with previously untreated advanced NSCLC with high PD-L1 expression (> 50%), pembrolizumab produced a higher response rate, longer median PFS, and longer median OS despite a 50% crossover rate.

The HR for PFS was 0.5, with a median PFS of 10.3 months in the pembrolizumab arm vs 6.0 months in the chemotherapy arm. The HR for death was 0.6, and median OS has not been not reached. It is a understatement to say that thoracic oncologists are not used to HRs in this range. To complete the fairy tale, tolerability was in favor of pembrolizumab, with only 26% grade 3/4 adverse events.

We do indeed have a new standard of care for this subgroup of patients with high expression of PD-L1. Yet the discussant, Jean-Charles Soria, MD, PhD, raised a very valid point: The portion of patients who can benefit from upfront immunotherapy desperately needs to be enlarged. If 1934 patients are screened but only 500 patients are randomized, it means we treat about 1 out of 4 of our everyday patients. On a positive note, he highlighted the response rate of 44%—a record in the first-line setting—and the HR was a record low of 0.35 in the squamous subgroup.

The future might well belong to combinations, with early-phase trial results—KEYNOTE-021, for instance—hinting at combinations massively outperforming monotherapy.

Corey Langer, MD, presented the results of cohort G from KEYNOTE-021, a randomized phase 2 trial. The response rate reached 55% in the combination arm vs 29% for chemotherapy alone. Median time to response was 1.5 months—much faster than with chemotherapy alone. The response rate reached a whopping 80% in PD-L1 high expressors. PFS was massively increased, with an HR of 0.53 and a median PFS of 13.0 vs 8.9 months. Of note, response rates were similar for PD-L1–positive and PD-L1–negative patients. These phase 2 findings must be confirmed by the sister phase 3 trials KEYNOTE-189 (platinum/pemetrexed with or without pembrolizumab in nonsquamous tumors) and KEYNOTE-407 (carboplatin/paclitaxel with or without pembrolizumab in squamous tumors).

The landscape is changing faster than we can fathom. We barely got used to the idea of pembrolizumab as first-line therapy in high expressors. Phase 3 trials will also provide insight into subgroups.

The million-dollar question now is whether chemotherapy is necessary at all in PD-L1–low subgroups, and whether pembrolizumab monotherapy can be beaten. Can we move to a chemotherapy-free regimen for most patients?

The answer may reside in the combination of cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and PD-1/PD-L1 checkpoint blockade. This is currently being pursued in at least three trials: CheckMate 227, NEPTUNE, and MYSTIC. CheckMate 227 is two studies, actually; PD-L1–positive patients are randomly assigned to receive ipilimumab plus nivolumab vs nivolumab alone vs chemotherapy, whereas PD-L1–negative patients are randomly assigned to two different schedules/doses of nivolumab plus ipilimumab, or to chemotherapy.

NEPTUNE is testing durvalumab plus tremilimumab vs chemotherapy, and MYSTIC is testing durvalumab alone, vs durvalumab plus tremelimumab, vs chemotherapy. Missing in these trials is a chemotherapy plus chemotherapy arm, which might now well be the adequate comparator arm

Breast Cancer 

Ribociclib is a new cyclin-dependent kinase 4/6 (CDK4/6) inhibitor for use in combination with letrozole in patients with metastatic hormone-dependent breast cancer that is HER2-negative. It is a similar drug to the recently approved palbociclib (Ibrance®; Pfizer).

Interim results from the MONALEESA-2 study^[3] presented at ESMO 2016 indicate that adding ribociclib to letrozole improves PFS by 44% and significantly improves overall response to therapy. After a median follow-up of 15.3 months, ribociclib was associated with a significant improvement in PFS, with an HR of 0.556 (P = 3.29 × 10⁶). This corresponded with a median PFS of 14.7 months in the placebo arm, whereas median PFS was not reached in the ribociclib arm.

Among patients with measurable disease at baseline, the overall response rate was 52.7% with ribociclib vs 37.1% with placebo (P < .001). The clinical benefit rate was 80% and 72%, respectively (P = .02).

The most common grade 3/4 adverse events reported in at least 5% of ribociclib and placebo recipients, respectively, were neutropenia (59% vs 1%), leukopenia (21% vs 1%), hypertension (10% vs 11%), and elevated alanine aminotransferase levels (9% vs 1%). Discontinuation rates because of adverse events were 7.5% and 2.1%, respectively.

We have all been waiting for a serious strategy to delay acquired resistance to frontline antihormone therapy. And yet we know all too well that not just any combination with aromatase inhibitors is a step in the right direction: Despite a massive improvement in PFS, the combination of exemestane and everolimus is poorly tolerated, and enthusiastic oncologists are few.

Enter ribociclib. The HR for PFS was 0.556, median PFS not reached (14 months in the letrozole alone arm). Neutropenia was very frequent, but febrile neutropenia rare. High-grade nonhematologic toxicity was rare. It looks like we have a serious contender after all.

Good points from the invited discussant, Stephen Johnston, MD, PhD, from the Royal Marsden Hospital in London: The FALCON study presented this morning during the breast cancer session demonstrated superior PFS with fulvestrant over the aromatase inhibitor anastrozole. Fortunately, MONALEESA-3 (ribociclib plus fulvestrant first-line/second-line) is fully accrued. Stay tuned.

Also, the curves separated early: A large portion of patients derived a benefit, in contrast with the aromatase inhibitor-alone arm, where we witnessed a rapid fall at the beginning of the PFS curve. Ribociclib results are in line with those for albociclib in the same setting, studied in the PALOMA-2 trial. It seems we actually have two good drugs to combine with first-line letrozole. Dr Johnston's conclusion: It is a game changer.

Metastatic Melanoma 

New results from the phase 3 EORTC study of adjuvant ipilimumab (Yervoy®; Bristol-Myers Squibb) used in high-risk stage III metastatic melanoma, now with a follow-up of more than 5 years, showed an improvement in overall survival with adjuvant ipilimumab, which has not been seen before.^[4]Previous trials in such patients with nodal involvement treated with interferon failed to show improved survival, according to principal investigator Alexander Eggermont, MD, PhD, director general of the Institut Gustave Roussy in Villejuif, France.

OS rates at 5 years were 65.4% with ipilimumab vs 54.4% with placebo, representing a 28% reduction of the relative risk for death (HR, 0.72; P = .001).

However, in this trial, ipilimumab was used at the higher dose of 10 mg/kg and was associated with a 40% rate of grade 3 and 4 adverse immune-related events. So the question remains of whether a lower dose with less toxicity, such as the 3 mg/kg that is now often used, would have similar efficacy in this adjuvant setting.

Patients with resected stage III melanoma are at high risk for recurrence. Their 5-year survival rate with adjuvant ipilimumab was 11 percentage points higher than with placebo (65% vs 54%), at the cost of significant immune-related toxicity.

It is fair to say that melanoma oncologists are unfamiliar with meaningfully effective adjuvant therapy. So there is no benchmark on how toxic an adjuvant therapy can be, and how effective it has to be. To make a long story short...

It was undeniably toxic. 13% of patients completed the 3 years, with the predominant cause of discontinuation being adverse events. The median number of doses was just four. Among the patients, 54% had grade 3/4 adverse events, 41% had immune-related adverse events, and 1% had drug-related toxic deaths.

It was undeniably effective. The 11% absolute improvement in 5-year survival—no patient at risk after that landmark—is much better that what is observed in NSCLC, and similar to or better than what we consider acceptable for early breast cancer.

Good points from a brilliant discussion of the abstract by Olivier Michielin, MD, PhD, from Lausanne University Hospital:

• There was no benefit in the stage IIIA population—because there are no ulcerated melanomas?
• An effective immune reaction can be mounted even if only residual disease is present.
• We will now be exposing the whole population to toxic immune-related effects, when only 11% truly benefit. We have a responsibility as a community to improve the toxicity/benefit ratio—better drugs, better patient selection.
• The data support stopping adjuvant therapy after four infusions.

His conclusion: EORTC 18071 sets a new historical landmark in our quest for the optimal treatment of melanoma.

ESMO 2016-TARGETED THERAPIES FOR BREAST CANCER

COPENHAGEN — Should a targeted therapy be added to endocrine therapy in the treatment of hormone-dependent metastatic breast cancer? Should such a combination now be standard of care? These questions were debated here at the European Society for Medical Oncology (ESMO) Congress 2016.

Opening the session, Michael Gnant, MD, director at the Department of Surgery, Vienna Medical University, Austria, said, "We've seen exciting data at this meeting, and previously, about advances in the treatment of ER [endocrine receptor]-positive breast cancer, and the controversy about it is going to go on."

He was referring to new data presented here for the investigational cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitor ribociclib (Novartis) with letrozole, as well as published data for palbociclib (Ibrance, Pfizer), in the treatment of ER-positive metastatic breast cancer. As previously reported by Medscape Medical News, experts here said that the new data are leading to a "paradigm shift" in the management of this disease.

But clinicians in the audience did not appear to be convinced.

The question for the debate was whether combined endocrine therapy with targeted agents should now be the standard of care for ER-positive metastatic breast cancer.

Clinicians in the audience were invited to cast their votes on six debate questions on different therapeutic scenarios (see below). Round 1 votes were cast before the debate began, and round 2 votes were cast after the debate.

Combination Superior to Single Agent 

The "yes" argument to support the motion that combined endocrine therapy with targeted agents should now be the standard of care for ER-positive metastatic breast cancer was outlined by Angelo di Leo, MD, PhD, head of the Medical Oncology Unit, Department of Oncology, Hospital of Prato, Istituto Toscani Tumori, Prato, Italy.

Dr di Leo said that the PALOMA 2 trial, which compared palbociclib and placebo in combination with letrozole; the PALOMA 3 trial, which compared palbociclib and placebo in the context of fulvestrant therapy; and the BOLERO 2 trial, which looked at everolimus or placebo with exemestane had changed practice in the treatment of ER-positive/human epidermal growth factor receptor (HER)-2–negative advanced breast cancer.

He said that the MONALEESA-2 trial, presented here at ESMO 2016, can now be added to this list. As reported by Medscape Medical News, this trial showed that adding the investigational CDK4/6 inhibitor ribociclib to letrozole showed a significant improvement in progression-free survival when compared with letrozole alone.

"Whatever the setting, whether first-line, second-line or third-line, the results of these important studies are clearly showing that combination therapy is better than single agent," he said.

Dr di Leo noted that most patients in these trials had previously benefited from a prior round of endocrine therapy, while the remainder were endocrine therapy naive. Before the latest results with combination therapy, it was assumed that they would receive endocrine therapy alone. However, combination therapy has been shown to be "better."

Specifically, progression-free survival (PFS) is improved with the treatments in the trials compared with placebo, and subgroup analysis has shown that there is "not one single" subgroup in which a single agent is better than combination therapy

However, Dr di Leo said, because the PFS curves show that many patients experience relapse, particularly in the first 6 months of treatment, predictive markers are required to identify these patients and potentially allow them to be treated in a different way.

Further considerations, he noted, are the safety profile of the combination therapy, the overall survival benefit, and the "financial" toxicity.

In terms of safety, he pointed out that no combination therapy is less toxic than a single agent. However, the safety impact of the current combinations is not serious because most adverse effects were grade 1.

Dr di Leo acknowledged the lack of overall survival data: The data from the PALOMA and MONALEESA studies are not yet mature, and BOLERO 2 showed no survival benefit.

He countered, however, that the trials were not powered to detect overall survival differences. Furthermore, overall survival is not a sensitive endpoint because its determination is often confounded by noninvestigational therapies being given after disease progression in trials and by crossovers between study groups.

The financial impact of the drugs is substantial, Dr di Leo conceded. However, he argued that health economy assessments "must not be the primary aim of treating physicians" and that the "main responsibility" of a physician is to use the latest treatments "according to the principles of evidence-based medicine."

High Relapse Rate 

Arguing on the "no" side of the debate, Jonas Bergh, MD, PhD, professor, Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden, argued that the initially high rate of relapse after initiation of combination therapy in the trials highlighted by Dr di Leo as requiring predictive markers can be readily explained. Pointing to a 2012 paper by Lindström et al, he said that clinically used breast cancer markers, such as estrogen receptor and HER2 status, are unstable throughout tumor progression.

Dr Bergh noted that the currently available guidelines for the treatment of breast cancer show a "great deal of uncertainty" regarding whether to recommend combination therapy in ER-positive breast cancer. He added: "There's a bit of 'concern,' 'could be considered,' 'may,' et cetera, so I think this is may be a slightly more reflective view on this complicated issue."

He also pointed out that there are no data on whether the drugs should indeed be used in combination or rather in sequence, "and the reason for that is, of course, that there are theoretical concerns but there are also concerns over harming the patient."

Dr Bergh agreed with Dr di Leo that the lack of an observed survival benefit with combination therapy could indeed be due to crossover or a lack of follow-up, "but the worst scenario is that these targets are not good enough" and the current data are "a little bit problematic."

Summarizing, he said that he cannot support the notion that combined endocrine therapy with targeted agents should now be the standard of care for ER-positive metastatic breast cancer because there have, so far, not been any survival gains and, in some cases, the side effects have been "quite challenging."

He said that chemotherapy should also be considered in these patients if indicated, although no prospective data currently support this. The financial impact is also of concern, particularly considering uptake and usage in different regions and countries.

Audience Responses

The audience then voted again on the same questions as before.

The second round of voting showed that the audience felt that not all patients with ER-positive metastatic breast cancer should receive first-line combination therapy, that patients with limited disease can receive endocrine therapy alone, and that the newer targeted agents postpone the use of chemotherapy. Most audience members agreed that cost could be an issue in preventing the widespread use of these agents.

The audience was largely split as to whether the overall survival data should be a factor in deciding whether to use targeted agents in ER-positive metastatic breast cancer. However, they were more certain that chemotherapy should not be used upfront as an indiction therapy

Dr Gnant commented that the debate did not substantially change audience opinions, although it did reduce the number of "don't know" responses and did strengthen some opinions. The audience was more persuaded, however, that cost should not be an issue in preventing the adoption of newer, targeted therapies.

Questions

1. Should all patients with ER-positive metastatic breast cancer receive first-line CDK4/6 inhibitors or mammalian target of rapamycin (mTOR) inhibitors together with endocrine therapy?
2. Can patients with limited disease (eg, single bone lesion) receive endocrine therapy as first-line treatment?
3. Is lack of overall survival data a key limitation in the use of targeted agents in ER-positive metastatic breast cancer?
4. Is cost an issue that should prevent a widespread use of these new agents?
5. Does the arrival of targeted agents postpone the use of chemotherapy in ER-positive metastatic breast cancer?
6. Should chemotherapies rather be used upfront, as induction, when patients usually can better tolerate side effects than in later lines, when they have progressed and likely tolerate these therapies less well?

Table. Audience Responses (Percentage) before (Round 1) and After (Round 2) the Debate

Question	Yes: Round 1	Yes: Round 2	No: Round 1	No: Round 2	Don't Know: Round 1	Don't Know: Round 2
1	21.3	22.7	69.5	74.9	9.2	2.3
2	86.0	83.2	11.7	15.3	2.3	1.5
3	41.8	41.1	50.8	56.9	7.3	2.0
4	71.8	65.7	23.7	31.9	4.6	2.4
5	79.9	70.4	14	23.5	6.1	6.1
6	24.1	25.5	69.2	70.5	6.7	4.0

No funding reported. Dr di Leo reports acting in an advisory role for AstraZeneca, Bayer, Celgene, Lilly, Novartis, Pfizer, and Roche and receiving lecture fees from AstraZeneca, Eisai, Genomic Health, Novartis, Pfizer, Pierre Fabre, and Roche.

European Society for Medical Oncology (ESMO) Congress 2016. "Should Combined Endocrine Therapy With Targeted Agents Now Be the Standard of Care for ER+ Metastatic Breast Cancer?" Presented October 8, 2016.