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At ESMO 2016, Many Phase III Trials Fail to Meet Primary Endpoints


The 2016 European Society for Medical Oncology (ESMO) Congress revealed many important positive findings from key trials in a number of tumor types, but many highly anticipated phase III trials in advanced disease failed to meet their primary endpoints. The ASCO Post has summarized several of these study results. Many of these agents showed some activity and will be investigated further.

Selumetinib Plus Docetaxel in Non–Small Cell Lung Cancer


Selumetinib plus docetaxel did not significantly improve progression-free survival compared with docetaxel plus placebo. Currently, there is no clear reason why the phase II results did not translate into a positive phase III study.
— Pasi A. Jänne, MD, PhD

The phase III SELECT-1 trial evaluated an agent that showed promise in a phase II trial of patients with KRAS-mutant non–small cell lung cancer (NSCLC).1 This is a population of patients with unmet treatment needs, according to Pasi A. Jänne, MD, PhD, of Dana-Farber Cancer Institute, Boston, who presented the study at ESMO.

“Oncogenic mutations of KRAS define the largest genomic subset of NSCLC. KRAS mutations are associated with activation of the RAS/RAF/MEK/ERK pathway, which converges as MEK1/2 and drives tumor growth. There are currently no targeted treatments specifically for patients with KRAS mutations,” he said.

Selumetinib, an oral, potent, and selective MEK1/2 inhibitor, was combined with docetaxel in an international phase III study, based on a significant improvement in response rates and progression-free survival in a phase II trial. The SELECT-1 trial randomized 510 patients with KRAS-mutated NSCLC to selumetinib at 75 mg twice daily plus docetaxel at 75 mg/m2 every 3 weeks or to docetaxel alone. The dose intensity was maintained throughout the study and was similar between the arms.

With 88% of the data mature, the primary endpoint, median progression-free survival, was not met. With overall survival data 68% mature, this endpoint was also not improved with selumetinib, Dr. Jänne reported.

Negative Phase III Trials at ESMO

  • In advanced KRAS-mutated non–small cell lung cancer (NSCLC), selumetinib added to docetaxel did not improve progression-free survival in the SELECT-1 trial.
  • In advanced nonsquamous NSCLC patients with disease progression on platinum-doublet chemotherapy, bavituximab plus docetaxel did not improve overall survival vs docetaxel alone in the SUNRISE trial; however, in the subset of patients with beta-2-glycoprotein-1 levels of 200 to 240 µg/mL, median overall survival was 13.2 vs 7.7 months, respectively. Investigators hypothesized that beta-2-glycoprotein-1 may be a biomarker of activity.
  • In the GOLD trial, Asian patients with gastric cancer had no improvement in median overall survival with olaparib at 100 mg twice daily plus weekly paclitaxel vs paclitaxel alone. In ATM protein–negative patients, median overall survival was also similar, though this subset showed a trend for better outcomes with the drug.
  • In the AFFINITY trial, the addition of custirsen to cabazitaxel/prednisone failed to improve survival in patients with previously treated metastatic castration-resistant prostate cancer, vs cabazitaxel/prednisone alone.
  • Although nintedanib showed clinical activity and a modest but negligible gain in progression-free survival in the phase III LUME-Colon 1 trial, the drug failed to improve overall survival in patients with metastatic colorectal cancer refractory to standard treatments.

Median progression-free survival was 3.9 months with the doublet and 2.8 months with docetaxel alone (hazard ratio [HR] = 0.93, P = .44). Objective response rates were 20% and 14%, respectively (P = .05), which is much lower than the rate of 37% vs 0% (P > .0001) observed in phase II. Adverse events ≥ grade 3 were more frequent in the selumetinib arm, as were serious adverse events and those leading to ­hospitalization.

“SELECT-1 was the first and largest prospective phase III randomized, double-blind trial of second-line treatment for patients with KRAS-mutated NSCLC,” Dr. Jänne said. “Selumetinib plus docetaxel did not significantly improve progression-free survival compared with docetaxel plus placebo. Currently, there is no clear reason why the phase II results did not translate into a positive phase III study.”

Exploratory analyses are ongoing or planned for different KRAS codon mutations and other potential factors. “There continues to be an urgent need to develop effective therapies for KRAS-mutant lung cancers,” Dr. Jänne noted.

Bavituximab Plus Docetaxel in Squamous NSCLC

The phase III SUNRISE trial evaluated the novel agent bavituximab plus docetaxel, which was shown in a previous phase II trial to improve overall survival. Bavituximab, a first-in-class IgG1 antibody, targets phosphatidylserine, which in the tumor microenvironment is highly immunosuppressive. Bavituximab exposure results in inhibition of phosphatidylserine upon binding to beta-2-glycoprotein-1. This enhances the production of proinflammatory cytokines, maturation of dendritic cells, and induction of tumor-specific cytotoxic T-lymphocyte immunity.

“Phosphatidylserine-targeting antibodies inhibit tumor growth and enhance the antitumor activity of chemotherapy and radiation,” according to David R. Spigel, MD, of Sarah Cannon Research Institute and Cancer Center, Nashville, who presented the results of the trial.2

SUNRISE enrolled 597 patients with advanced nonsquamous NSCLC who had disease progression on platinum-doublet chemotherapy. Patients received up to 6 cycles of docetaxel in combination with either weekly 3 mg/ kg of bavituximab or placebo.


We think that [beta-2-glycoprotein-1] levels may provide a biomarker for patients who may be more likely to benefit from treatment with bavituximab. This will be evaluated prospectively in future trials.
— David R. Spigel, MD

With 70% of the targeted overall survival events reached, the primary endpoint was not met. However, some interesting observations were observed in a subset of patients: Median overall survival was 10.7 months for the bavituximab group and 10.8 months in the placebo arm (HR = 1.10, P = .382). In patients with pretreatment beta-2-glycoprotein-1 levels ≥ 200 µg/mL, median overall survival was 11.9 and 10.1 months, respectively (HR = 0.81, P = .155)—still not significant. For patients whose beta-2-glycoprotein-1 levels fell within the range of 200 to 240 µg/mL, however, median overall survival was 13.2 vs 7.7 months, respectively (HR = 0.67, P = .049), Dr. Spigel reported.

“SUNRISE did not meet the primary objective of superior overall survival in patients with previously treated nonsquamous NSCLC; however, in patients with high [beta-2-glycoprotein-1], the addition of bavituximab to docetaxel demonstrated a trend for prolonged survival,” he said. “We think that [beta-2-glycoprotein-1] levels may provide a biomarker for patients who may be more likely to benefit from treatment with bavituximab. This will be evaluated prospectively in future trials.”

Olaparib Just Misses the Mark in Advanced Gastric Cancer

In the phase III GOLD trial, the addition of the oral PARP (poly ADP ribose polymerase) inhibitor olaparib (Lynparza) to paclitaxel, vs paclitaxel alone, did not meet its primary endpoint of overall survival in patients with advanced gastric cancer, reported Yung-Jue Bang, MD, PhD, of Seoul National University in Korea.3


We saw a trend toward a survival benefit within the total population, and numerical improvements in secondary endpoints of progression-free survival, objective response rate, and health-related quality of life, particularly in ATM protein–negative patients.
— Yung-Jue Bang, MD, PhD

Although a numerical improvement was found, the results just missed statistical significance. The lack of benefit was seen in both the entire study population and in patients selected for ataxia telangiectasia mutated (ATM) protein negativity. ATM protein is a serine/threonine protein kinase that is recruited and activated by DNA double-strand breaks. Olaparib has shown antitumor activity in other cancers with deficiencies in DNA repair, and in phase II studies in gastric cancer, a greater survival benefit was shown in patients whose tumors were ATM protein–negative.

The study randomized 525 Asian patients to olaparib at 100 mg twice daily plus weekly paclitaxel or paclitaxel alone. The co-primary endpoints were overall survival in all patients and overall survival in patients with ATM protein–negative tumors. Statistical significance was defined as P < .025 for each analysis.

Median overall survival was 8.8 months in the olaparib arm and 6.9 months in the placebo arm (HR = 0.79, P = .0262). In ATM protein–negative patients (n = 94), median overall survival was 12.0 vs 10.0 months, respectively (HR = 0.73, P = .2458). Overall, the doublet was well tolerated, and no new safety signals were observed.

“We saw a trend toward a survival benefit within the total population, and numerical improvements in secondary endpoints of progression-free survival, objective response rate, and health-related quality of life, particularly in ATM-negative patients,” Dr. Bang reported. “Further investigation of olaparib in gastric cancer patients is ongoing.”

Custirsen in Metastatic Prostate Cancer

The addition of custirsen to cabazitaxel (Jevtana)/prednisone failed to improve survival significantly in patients with previously treated metastatic castration-resistant prostate cancer vs cabazitaxel/prednisone alone, according to results of the phase III AFFINITY trial.4 These results were disappointing in light of the promising findings of a phase II trial, where the addition of custirsen to docetaxel improved survival by an absolute value of 7 months compared with docetaxel alone.

©GMG_Scott Morgan
Despite the negative outcome of this trial, the evaluation of custirsen in prostate cancer was conducted on the basis of solid preclinical and clinical evidence supporting antitumor activity…. Just because the drug failed in one tumor type does not predict the outcome of trials in other indications.
— Karim Fizazi, MD, PhD

“Despite the negative outcome of this trial, the evaluation of custirsen in prostate cancer was conducted on the basis of solid preclinical and clinical evidence supporting antitumor activity,” commented principal investigator Karim Fizazi, MD, PhD, of the Institut Gustave Roussy in Villejuif, France.

Custirsen is an investigational drug that blocks the production of clusterin, a cytoprotective protein that prevents apoptosis and protects cancer cells against chemotherapy. The rationale for AFFINITY was based on a phase II trial showing a 40% reduction in the risk of death when custirsen was added to docetaxel.

AFFINITY randomly assigned 635 men with metastatic castration-resistant prostate who experienced treatment failure on hormonal therapy and chemotherapy to receive 21-day cycles of custirsen plus cabazitaxel/prednisone vs cabazitaxel/prednisone alone. Patients were treated for 10 cycles or until the development of disease progression or unacceptable toxicity.

Median overall survival was 14.2 months in the custirsen arm and 13.4 months in the chemotherapy-alone arm. In 62% of patients who were categorized as poor prognosis, median overall survival was 11.1 vs 10.9 months, respectively.

In the custirsen arm, 28.9% discontinued treatment due to progressive disease compared with 25% in the chemotherapy-alone arm. The rates of discontinuation due to adverse events were 21.9% vs 18.9%, respectively. Neutropenia, anemia, fatigue, asthenia, bone pain, and febrile neutropenia were the most frequently reported adverse events.

To explain the negative results of AFFINITY, Dr. Fizazi suggested clusterin may be the wrong target in metastatic castration-resistant prostate cancer or that custirsen is not a sufficiently potent drug. He noted that custirsen is currently being evaluated in NSCLC. “Just because the drug failed in one tumor type does not predict the outcome of trials in other indications,” he said.

Nintedanib in Colorectal Cancer

Nintedanib is an oral multitargeted kinase pathway inhibitor. The drug is approved in some countries for the second-line treatment of NSCLC. (In the United States, nintedanib is approved only for the treatment of idiopathic pulmonary fibrosis.)

Although nintedanib (Ofev) showed clinical activity and a modest but negligible gain in progression-free survival in the phase III LUME-Colon 1 trial, the drug failed to improve overall survival in patients with metastatic colorectal cancer refractory to standard treatments, including chemotherapy and agents targeting the epidermal growth factor receptor (EGFR) or vascular endothelial growth factor (VEGF).5


[Nintedanib] was well tolerated, and we plan to do further analysis to interrogate the efficacy findings, including biomarker analyses.
— Eric Van Cutsem, MD, PhD

“Many patients with progressive disease still have adequate organ function and performance status. An effective treatment for patients [in whom standard therapy fails] is an unmet need. The drug was well tolerated, and we plan to do further analysis to interrogate the efficacy findings, including biomarker analyses,” said lead investigator Eric Van Cutsem, MD, PhD, of University Hospitals, Leuven, Belgium.

The phase III trial enrolled 768 patients and randomized them to receive nintedanib plus best supportive care vs placebo and best supportive care. The co-primary endpoints were progression-free survival and overall survival.

Although nintedanib significantly improved progression-free survival from 1.4 months in the placebo arm to 1.5 months in the experimental arm (HR = 0.58, P < .0001), this difference was clinically meaningless. Nintedanib failed to improve median overall survival, which was 6.4 vs 6.1 months, respectively, Dr. Van Cutsem reported.

Nintedanib did, however, improve disease control, the rates of which were 26% vs 11% (odds ratio = 2.96, P < .0001), he added.

Rates of serious adverse events were similar in both arms: 39% with nintedanib and 35% with best supportive care alone. The most frequent grade 3 or higher treatment-related toxicities were liver-related (16% vs 8%, respectively) and fatigue (9% vs 6%). ■

Disclosures: Drs. Jänne, Fizazi, and Spigel reported no potential conflicts of interest. Dr. Bang has been an advisor/consultant to AstraZeneca. Dr. Van Cutsem has received research funding via his institution) from Amgen, Bayer, Boehringer Ingelheim, Lilly, Merck Serono, Novartis, Roche, and Sanofi.

References

1. Jänne PA, van den Heuvel M, Barlesi F, et al: Selumetinib in combination with docetaxel as second-line treatment for patients with KRAS-mutant advanced NSCLC: Results from the phase III SELECT-1 trial. 2016 ESMO Congress. Abstract LBA47_PR. Presented October 11, 2016.

2. Spigel DR, Bondarenko I, Losonczy G, et al: Top-line results from SUNRISE: A phase III, randomized, double-blind placebo-controlled multicenter trial of bavituximab plus docetaxel in patients with previously treated stage IIIb/IV non-squamous non-small cell lung cancer. 2016 ESMO Congress. Abstract LBA45. Presented October 11, 2016.

3. Bang Y-J, Boku N, Chin K, et al: Olaparib in combination with paclitaxel in patients with advanced gastric cancer who have progressed following first-line therapy: Phase III GOLD Study. 2016 ESMO Congress. Abstract LBA25. Presented October 8, 2016.

4. Fizazi K, Hotte SJ, Saad F, et al: Final overall survival from the AFFINITY phase 3 trial of custirsen and cabazitaxel/prednisone in men with previously treated metastatic castration-resistant prostate cancer. 2016 ESMO Congress. Abstract LBA9. Presented October 10, 2016.

5. Van Cutsem E, Yoshino T, Lenz H-J, et al: Nintedanib plus best supportive care versus placebo plus BSC for the treatment of patients with colorectal cancer refractory to standard therapies: Results of the phase III LUME-colon 1 study. 2016 ESMO Congress. Abstract LBA20. Presented October 9, 2016.



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