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Meeting Highlights

European Society for Medical Oncology 2017

Walter Alexander

The European Society for Medical Oncology (ESMO) 2017 Congress hosted nearly 24,000 participants from 131 countries in Madrid from September 8 to 12, offering 1,736 abstract presentations. Key sessions summarized here present clinical trials of medications for ovarian, lung, gastric, and head-and-neck cancers.

ARIEL3: A Phase 3, Randomized, Double-Blind Study of Rucaparib Versus Placebo Following Response to Platinum-Based Chemotherapy For Recurrent Ovarian Carcinoma

  • Jonathan Ledermann, MD, University College London (UCL) Cancer Institute and UCL Hospitals, London, United Kingdom

Among 564 women with high-grade ovarian cancer (BRCA mutant and recurrent), maintenance therapy with rucaparib (Rubraca, Clovis Oncology) compared with placebo significantly improved progression-free survival (PFS), according to late-breaking trial results.

When women present with ovarian cancer, it is usually already advanced and will recur after first-line treatment in 80% of cases, Dr. Ledermann stated. He noted further that patients often respond again, especially to platinum-based chemotherapy, but relapse and death from ovarian cancer are almost inevitable. The unmet need for maintenance therapy to reduce relapse is plainly evident.

While DNA repair processes are inherently impaired in tumor cells with BRCA mutations, the poly(ADP-ribose) polymerase (PARP) enzyme helps to initiate the repair of DNA damage so that cells can continue to divide. PARP inhibitors such as rucaparib block DNA repair so that cells with BRCA mutations die. About 20% of patients with ovarian cancer have BRCA mutations and are susceptible to PARP inhibitors. Some other patients with the disease are also susceptible, such as patients who respond to platinum-based chemotherapy and those with a high degree of genomic loss of heterozygosity (LOH)—meaning the tumor DNA is scarred and DNA repair mechanisms are faulty, Dr. Ledermann explained.

Patients included in ARIEL3, all of whom had responded to platinum-based second- or third-line chemotherapy, were randomized 2:1 to rucaparib maintenance therapy or placebo. The primary endpoint was PFS measured sequentially in three groups if benefit was found in the previous group: 1) BRCA mutant; 2) BRCA mutant or BRCA wild-type with high LOH (together called homologous recombination deficient [HRD]); and 3) intention to treat.

Dr. Ledermann reported that PFS increased from 5.4 months to 16.6, 13.6, and 10.8 months, respectively, in groups 1, 2, and 3 (all P < 0.0001), with hazard ratios of 0.23, 0.32, and 0.36. He noted that while improvement was significant in all three groups, it was larger (77%) in the BRCA-mutated group.

Investigators also looked at wild-type patients, dividing them into high and low LOH. The exploratory analysis, as expected, showed greater PFS improvement in those with high LOH receiving rucaparib (P < 0.0001), but both were better than placebo (P = 0.01 for low LOH versus placebo).

The safety profile of rucaparib in ARIEL3 was consistent with previous phase 2 studies, with a 13% discontinuation rate for adverse events.

Andrés Poveda, MD, Head of the Gynecological Cancer Clinic at the Oncology Foundation Institute in Valencia, Spain, commented: “ARIEL3 achieved a huge decrease in the risk of relapse with rucaparib. … The addition of rucaparib would expand the population of patients receiving benefit from this type of drugs.”

Dr. Ledermann concluded, “Rucaparib is clearly an exemplary member of this exciting class of drugs [PARP inhibitors] that can be used to treat women with recurrent ovarian cancer in the maintenance setting.”

PACIFIC: A Double-Blind, Placebo-Controlled Phase 3 Study of Durvalumab After Chemoradiation Therapy in Patients With Stage III, Locally Advanced, Unresectable NSCLC

  • Luis Paz-Ares, MD, Hospital Universitario Doce de Octubre, Madrid, Spain

Based on significant improvements in progression-free survival (PFS), durvalumab (Imfinzi, AstraZeneca), a programmed death ligand-1 (PD-L1) inhibitor, is a promising option in patients with stage III, locally advanced, unresectable non–small-cell lung cancer (NSCLC), according to PACIFIC trial results.

Despite concurrent chemoradiation therapy (cCRT), most patients with locally advanced, unresectable NSCLC develop recurrent disease, Dr. Paz-Ares said in an ESMO press conference. Based on evidence of synergy between radiotherapy and immunotherapy, PACIFIC investigators explored the impact of PD-L1 inhibition with durvalumab after standard chemoradiation.

In PACIFIC, patients with good performance status (World Health Organization 0/1) who had received two or more cycles of platinum-based cCRT without progression were randomized (2:1) up to 42 days post-cCRT to receive durvalumab 10 mg/kg intravenously every two weeks or placebo for up to 12 months. Overall survival (OS) and PFS were the coprimary endpoints. The trial was conducted at 235 centers in 26 countries.

PACIFIC investigators enrolled 713 patients (473 on durvalumab and 236 on placebo) and performed a planned interim analysis at a median of 14.5 months. Those receiving durvalumab had significantly longer PFS (16.8 months, 95% confidence interval [CI], 13.0–18.1) versus placebo (5.6 months, 95% CI, 4.6–7.8; stratified hazard ratio [HR], 0.52; 95% CI, 0.42–0.65; P < 0.0001). Also, 12- and 18-month PFS rates for durvalumab and placebo were 55.9% versus 35.3% and 44.2% versus 27.0%, respectively. The objective response rate (ORR) was higher (28.4% versus 16.0%; P < 0.001) and median duration of response was longer (not reached versus 13.8 months) with durvalumab consolidation therapy.

Grade 3 or 4 adverse events occurred in 32.0% of patients receiving durvalumab and in 27.8% of the placebo group, leading to a higher discontinuation rate of 15.4% versus 9.8%, respectively. The most common adverse event, pneumonia, occurred in 4.3% of patients receiving durvalumab and in 4.3% taking placebo. The rate of immune-mediated adverse events was 24% with durvalumab and 8% with placebo.

“Overall there was a slight increase in toxicity in the durvalumab arm, but severe toxicity was similar between groups,” Dr. Paz-Ares said. He concluded, “Durvalumab is a reasonably well-tolerated treatment with a manageable safety profile that improved progression-free survival by 11 months. PD-L1 inhibition after chemoradiation appears to be a new option for patients with locally advanced, unresectable stage III lung cancer.”

The ESMO commentator was Pilar Garrido of Ramón y Cajal University Hospital in Madrid, Spain. “Giving durvalumab after finishing chemoradiation improved progression-free survival by threefold compared to placebo, which is a clinically relevant benefit,” she said. “The magnitude of progression-free survival benefit supports this combination as a new standard of care for unresectable stage III NSCLC patients who had no progression following standard care with platinum-based chemotherapy and concomitant radiotherapy.”

Osimertinib Versus Standard-of-Care EGFR-TKI as First-Line Therapy in Patients With EGFRm Advanced NSCLC: FLAURA

  • Suresh S. Ramalingam, Winship Cancer Institute, Emory University, Atlanta, Georgia

In FLAURA, osimertinib (Tagrisso, AstraZeneca) reduced the risk of cancer progression and extended time to progression compared with the standard of care (SOC) in patients with EGFR-mutated non–small-cell lung cancer (NSCLC), Dr. Ramalingam said at an ESMO press conference.

EGFR mutations are found in about 35% of NSCLC patients in Asia, with a rate of about 15% in Western populations. While EFGR inhibitors are better than chemotherapy for first-line treatment of these patients, with high response rates and good progression-free survival (PFS), resistance to drugs such as erlotinib (Tarceva, OSI Pharmaceuticals) and gefitinib (Iressa, AstraZeneca) is inevitable. The T790M mutation mediates resistance in the majority of patients.

Osimertinib, a third-generation EGFR tyrosine kinase inhibitor (TKI) active in the central nervous system, potently and selectively inhibits both EGFRm and EGFR T790M resistance mutations. Early data suggested osimertinib efficacy as initial therapy for EGFRm advanced NSCLC. A preliminary study in 60 treatment-naïve patients with EGFR mutations found a median PFS of 20.5 months, almost twofold higher than results achieved with erlotinib or gefitinib.

The phase 3, double-blind, randomized FLAURA trial (NCT02296125) compared first-line osimertinib 1:1 to a SOC EGFR TKI in 556 patients (279 on osimertinib; 277 on SOC) from Asia, Europe, and North America with EGFRm (exon 19 or 21) advanced NSCLC. Dr. Ramalingam reported that a PFS benefit for osimertinib was consistent across all subgroups, including those with or without brain metastases, at 17.2 months versus 8.5 months for SOC. Overall response rates were 80% and 76% for osimertinib and SOC, respectively.

Also, patients receiving osimertinib had a twofold-higher median duration of response at 17.2 months versus 8.5 months for SOC. An early analysis of survival showed a nonsignificant trend favoring osimertinib (hazard ratio, 0.63).

Despite longer treatment duration with osimertinib (16.2 months versus 11.5 months), grade 3 or higher toxicities were lower with osimertinib than with SOC treatment (34% versus 45%).

Dr. Ramalingam concluded, “Osimertinib was clearly superior to standard first-line treatment in patients with EGFR-mutated NSCLC.” Regarding the nearly identical PFS for patients with and without brain metastases, he added, “This is important because brain metastasis is a common problem in EGFR-mutated patients.”

ESMO commentator Enriqueta Felip, MD, from the Vall d’Hebron Institute of Oncology in Barcelona, Spain, said: “Based on these results, osimertinib should be considered a new first-line treatment option for patients with EGFR mutations.”

KEYNOTE-059 Update: Efficacy and Safety of Pembrolizumab Alone or in Combination With Chemotherapy in Patients With Advanced Gastric or Gastroesophageal (G/GEJ) Cancer

  • Zev A. Wainberg, Medicine, Hematology, and Oncology, David Geffen School of Medicine, University of California–Los Angeles

Updated results of the KEYNOTE-059 trial of pembrolizumab (Keytruda, Merck) with and without chemotherapy in patients with recurrent or metastatic gastric or gastroesophageal adenocarcinoma show manageable safety profiles and promising antitumor activity. The finding is consistent with prior results from the global phase 2 study, Dr. Wainberg said.

Survival among metastatic gastric cancer patients is generally less than a year, and very few drugs have been approved for this population in the past decade, Dr. Wainberg noted. KEYNOTE-059, one of the largest studies investigating immunotherapy in recurrent or metastatic gastric cancer, included three cohorts: 1) 259 patients with metastatic gastric cancer who received the programmed death-1 (PD-1) inhibitor pembrolizumab alone after pretreatment with two or more lines of chemotherapy; 2) 25 patients with newly diagnosed metastatic gastric cancer who received a combination of pembrolizumab and chemotherapy; and 3) 31 patients with newly diagnosed metastatic gastric cancer who received pembrolizumab alone. Safety in all three cohorts and objective response rate (ORR) in cohorts 1 and 3 were the primary endpoints.

While patients were enrolled in cohorts 1 and 2 regardless of tumor programmed death ligand-1 (PD-L1) expression, only patients with PD-L1–positive tumors were enrolled in cohort 3. Cohort 1 patients received pembrolizumab alone after at least two prior lines of therapy, and cohort 2 patients received pembrolizumab plus cisplatin (80 mg/m2 day 1) plus 5-fluorouracil (800 mg/m2 days 1–5 every three weeks) or capecitabine (in Japan only, 1,000 mg/m2 twice daily) as first-line therapy. Cohort 3 patients received pembrolizumab alone as first-line treatment. In all cohorts, pembrolizumab was given at 200 mg every three weeks for up to two years.

The ORR in cohort 1 (pretreated patients) after a median follow-up of six months was 12%. ORR was 16%, however, in patients expressing PD-L1 and 6% in those who did not. Many responses, Dr. Wainberg said, were durable. In cohort 2, the confirmed ORR was 60% (95% confidence interval [CI], 39–79) overall; 73% (95% CI, 45–92) in PD-L1–positive tumors; and 38% (95% CI, 9–76) in PD-L1–negative tumors. In cohort 3, the confirmed ORR was 26% (95% CI, 12–45). Median PFS (with 95% CIs) in cohorts 1, 2, and 3, respectively, was two months (2–2), seven months (6–11), and three months (2–6).

Grade 3 to 5 treatment-related adverse events (AEs) occurred in 18% of patients in cohort 1, leading to discontinuation in 3% (and death in 1%). In cohort 2, the AE rate of 76% led to discontinuation in 12%; cohort 3 had an AE rate of 23% with one death (3%).

“The expected response rate in these heavily pretreated patients was close to zero, so the findings are encouraging,” Dr. Wainberg said. He noted further that the results “set the stage for a larger follow-up study, which is already enrolling patients.”

ESMO commentator Ian Chau, MD, of Royal Marsden Hospital in London and Surrey, United Kingdom, stated that pembrolizumab will likely become a standard treatment option in this setting. He cautioned, however, “Unlike with chemotherapy, toxicities from immunotherapy tend to occur later on. We need to await longer-term results from an ongoing clinical trial in an earlier line of treatment to know the full impact of this drug in metastatic gastric cancer.”

Pembrolizumab Versus Standard Of Care for Recurrent or Metastatic Head-and-Neck Squamous Cell Carcinoma: Phase 3 KEYNOTE-040 Trial

  • Ezra E. Cohen, MD, University of California, San Diego, Moores Cancer Center, La Jolla, California

While benefits from pembrolizumab (Keytruda, Merck) did not reach the prespecified efficacy boundary, pembrolizumab reduced death risk by 19% in patients with recurrent or metastatic head-and-neck squamous cell carcinoma and provided significant benefits in patients with tumors expressing programmed death ligand-1 (PD-L1). The findings from the KEYNOTE-040 trial, all with standard of care (SOC) (investigator’s choice of either methotrexate, docetaxel, or cetuximab) as the comparator, suggest that immunotherapy with the checkpoint inhibitor may be a better option than standard treatments for patients whose head-and-neck cancer has spread or recurred after an initial round of chemotherapy, according to Dr. Cohen.

Patients in KEYNOTE-040, a global, open-label phase 3 study, had squamous cell carcinoma of the oral cavity, oropharynx, hypopharynx, or larynx; in all, disease had recurred or progressed after a platinum-containing regimen. They were randomized to pembrolizumab (n = 247) or SOC (n = 248) and treated until confirmed progressive disease or intolerable toxicity. The primary endpoint was overall survival (OS).

After a median follow-up of 7.3 months, 8.9% of patients remained on pembrolizumab and 0.9% remained on SOC. While pembrolizumab prolonged median OS in the intention-to-treat population, the difference did not achieve statistical significance (hazard ratio [HR], 0.81, P = 0.02). For the subset of patients with tumors expressing PD-L1 (at least 1%), pembrolizumab was associated with significantly improved outcomes (median OS of 8.7 months versus 7.1 months with standard treatments; HR, 0.75; 95% confidence interval [CI], 0.59–0.95; P = 0.0078). Among patients with PD-L1 expression in more than 50% of their cancer cells, median OS was 11.6 compared with 7.9 months for SOC (HR, 0.54; 95% CI, 0.35–0.82; P = 0.0017).

“Even though the study did not meet its primary endpoint, I still think it is a positive trial,” Dr. Cohen said. “It reinforces that pembrolizumab should continue to be offered as an important option for all patients with this devastating disease.” He also observed that subsequent immunotherapy in the SOC arm may have confounded OS analysis.

The side effect profile of pembrolizumab was better than that of SOC treatments, Dr. Cohen noted, with the exception of hypothyroidism occurring in 13% for pembrolizumab and 1% for SOC.

ESMO commentator Amanda Psyrri, MD, from the University of Athens Medical School and Attikon University Hospital in Athens, said: “Keynote-040 did not reach its primary endpoint of overall survival. However, pembrolizumab was superior to investigator’s choice in terms of toxicity, an important consideration in treatment decisions for these poor-prognosis patients.” She suggested also that for patients with 50% or more PD-L1 expression, pembrolizumab may represent the preferable treatment option.

Author bio: 

The author is a freelance writer living in New York City.