Buparlisib Extends PFS in Head and Neck Cancer

Denis Soulières, MD

Adding the pan-PI3K inhibitor buparlisib (BKM120) to chemotherapy reduced the risk of disease progression or death by 35% in patients with advanced head and neck squamous cell carcinoma (SCCHN), according to results from the phase II BERIL-1 trial presented at the 2016 ASCO Annual Meeting.

“Buparlisib and paclitaxel should be considered a standard second-line therapy for patients with SCCHN who are eligible for taxane therapy,” lead author Denis Soulières, MD, a hematologist and medical oncologist at Centre Hospitalier de l’Université de Montréal, said when presenting the results at ASCO.

BERIL-1 randomized 158 patients with recurrent or metastatic SCCHN who progressed following platinum-based therapy to buparlisib plus paclitaxel (n = 79) or placebo plus paclitaxel (n = 79). The median age was approximately 59 years and over 80% of patients in each arm were male.

Sixty-one percent of patients in the buparlisib arm and 67% of patients in the control arm had an ECOG performance status (PS) ≤1. The remaining patients in each arm had an ECOG PS of 0. Sixty-two percent of patients receiving buparlisib and 60% of patients in the control arm were former smokers. The rates of never smokers in each arm were 24% and 19%, respectively.

The rates of primary tumor locations—which included the oral cavity, oropharynx, hypopharynx, and larynx—were similar between the 2 treatment arms. Sixty-seven percent of patients in the buparlisib group and 79% of patients in the control arm were HPV-negative.

In the buparlisib arm, the percent of patients who had received ≥1, ≥2, or ≥3 prior lines of therapy in any setting were 100%, 56% and 11%, respectively. The corresponding rates were 100%, 53%, and 9% in the control arm.

In the metastatic setting, 90% of patients in the buparlisib group had received 1 prior line of therapy, with 4% having received 2. The corresponding rates were 98% and 3%, respectively, in the control group. Fifty-two percent of patients in buparlisib arm and 38% of patients in the placebo group had received an EGFR inhibitor.

Patients were not eligible if they had received a taxane-based regimen for metastatic disease or an AKT, mTOR, or PI3K inhibitor. Individuals who received more than 1 chemotherapy regimen in the recurrent or metastatic setting were also excluded.

The population was stratified by prior lines of therapy and study location. Progression-free survival (PFS) was the primary endpoint. Secondary outcome measures included overall survival (OS), overall response rate (ORR), and safety.

Buparlisib was administered at 100 mg daily and paclitaxel was dosed at 80 mg/m2 weekly. Patients were treated until disease progression or discontinuation. At the time of the analysis, the median duration of treatment was 3.4 months and 2.6 months, respectively, with median dose intensities of 86% and 95%, in the 2 arms.

The median PFS was 4.6 months with buparlisib versus 3.5 months in the control arm (HR, 0.65; 95% CI, 0.45-0.95; P = .011). The 6-month PFS rate was 34% versus 19%, respectively.

The median OS was 10.4 months with buparlisib versus 6.5 months in the control arm (HR, 0.72; 95% CI, 0.56-0.92; P = .041). The 12-month OS rates were 43% versus 33%, respectively.

“Of note, the number of patients who went on to receive further lines of therapy after progression was similar between the 2 groups, and the types of agents that were received were also similar,” said Soulières.

The ORR was 39.2% in patients receiving buparlisib compared with 13.9% in the control group (P <.001). Among HPV-negative patients, the ORR was 39.6% versus 11.3%, respectively. The ORR also favored buparlisib among HPV-positive patients, but at a lower rate of 35.3% versus 27.3%.

The efficacy [of buparlisib] was maintained across most patient subgroups, and was higher in patients with poor-prognosis SCCHN, including those with HPV-negative status, progression on prior therapy, or nonoropharyngeal disease,” said Soulières.

Soulières also noted that patients with TP53 mutations and those with a low mutational load had a greater overall survival benefit and a higher At the time of the analysis, 5% of patients in the buparlisib cohort were still receiving treatment compared with 3% of patients in the placebo arm. Thirty-eight percent of patients in the buparlisib arm and 17% of patients in the placebo arm had a dose reduction. Sixty-two percent and 37% of patients in the two arms, respectively, had dose interruptions.

The primary reasons for treatment discontinuation were progressive disease (49% in the buparlisib arm vs 65% in the in control arm), adverse events ([AEs]; 10% vs 14%), death (11% vs 10%), and other (20% vs 8%).

Seventy-six patients in the buparlisib arm and 78 patients receiving placebo were evaluable for safety. The most common all-grade AEs were hyperglycemia (63% in the buparlisib arm vs 35% in the control group), anemia (41% vs 42% ), fatigue (41% vs 22%), diarrhea (38% vs 17%), neutropenia (33% vs 12%), alopecia (32% vs 19%), stomatitis (32% vs 13%), appetite decrease (30% vs 19%), asthenia (28% vs 22%), nausea (26% vs 17%), vomiting (26% vs 14%), and weight decrease (25% vs 12%).

The most common grade 3/4 AEs occurring in the buparlisib arm included hyperglycemia (22% vs 3% in the control arm), anemia (18% vs 12%), neutropenia (17% vs 5%), stomatitis (9% vs 1%), fatigue (8% vs 10%), asthenia (8% vs 4%), appetite decrease (7% vs 5%), and vomiting (4% vs 0).

Soulières D, Faivre SJ, Mesia R, et al. BERIL-1: a phase II, placebo-controlled study of buparlisib (BKM120) plus paclitaxel in patients with platinum-pretreated recurrent/metastatic head and neck squamous cell carcinoma (SCCHN). J Clin Oncol. 34, 2016 (suppl; abstr 6008).