Sunil R. Hingorani, MD, PhD
Adding PEGPH20 to standard nab-paclitaxel (Abraxane) and gemcitabine demonstrated improvements in progression-free survival (PFS) compared with nab-paclitaxel/gemcitabine alone for untreated patients with advanced pancreatic cancer, with the best results observed in those with high expression levels of the biomarker hyaluronan (HA), according to new findings from the phase II Study 202 trial presented during a webcast by Halozyme, the company developing the medicine.
Across 279 patients in the study, the primary endpoint of median PFS was 6.0 months in the PEGPH20 arm versus 5.3 months for nab-paclitaxel/gemcitabine (HR, 0.73; 95% CI, 0.53-0.99; P
= .045). The overall response rate (ORR) was 40% with PEGPH20 and 33% in the control arm.
In those with HA expression on ≥50% of cells, the median PFS was 9.2 months with PEGPH20 (n = 49) compared with 5.2 months in the control arm (n = 35; HR, 0.51; 95% CI, 0.26-1.00; P
= .048); however, overall survival (OS) was not significantly improved (11.5 vs 8.5 months; HR, 0.96; 95% CI, 0.57-1.61). The ORR was 45% with PEGPH20 versus 31% in the control arm.
"The analysis suggests statistically significant and clinically important progress in this very difficult to treat cancer," lead investigator Sunil R. Hingorani, MD, PhD, medical oncologist with the Seattle Cancer Care Alliance, said in a statement. "The median PFS is a notable increase over the current standard of care and supports ongoing exploration in the current phase III study."
Study 202 was placed on clinical hold in 2014 to address concerns regarding thromboembolic events in the PEGPH20 arm, after enrolling 146 patients in the first stage of the trial. To address this hold, the protocol was amended to exclude those at high risk for a thromboembolic event. Additionally, prophylaxis with low weight molecular heparin was required. One hundred thirty-three patients were enrolled into the second stage of the trial.
The primary endpoint of the study was PFS across the full population. With the protocol change, a second primary endpoint was added to assess thromboembolic events. Secondary endpoints included ORR, PFS by HA level, and OS. Stage 2 of the study also focused on validating a companion diagnostic for HA levels, which is being used in an ongoing phase III study of the combination for patients with untreated stage IV HA-high pancreatic cancer (NCT02715804).
In the phase II study, PEGPH20 was administered at 3 µg/kg twice weekly for cycle 1 followed by weekly administration in subsequent cycles. Nab-paclitaxel and gemcitabine were administered at their standard FDA-approved doses. Tumor biopsy samples for the HA analysis were available for 138 patients treated with PEGPH20 and 79 treated in the control arm across both stages of the study. Overall, 49 patients in the PEGPH20 arm and 35 in the control group had HA expression of ≥50%.
In stage 1 of the study, the median PFS in the HA-high group was 9.2 months with PEGPH20 versus 4.3 months in the control arm; however, these findings were not statistically significant (HR, 0.48; 95% CI, 0.18-1.32). The median OS in the HA-high group for the PEGPH20 arm was 11.5 versus 10.9 months, which was also not statistically significant (HR, 1.37; 95% CI, 0.69-2.70).
In stage 2, similar non-statistically significant findings were seen for PFS and OS in the HA-high group of patients (n = 35). The median PFS was 8.6 months with PEGPH20 (n = 24) versus 4.5 months with gemcitabine/nab-paclitaxel alone (n = 11; HR, 0.63; 95% CI, 0.21-1.93). The 12-month PFS rate was 28% with PEGPH20 versus 30% in the control arm. The median OS was 11.7 versus 7.8 months, with and without PEGPH20, respectively (HR, 0.52; 95% CI, 0.22-1.23).
In those with HA-low tumors, those treated with PEGPH20 (n = 53) had a median PFS of 6.0 months versus 7.2 in the control arm (n = 23; HR, 1.21; 0.63-2.30). The median OS in this group with PEGPH20 was 11.9 versus 10.2 months in the control (HR, 0.69).
"The Study 202 data confirm for the first time in a randomized phase II trial using the current standard of care that a biopsy-based biomarker for hyaluronan content can potentially identify patients who will have a meaningfully greater response when PEGPH20 is added to their treatment," said Hingorani.
Almost all patients experienced at least 1 treatment-related adverse event. Grade ≥3 adverse events were experienced by 86.3% of those in the PEGPH20 arm versus 75% in the control group. The most common grade ≥3 events were neutropenia (29.4% vs 18%), fatigue (20.6% vs 16%), anemia (16.9% vs 20%), and thrombocytopenia (16.3% vs 9%).
Patients enrolled in stage 2 received low weight molecular heparin at a starting dose of 40 mg/day or 1 mg/kg/day, to counter thromboembolic events. Across all patients, thromboembolic events were experienced by 14% of those in the PEGPH20 group versus 10% of those in the nab-paclitaxel/gemcitabine arm. These events were lower with the 1 mg/kg/day dose (10% vs 6%, respectively).
"The data overall and the cumulative experience overall is very reassuring that we can manage the thromboembolic event rate appropriately. Pancreatic cancer itself is considered a hypercoagulative state, so there are always challenges treating these patients," Hingorani noted. "The rates are equivalent between the two arms."
A phase III study, known as HALO 301, is currently assessing PEGPH20 in combination with nab-paclitaxel and gemcitabine for patients with metastatic pancreatic cancer with high HA levels. The primary endpoint of the study is PFS, with secondary outcomes measures focused on toxicity and OS. The use of low weight molecular heparin is mandated in the study.
"The randomized phase II results continue to support the ongoing phase III trial," said Athena Countouriotis, MD, chief medical officer at Halozyme. "There is consistency between the phase II and phase III programs, with the same patient population and companion diagnostic cutoff in the study."
Countouriotis A. Study 202 Overall Results and Stage 2 Results [webcast]. Halozyme Investor Call; January 5, 2017. http://event.on24.com/wcc/r/1289434/154D4E3FE46A91B931B0B1FF6FFD4549. Accessed January 5, 2017.