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BeiGene’s Phase III BGB-3111 in WMHas Unclear Efficacy Advantage Over Imbruvica

BeiGene’s (NASDAQ:BGNE) BGB-3111 for Waldenström’s macroglobulinemia (WM) will need longer patient follow-up in its Phase I study to ultimately determine if it is superior to AbbVie (NYSE:ABBV) and Johnson & Johnson’s (NYSE:JNJ) Imbruvica (ibrutinib), experts said. Despite impressive early data, its prematurity led experts to say for now it appears comparable to the Imbruvica, which like BGB-3111 is a Bruton’s tyrosine kinase (BTK) inhibitor.

Analysts said the Phase I (NCT02343120) data appeared to show superiority over Imbruvica for BGB-3111, which BeiGene describes as a more selective inhibitor than drug from AbbVie/ Johnson & Johnson (J&J). BGB-3111 is in a global, 167-patient, head-tohead Phase III study (NCT03053440), but experts said at least a couple more years will be needed to fully assess whether it is superior. The trial’s completion date is in June 2021. Rather than simply the current response rate figures, duration of response and toxicity -- both secondary endpoints in the Phase III study, along with the complete response (CR)/very good partial response (VGPR) rate primary endpoint -- will be the distinguishing factors, experts noted.

Meanwhile, experts said they do not expect surprises from an anticipated update at the 2017 ASH meeting. Phase I study data in B-cell malignancies was presented at the International Conference on Malignant Lymphoma (ICML) in Lugano, Switzerland, on 15 June. This news service reported 16 October that as of 3 October the Phase III study had enrolled 53 patients, and Parexel (NASDAQ:PRXL) is the CRO.

The 48-patient dataset for BGB-3111 is comparable in size to the 63-patient dataset that led to Imbruvica’s WM label expansion in January 2015, a BeiGene spokesperson said, adding the response quality appears very favorable compared to what was observed with Imbruvica.

Efficacy advantage over Imbruvica unclear

Experts said they did not expect significant surprises in terms of efficacy or toxicity at ASH assuming Phase I data is updated from the ICML data given the short follow-up. However, they agreed that it will take another two or three years before a clear efficacy picture emerges due to WM’s indolent nature, and duration of response will be a better way than response rates alone to differentiate BGB-3111 from Imbruvica.

The WM Phase I efficacy data presented at ICML looks comparable to Imbruvica, with the possibility that it could be better with longer-term follow-up, agreed an investigator, Dr. Bertrand Coiffier, head, Department of Hematology, University Claude Bernard, Lyon, France, and Dr. Stefan Barta, associate professor, Department of Hematology/ Oncology, Temple University Fox Chase Cancer Center, Philadelphia, Pennsylvania.

"While the BGB-3111 data looked comparable to Imbruvica or potentially better, an important factor to consider when comparing the two drugs is how heavily pretreated patients were"

While the efficacy data for the moment appears comparable to Imbruvica, it does not have sufficient follow-up to get a firm sense of efficacy, said Dr. Martin Hutchings, hematologist, National Hospital, Copenhagen, Denmark. The BeiGene study data from ICML showed an ORR of 90% among 42 efficacy-evaluable patients including a 40% VGPR rate, according to a 15 June press release.

While the BGB-3111 data looked comparable to Imbruvica or potentially better, an important factor to consider when comparing the two drugs is how heavily pretreated patients were, Barta said. Dr. Marco Ladetto, head, Hematology Division, Saints Antonio Biagio and Cesare Arrigo Hospital, Alessandria, Italy, agreed, adding that newly diagnosed patients tend to show very high response rates. Imbruvica’s label expansion was entirely for relapsed/refractory patients, while BeiGene’s press release noted the Phase I study included treatment-naïve patients.

Patients in the BGB-3111 study received between 0-8 prior therapies, according to the ICML abstract (no. 59). WM patients in the study that led to Imbruvica’s label expansion had received 1-9 prior therapies and achieved a 61.9% ORR, including 11.1% VGPRs and 50.8% PRs (Treon et al. N Engl J Med 2015; 372:1430-1440). Subsequent Phase III data at ASH 2015 from a Phase III study of Imbruvica in WM patients refractory to Roche’s (VTX:ROG) Rituxan (rituximab) and with 1-8 prior therapies showed an 84% ORR.

Potential for toxicity advantage

BGB-3111 appears to show hints of a toxicity difference from Imbruvica, the investigator and Ladetto agreed. Indeed, added Ladetto and Coiffier, toxicity will be an important differentiating factor for the drug relative to Imbruvica, especially with respect to bleeding and cardiac events.

According to the BeiGene release, adverse events occurring in more than 10% of the 48 safetyevaluable patients included Grade 1-2 petechiae/ purpura/contusion (35%), upper respiratory tract infection (31%), constipation (25%), diarrhea (19%), epistaxis (19%), nausea (17%), cough (15%), anemia (15%), headache (15%), neutropenia (13%) and rash (13%). In addition, there were three Grade 1-2 cases of atrial fibrillation (AF) and one case of hemothorax, defined as serious hemorrhage at Grade 3 or higher.

There is clearly a lower rate of AF and serious bleeding than is seen with Imbruvica, Barta said, but it is unclear whether it represents a BTK inhibitor class effect or is an effect specific to Imbruvica. Given BGB-3111’s greater specificity to BTK, the investigator expected fewer off-target drug effects. With respect to the cardiac toxicity, the patients who get WM tend to have a higher risk of cardiac events anyway, the investigator added.

Imbruvica’s label warns that Grade 3 or higher bleeding events -- including fatal events – have occurred in up to 6% of patients treated with the drug. AF and atrial flutter have occurred in 6-9% of patients.

November 6, 2017

Alaric DeArment

Reporter, New York

Alaric DeArment joined in March 2014 as a reporter primarily focusing on hematology oncology indications. In addition to analysis of clinical trials, regulatory issues, market uptake and pricing and reimbursement, he has broken news on material drug developments and provided coverage from major medical conferences including ASH, ASCO, EHA and others. In 2016, he moderated a panel discussion at the Clinical Trials Innovation Programme in Miami and was also awarded a fellowship with the Association of Health Care Journalism Comparative Effectiveness Research in Washington. Alaric previously covered prescription drugs as associate editor of Drug Store News, from August 2008 until January 2013. He has a bachelor degree in journalism from Ball State University. A native of Seattle, he also lived in China from September 2001 until September 2004.


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