New Directions in Oncology Biosimilars

During a session at the 2018 American Society of Clinical Oncology Annual Meeting, held June 1-5 in Chicago, Illinois, researchers gave a glimpse into new directions in oncology biosimilars through providing results on several studies testing the safety, efficacy, and usage of different biosimilars.

Filgrastim

Based on a comparative analysis, Sandoz’s biosimilar filgrastim, Zarxio, prevented febrile neutropenia in both a randomized controlled trial and in real-world practice in patients with breast cancer receiving neo-adjuvant therapy.

Nadia Harbeck, MD, PhD, head of the Breast Center at the University of Munich, Germany, presented findings from an analysis comparing efficacy and safety results of biosimilar filgrastim from the randomized controlled PIONEER trial and real-world surveillance from MONITOR-GCSF.

The pivotal phase 3 PIONEER trial compared biosimilar filgrastim to its reference product in primary breast cancer patients receiving Taxotere, Adriamycin, and cyclophosphamide (TAC) chemotherapy. Patients were randomized to receive the biosimilar, its reference, or to alternate between the 2.

MONITOR-GCSF was a prospective, observational, open-label post-marketing surveillance of biosimilar filgrastim in patients with solid/hematological malignancies receiving myelosuppressive chemotherapy. Patients received primary or secondary prophylaxis with biosimilar filgrastim.

Researchers compared data from 217 patients from PIONEER and 466 patients from MONITOR-GCSF.

The incidence of febrile neutropenia (FN) was comparable between the 2 studies, with 5.1% of PIONEER patients experiencing FN in any cycle and 6.2% of MONITOR-GCSF patients experiencing FN.

However, 74.3% of PIONEER patients experienced severe neutropenia, compared to 19.5% of MONITOR-GCSF patients. Similarly, more patients from PIONEER experienced fever (5.6% vs 3.4%). Meanwhile, a greater proportion of MONITOR-GCSF patients experienced infection (15.5% vs 7.9%).

Looking at safety data, the grade of adverse events was generally higher in the PIONEER cohort, including musculoskeletal and connective tissue disorders (261 vs 20), infections and infestations (31 vs 3), skin and subcutaneous tissue disorders (258 vs 5), and general disorders and administration-site conditions (673 vs 7).

Harbeck underscored the fact that different chemotherapies were used in each study, with TAC being known to have a number of chemotherapy-associated side effects. In addition, since MONITOR-GCSF used a real-world data source, it should be assumed that there was some underreporting of adverse events, she noted.

Rituximab

“We know rituximab is the golden standard of care for patients with non-Hodgkin lymphoma [NHL],” said Alessandra Franceschetti, IPSOS Healthcare, as she presented an analysis of treatment approaches for NHL.

As rituximab has several biosimilars approved in the European Union (EU), the analysis determined shifts in prescribing activity by physicians from the branded version of the drug to a biosimilar version for the treatment of NHL and what the clinical drivers were.

The multi-center medical chart study included 97 physicians responsible for prescribing anti-cancer drug treatments who reported online medical charts of patients with NHL. A total of 640 medical charts of patients with NHL from France, Italy, Germany, Spain, and the United Kingdom were analyzed from July 2017 through September 2017.

Among the 640 patients, 77% were reported as treated with a regimen including rituximab. Of those patients, 7% were treated with a rituximab biosimilar, which was largely driven by Germany and the United Kingdom (14% and 13%, respectively). “This is aligned with what we were expecting, because at the time of the analysis, these were the 2 countries where the commercialization of biosimilars of rituximab had started first,” explained Franceschetti.

In the United Kingdom and Germany, the prescribing of rituximab biosimilars among patients recently initiated to their current line of therapy increased as the line of therapy progressed. In the first-line setting, 11% were treated with a rituximab biosimilar. By the third-line setting, 30% were treated with a rituximab biosimilar.

Those being treated with a rituximab biosimilar were more likely to have indolent rather than aggressive NHL (70% vs 52%) and have Follicular Lymphoma as a sub-type of NHL (56% vs 35%).

“This leads us to conclude that physicians who prescribe a rituximab biosimilar seem to adopt a precautionary strategy, initiating the biosimilar in situations where potential side effects would be less debilitating, such as for patients in better overall health or those associated with a better prognosis,” concluded Franceschetti.

Bevacizumab

Analytical studies have shown that PF-06439535, a proposed bevacizumab biosimilar, has similar structure to US-licensed bevacizumab and EU-licensed bevacizumab; nonclinical studies have shown it has similar toxicity, toxicokinetics, and immunogenicity to the EU drug in cynomolgus monkeys; and comparative clinical pharmacologic studies have shown it has similar pharmacokinetics (PK), safety, and immunogenicity to both the EU- and US-licensed drugs in healthy male volunteers, explained Mark A. Socinski, MD, executive medical director, Florida Hospital Cancer Institute.

Now, comparative clinical study results have demonstrated the proposed biosimilar has similar efficacy, safety, PK, and immunogenicity as EU-licensed bevacizumab in patients with non-squamous non—small cell lung cancer (NSCLC).

In the double-blind, multicenter study, 719 patients with advanced non-squamous NSCLC were randomized to receive carboplatin and paclitaxel every 3 weeks in combination with either the EU-licensed bevacizumab or PF-06439535. The primary endpoint was overall response rate (ORR) by week 19 (and confirmed by week 25). Secondary endpoints included safety, duration of response, 1-year progression-free survival (PFS) rate, 1-year survival rate, and immunogenicity.

The researchers observed that the ORR was 45.3% for those treated with PF-06439535 and 44.6% for those treated with the reference. The median PFS was 9 months for PF-06439535 and 7.7 months for the reference, and the overall survival rate was approximately 66% for both cohorts, with a median of approximately 18 months in both groups.

In regard to adverse events, the rate of hypertension was the same in both arms at slightly less than 10%. Rates of all other adverse events—cardiac disorders, bleeding, VTEs, protein urea, ATEs, and health failure—were not statistically different between the 2 cohorts.

Socinski concluded by asserting the similarity between PF-06439535 and EU-licensed bevacizumab was demonstrated for the primary efficacy endpoint of ORR, and that there were no notable differences in 1-year PFS rate or 1-year OS rate.

“These results confirm similarity demonstrated in earlier analytical, non-clinical, and clinical studies of PF-06439535 and bevacizumab-EU,” he said.

Trastuzumab

Hope Rugo, MD, director of the breast oncology clinical trials program at the University of California at San Francisco and advisory board member of The Center for Biosimilars^® concluded the session with updated results from the HERITAGE trial.

The multicenter, double-blind, randomized, parallel-group, phase 3 study is evaluating the efficacy and safety of trastuzumab-dkst (approved in the United States as Ogivri) compared to reference trastuzumab in combination with a taxane as first-line therapy in patients with HER2-positive metastatic breast cancer.

Patients were randomized to trastuzumab-dkst or trastuzumab, combined with taxane, every 2 weeks. After 24 weeks, patients with responding or stable disease received monotherapy. Patients were followed through 48 weeks for PFS and 36 months for OS. The primary endpoint was ORR and secondary endpoints include time to progression, PFS, and OS at week 48, as well as OS at 36 months or after 240 patient deaths.

Of the 230 patients treated with trastuzumab-dkst, 70% achieved an ORR, compared to 64% of the 228 treated with trastuzumab at week 24. The proportion of patients being treated with trastuzumab-dkst or trastuzumab experiencing a serious adverse event (SAE) at week 24 was also similar (38.1% and 36.2%, respectively). The most common SAE was neutropenia.

Through 48 weeks, PFS was 11.1 months for both cohorts. As assessments are currently ongoing, OS will be calculated after the 36 months or 240 deaths.

At week 24, 1.3% of those in the trastuzumab-dkst cohort and 0% of those in the trastuzumab cohort demonstrated a complete response, and 68.3% of the trastuzumab-dkst cohort and 64% of the trastuzumab cohort demonstrated partial response.

Through week 48, SAEs were still comparable across the trastuzmab-dkst and trastuzumab cohorts (39.3% vs 37%).

“In patients with HER2-positive breast cancer, HERITAGE demonstrated that tratuzumab-dkst, when administered in combination with taxane, results in equivalent ORR compared with originator trastuzumab, it is well-tolerated as first-line therapy, and as maintenance monotherapy after combination therapy results in similar PFS at 48 weeks and OS is comparable, but still immature,” Rugo concluded.