The phase 3 COSMIC-312 trial (NCT03755791) treated patients with advanced hepatocellular carcinoma (HCC) through a combination of cabozantinib (Cabometyx) and atezolizumab (Tecentriq) which resulted in superior progression-free survival (PFS) compared to sorafenib (Nexavar), meeting a primary end point of the trial.1

The combination of cabozantinib (Cabometyx) and atezolizumab (Tecentriq) was found to significantly improve progression-free survival (PFS) compared with sorafenib (Nexavar) when used in the first-line treatment of patients with advanced hepatocellular carcinoma (HCC), meeting a primary end point of the phase 3 COSMIC-312 trial (NCT03755791)

In the planned primary analysis for PFS in the intent-to-treat patient population, cabozantinib plus atezolizumab resulted in a significant 37% reduction in the risk of disease progression or death vs sorafenib (HR, 0.63; 95% CI, 0.44-0.91; 

Additional data from a prespecified interim analysis for the second primary end point of overall survival (OS), which was done at the same time as the primary analysis for PFS, demonstrated a trend toward the doublet over sorafenib but was not found to reach statistical significance.

Based on the preliminary findings for OS, Exelixis Inc., shared that the probability of reaching statistical significance at the time of the final analysis is low. However, the trial will continue as planned to the final analysis of OS, and data are anticipated in early 2022.

The safety of the doublet appears to be consistent with the known profiles of both agents. No new safety signals were observed with the combination in this trial.

“While we are encouraged by the data supporting the potential for the combination of cabozantinib and atezolizumab to reduce the risk of disease progression or death, we are disappointed by the interim result of lack of significant improvement on OS vs the comparator arm,” Michael M. Morrissey, PhD, president and chief executive officer of Exelixis, Inc. stated in a press release. “As these data continue to mature, we are working to understand the potential impact of various contributing factors on the results, including patient demographics, subsequent anticancer therapy and the impact of COVID-19 on the trial. We anticipate presenting the results at a future medical conference.”

In the global, multicenter, randomized, phase 3 trial, investigators set out to examine the safety and efficacy of cabozantinib plus atezolizumab vs standard-of-care sorafenib in adult patients with advanced HCC who have not previously received systemic anticancer therapy.

The trial is aimed to enroll approximately 840 patients. To be eligible for enrollment, patients needed to have histological or cytological diagnosis of HCC, disease that is not amenable to a curative approach, measurable disease per RECIST v1.1 criteria, Barcelona Clinic Liver Cancer stage category B or C disease, and an ECOG performance status of 0 to 1.

If patients had fibrolamellar carcinoma, sarcomatoid HCC or mixed hepatocellular cholangiocarcinoma, received previous systemic anticancer therapy for advanced disease, or underwent radiation therapy for bone metastasis within 2 weeks of treatment or any other radiation therapy within 8 weeks before randomization, they were excluded. Moreover, if patients had known brain metastases or cranial epidural disease and if they were receiving concomitant anticoagulation with oral anticoagulants, they were not included on the study.

Study participants was randomized 2:1:1 into 1 of 3 arms: cabozantinib at a daily dose of 40 mg plus atezolizumab at 1200 mg every 3 weeks; sorafenib alone at a twice-daily dose of 400 mg; or cabozantinib monotherapy at a daily dose of 60 mg.

The co-primary end points of the trial were PFS and OS in the experimental arm vs the control arm. The secondary end point focused on PFS in the single-agent arm vs the control arm.

Exelixis, Inc. plan to discuss the data from COSMIC-312 and next steps for potential regulatory filing with the FDA.

Exelixis and Ipsen announce cabozantinib in combination with an immune checkpoint inhibitor significantly improved progression-free survival in phase 3 COSMIC-312 pivotal trail in patients with previously untreated advanced liver cancer. News release. Exelixis, Inc. June 28, 2021. Accessed June 28, 2021. 

Study of cabozantinib in combination with atezolizumab versus sorafenib in subjects with advanced HCC who have not received previous anticancer therapy (COSMIC-312). ClinicalTrials.gov. Updated June 4, 2021. Accessed June 28, 2021. 

https://clinicaltrials.gov/ct2/show/NCT03755791

This article was originally posted on OncLive as 

“Frontline Cabozantinib Plus Atezolizumab Significantly Improves PFS in Advanced HCC”

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A combination of cabozantinib and atezolizumab improved the PFS in patients with Advanced HCC

Cabozantinib/Atezolizumab Shows Promise in Treating Advanced HCC 

Epoetin alfa-epbx (Retacrit), the biosimilar to epoetin alfa (Procrit/Epogen), has been launched in the United States at a significant 

, according to Pfizer, the drug’s developer.

 The shipment of the biosimilar to wholesalers throughout the United States began on Nov. 12, 2018.

 on May 15, 2018, as a treatment for anemia caused by chronic kidney disease, chemotherapy, or the use of zidovudine in patients with HIV infection.

Epoetin alfa-epbx is also indicated for use prior to and following surgery to decrease the likelihood that patients will need a red blood cell transfusion due to blood loss from surgery.

“We are delighted to introduce our third biosimilar in the United States,” said John P. Kennedy, general manager of US Biosimilars at Pfizer Essential Health, in a recent statement. “Pfizer is committed to fostering a sustainable marketplace for biosimilars and advocates for policies that bring these important medicines to patients and physicians as quickly as possible.”

The manufacturer of the biosimilar, Hospira, a Pfizer company, submitted the biologics license application (BLA) based on data yielded from the 2 single-center, randomized, open-label EPOE-12-02 and EPOE-14-01 studies.

The first study was designed to establish the pharmacokinetics (PK) and pharmacodynamics (PD; reticulocyte count) of the biosimilar following a single subcutaneous dose of 100 u/kg in healthy participants (n = 81). The investigators compared the biosimilar data with that of epoetin alfa.

Investigators found that the biosimilar met the prespecified acceptance criteria for similarity, the geometric mean of AUC

 (1.03 mIU-h/mL; 90% CI, 0.97-1.09), and C

 (1.09 mIU-h/mL; 90% CI, 1.01-1.18). The same was true of PD for AUEC

The second study, EPOE-14-01, aimed to determine the drug’s PK and PD (hemoglobin level) after multiple doses of subcutaneous 100 u/kg of the biosimilar 3 times weekly for the duration of 4 weeks in health participants (n = 129). Again, these data were compared with data associated with epoetin alfa.

This study also met prespecified acceptance criteria for PD similarity of geometric mean of hemoglobin level AEUC 

The FDA’s Oncologic Drugs Advisory Committee voted 14 to 1 in favor of the approval of the BLA for the biosimilar in May 2017. At that time, the committee reported that the analytical similarity data supported the conclusion that, overall, epoetin alfa-epbx was “highly similar to US-licensed Epogen/Procrit, notwithstanding minor differences in clinically inactive components.” They added that “there were no clinically relevant differences” in the data associated with PK, PD, safety, efficacy, and immunogenicity between the 2 drugs.

Not long afterward, however, the FDA issued a complete response letter to Hospira expressing concerns regarding manufacturing the biosimilar at the company’s facility based in McPherson, Kansas. Particular issues identified by the FDA included: in-process specifications, failure to follow procedures developed to prevent contamination of products, and lack of appropriate sampling plans for analytical and inspection activities.

However, Pfizer emphasized that these concerns were not specifically related to epoetin alfa-epbx, and, in an attempt to address the FDA’s concerns, the company submitted a corrective and preventative action plan in March 2017.

Epoetin alfa-epbx will now be introduced to the market at a substantial discount at a Wholesale Acquisition Cost (WAC) of $11.03 per 1000 units/mL, which is 57.1% below the WAC of Procrit ($25.72 per 1000 units/mL), and 33.5% below the WAC of its reference product, Epogen ($16.58 per 1000 units/mL).

Epoetin alfa-epbx has been granted 2 unique assigned Q codes from the Centers for Medicare and Medicaid Services: Q5105 for End-Stage Renal Disease (ESRD) and Q5106 for non-ESRD. Under the hospital outpatient prospective payment system, epoetin alfa-epbx qualifies for pass-through status.

Pfizer. Pfizer introduced biosimilar Retacrit (epoetin alfa-epbx) injection in the US at a substantial discount. Published November 14, 2018.

Pfizer. Pfizer’s biosimilar RETACRIT® (epoetin alfa-epbx) approved by U.S. FDA. Published May 15, 2018. https://bit.ly/2Pd4J3L. Accessed November 14, 2018.

Epoetin Alfa Biosimilar Launched in United States at Discounted Cost

Epoetin alfa-epbx (Retacrit), the biosimilar to epoetin alfa (Procrit/Epogen), has been launched in the United States at a significant discount. The shipment of the biosimilar to wholesalers throughout the United States began on Nov. 12, 2018.

Kristie Rosa

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Cabozantinib/Atezolizumab Shows Promise in Treating Advanced HCC

Epoetin Alfa Biosimilar Launched at Significant Discount in US