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Approval of Isatuximab-Irfc for Multiple Myeloma

The FDA approved isatuximab-irfc in combination with pomalidomide and dexamethasone for adult patients with multiple myeloma who have received at least two prior therapies including lenalidomide and a proteasome inhibitor.

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ICARIA-MM (NCT02990338), a multicenter, multinational, randomized, open-label, two-arm, phase III study, included 307 patients with relapsed and refractory multiple myeloma who had received at least two prior therapies including lenalidomide and a proteasome inhibitor. Patients were randomized (1:1) to receive either isatuximab-irfc with pomalidomide and low-dose dexamethasone (Isa-Pd, 154 patients) or pomalidomide and low-dose dexamethasone (Pd, 153 patients).


The main efficacy outcome measure was progression-free survival (PFS) assessed by an independent committee based on central laboratory data for M-protein and central radiologic imaging review using International Myeloma Working Group criteria. The improvement in PFS represented a 40 percent reduction in the risk of disease progression or death in patients treated with Isa-Pd (HR 0.596; 95% CI: 0.44-0.81; p=0.0010). Median PFS for the patients who received Isa-Pd was 11.53 months (95% CI: 8.94-13.9) vs. 6.47 months (95% CI: 4.47-8.28) for those who received Pd.


The most common adverse reactions (>=20% of patients) were neutropenia, infusion-related reactions, pneumonia, upper respiratory tract infection, and diarrhea.


The recommended isatuximab-irfc dose is 10 mg/kg as an intravenous infusion every week for 4 weeks followed by every 2 weeks in combination with pomalidomide and dexamethasone until disease progression or unacceptable toxicity.


Nivolumab & Ipilimumab Combination for Hepatocellular Carcinoma

The FDA granted accelerated approval to the combination of nivolumab and ipilimumab for patients with hepatocellular carcinoma (HCC) who have been previously treated with sorafenib.


Efficacy of the combination was investigated in Cohort 4 of CheckMate-040, (NCT01658878) a multicenter, multiple cohort, open-label trial conducted in patients with HCC who progressed on or were intolerant to sorafenib.


A total of 49 patients received nivolumab 1 mg/kg in combination with ipilimumab 3 mg/kg every 3 weeks for four doses, followed by single-agent nivolumab 240 mg every 2 weeks until disease progression or unacceptable toxicity.


The main efficacy outcome measures were overall response rate and duration of response as determined by blinded independent central review using RECIST v1.1. ORR was 33 percent (n=16; 95% CI: 20, 48), with 4 complete responses and 12 partial responses. Response duration ranged from 4.6 to 30.5+ months, with 31 percent of responses lasting at least 24 months.


The most common adverse reactions (20%) with nivolumab in combination with ipilimumab are fatigue, diarrhea, rash, pruritus, nausea, musculoskeletal pain, pyrexia, cough, decreased appetite, vomiting, abdominal pain, dyspnea, upper respiratory tract infection, arthralgia, headache, hypothyroidism, decreased weight, and dizziness.


For HCC, the recommended doses are nivolumab 1 mg/kg followed by ipilimumab 3 mg/kg on the same day every 3 weeks for 4 doses, then nivolumab 240 mg every 2 weeks or 480 mg every 4 weeks.


Fast Track Designation for Tipifarnib in T-Cell Lymphomas

The FDA has granted Fast Track designation to tipifarnib for the treatment of adult patients with relapsed or refractory angioimmunoblastic T-cell lymphoma (AITL), follicular T-cell lymphoma, and nodal peripheral T-cell lymphoma with T follicular helper phenotype.


In December 2019, clinical data at the ASH Annual Meeting showed robust and durable activity from tipifarnib as a monotherapy in relapsed or refractory AITL. The data demonstrated an objective response rate (ORR) of approximately 50 percent in a heavily pre-treated patient population, with a median of three prior regimens. Additionally, enhanced anti-tumor activity was observed in patients who carried mutations in the killer-cell immunoglobulin-like receptor, or KIR, a CXCL pathway-associated biomarker. These patients had an ORR of 70 percent and a complete response rate of 40 percent.


Biologics License Application for Proposed Biosimilar Bevacizumab

The FDA has accepted a Biologics License Application (BLA) for MYL-1402O, a proposed biosimilar to bevacizumab, for review under the 351(k) pathway.


The BLA seeks approval of bevacizumab for first-line and second-line treatment of patients with metastatic colorectal cancer in combination with fluorouracil-based chemotherapy; first-line use for patients with non-squamous non-small cell lung cancer; recurrent glioblastoma; metastatic renal cell carcinoma in combination with interferon alfa; and persistent, recurrent, or metastatic cervical cancer.


The FDA goal date set under the Biosimilar User Fee Act is Dec. 27, 2020.


The proposed biosimilar bevacizumab is expected to be the third biosimilar from the partnered portfolio for cancer patients in the U.S. It is currently available in India and other developing markets.


The BLA is supported by a global randomized, controlled, phase III clinical trial to evaluate the efficacy, safety, and immunogenicity of proposed biosimilar bevacizumab versus bevacizumab. The study included patients diagnosed with stage IV non-squamous non-small cell lung cancer.


Eligible patients were randomised to receive either the proposed biosimilar bevacizumab or bevacizumab along with carboplatin and paclitaxel for up to 6 cycles (18 weeks), after which the patients continued to receive monotherapy until week 42. Additionally, patients benefitting from the treatment continued on bevacizumab monotherapy. The primary endpoint was overall response at week 18, using RECIST 1.1. Secondary endpoints included safety, progression-free survival, and overall survival at week 18 and 42.


A total of 671 patients were randomized. At week 18, the study met the primary endpoint and the 90 percent confidence interval for the best ORR (objective response rate) ratio was within the pre-specified equivalence margin. The safety which included immunogenicity was found to be similar to bevacizumab.


Breakthrough Therapy Designation for JNJ-6372 in NSCLC

The FDA has granted Breakthrough Therapy Designation for JNJ-61186372 (JNJ-6372) for the treatment of patients with metastatic non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) Exon 20 insertion mutations, whose disease has progressed on or after platinum-based chemotherapy. JNJ-6372 is an EGFR-mesenchymal epithelial transition factor (MET) bispecific antibody that targets activating and resistant EGFR and MET mutations and amplifications (Pharmacol Ther 2019;201:103-119). Currently, there are no FDA-approved targeted therapies for patients with lung cancer who have EGFR Exon 20 insertion mutations (Lancet Oncol 2012;13:e23-31).


Patients with NSCLC and EGFR Exon 20 insertion mutations have a form of disease that is generally insensitive to EGFR tyrosine kinase inhibitor (TKI) treatments and carries a worse prognosis compared to patients with more common EGFR mutations (Exon 19 deletions/L858R substitution) (Sig Transduct Target Ther 2019;4:5). The current standard of care for this patient population is conventional cytotoxic chemotherapy (BMC Cancer 2019;19:701).


The Breakthrough Therapy Designation is supported by data from a phase I, first-in-human, open-label, multicenter study (NCT02609776). The study evaluates the safety, pharmacokinetics, and preliminary efficacy of JNJ-6372 monotherapy and in combination with lazertinibi, a novel third-generation EGFR TKI, in adult patients with advanced NSCLC.


The study seeks to determine the recommended phase II dose in patients with advanced NSCLC. Enrollment into the part 2 dose expansion cohorts is ongoing, as the study evaluates JNJ-6372 monotherapy activity in multiple NSCLC sub-populations with genomic alterations such as those with C797S resistance mutation or MET amplification.


A U.S. FDA Breakthrough Therapy Designation is granted to expedite the development and regulatory review of an investigational medicine that is intended to treat a serious or life-threatening condition. The criteria for Breakthrough Therapy Designation require preliminary clinical evidence that demonstrates the drug may have substantial improvement on at least one clinically significant endpoint over available therapy.


JNJ-6372 is an EGFR-MET bispecific antibody with immune cell-directing activity that targets activating and resistant EGFR and MET mutations and amplifications.


In the U.S., lung cancer is the second most common cancer in both men and women, after skin cancer; NSCLC makes up 80-85 percent of all lung cancers. The main subtypes of NSCLC are adenocarcinoma, squamous cell carcinoma, and large cell carcinoma.


The most common driver mutation for NSCLC is the EGFR genetic alteration, which is a receptor tyrosine kinase that helps cells grow and divide. EGFR mutations are present in 10-15 percent of patients with NSCLC and occur in 40-50 percent of Asian patients who have NSCLC adenocarcinoma.


EGFR exon 20 insertion mutations identify a distinct subset of lung adenocarcinomas, accounting for at least nine percent of all EGFR mutations. The 5-year survival rate for patients with metastatic NSCLC is currently 6 percent.