US FDA approves Lilly's Cyramza to treat metastatic EGFR-mutated NSCLC

Eli Lilly and Company announced that the US Food and Drug Administration (FDA) has approved Cyramza (ramucirumab injection, 10 mg/mL solution), in combination with erlotinib, for the first-line treatment of people with metastatic non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) exon 19 deletions or exon 21 (L858R) mutations. With this approval, Cyramza has now received six FDA approvals to treat certain types of lung, liver, stomach and colorectal cancers.

Cyramza plus erlotinib is the first and only FDA-approved anti-VEGFR/EGFR TKI combination therapy for metastatic EGFR-mutated NSCLC. This approval is based on the efficacy and safety from the global, randomized, placebo-controlled phase 3 RELAY trial. In the RELAY study, Cyramza, a VEGF receptor 2 antagonist, in combination with erlotinib, a globally approved EGFR-targeting tyrosine kinase inhibitor (TKI), demonstrated a statistically significant and clinically meaningful improvement in progression-free survival (PFS) – the time patients lived without their cancer growing or spreading after starting treatment – compared to placebo in combination with erlotinib [19.4 months in the Cyramza-containing arm compared to 12.4 months in the placebo-containing arm (HR=0.59; 95% CI, 0.46, 0.76; p<0.0001)]. The PFS treatment effect was consistent across exon 19 and exon 21 subgroups. The overall safety profile observed in the RELAY study was consistent with that of its individual components. RELAY is the second positive phase 3 trial of Cyramza in metastatic NSCLC. The first was REVEL, which supported the approval of Cyramza plus docetaxel as a treatment for people with metastatic NSCLC whose cancer has progressed after prior platinum-based chemotherapy.

"The approval of this new first-line metastatic EGFR-mutated non-small cell lung cancer regimen, which inhibits the VEGFR and EGFR pathways together, is an important milestone in the treatment of this disease. It is wonderful that patients now have multiple options for initial therapy capable of delaying disease progression for considerably longer than erlotinib, which has been our traditional standard approach," said Edward Garon, M.D., David Geffen School of Medicine, University of California, and North America lead investigator of the RELAY trial. "Ramucirumab, in combination with erlotinib, is a welcomed first-line option to offer our patients with metastatic EGFR-mutated non-small cell lung cancer."

"This Cyramza combination regimen represents a new and meaningful treatment option for people with metastatic EGFR-mutated non-small cell lung cancer, and we are proud that it has been approved by the FDA for patients with this disease and the doctors who treat them," said Anne White, president of Lilly Oncology. "Today's approval underscores Lilly's continued commitment to people living with lung cancer and to delivering meaningful medicines that are tailored for those with advanced or metastatic cancers. It also further reinforces the value that Cyramza can provide in treating certain advanced or metastatic cancers."

Fifty per cent of people with NSCLC present with advanced or metastatic disease at diagnosis. The five-year survival rate for metastatic NSCLC patients is six per cent. In the US, it is estimated that approximately 15 per cent of people diagnosed with NSCLC have an EGFR mutation.

"We're encouraged by Cyramza's latest approval, which represents one step towards our goal of making EGFR-mutated non-small cell lung cancer into a manageable chronic disease," said Ivy Elkins, cofounder of EGFR Resisters. "Each new treatment option gives hope to those living with this disease and provides oncologists with more options that may help slow the spread of this deadly cancer, which is an important goal for many patients."

The labeling for Cyramza contains warnings and precautions for hemorrhage and gastrointestinal (GI) hemorrhage, including severe and sometimes fatal events; GI perforations, a potentially fatal event; impaired wound healing; arterial thromboembolic events (ATEs), including serious and sometimes fatal events; hypertension; infusion-related reactions (IRR) including severe and life-threatening reactions; worsening of pre-existing hepatic impairment; Posterior Reversible Encephalopathy Syndrome (PRES); proteinuria including nephrotic syndrome; thyroid dysfunction; and embryo-fetal toxicity. Cyramza should be permanently discontinued in patients who experience severe bleeding, a GI perforation, an ATE, uncontrolled hypertension, Grade 3 or 4 IRR, PRES, or nephrotic syndrome. Withhold Cyramza for 28 days prior to elective surgery. Do not administer Cyramza for at least two weeks following a major surgical procedure and until adequate wound healing.

The most common adverse reactions (all grades) observed in Cyramza with erlotinib-treated patients at a rate of =30% of patients and =2% higher than placebo with erlotinib-treated patients were infections, hypertension, stomatitis, proteinuria, alopecia, and epistaxis. The most common laboratory abnormalities =30% and =2% higher than the placebo were increased alanine aminotransferase, increased aspartate aminotransferase, anemia, thrombocytopenia, and neutropenia. Please see Important Safety Information below.

In addition to a recent approval for Cyramza in the European Union based on the RELAY results, Lilly has made a submission in Japan with regulatory action expected by the end of 2020.

RELAY is a global randomized, double-blind, placebo-controlled Phase 3 study of Cyramza in combination with erlotinib, compared to placebo in combination with erlotinib, as a first-line treatment in previously untreated patients with metastatic NSCLC whose tumors have EGFR exon 19 deletions or exon 21 (L858R) substitution mutations. EGFR-targeting TKIs are the current standard treatment options for EGFR-mutated NSCLC. Erlotinib, the TKI included in the RELAY trial regimen, is a globally approved treatment option for this type of lung cancer.

Initiated in 2015, the study randomized 449 patients across North America, Europe and Asia. The primary endpoint of the RELAY trial is PFS; key secondary endpoints include safety, overall response rate (ORR), duration of response (DoR), and overall survival (OS). On the primary endpoint of investigator-assessed PFS, Cyramza plus erlotinib (N=224) demonstrated statistically significant and clinically meaningful improvement in median PFS – the time patients lived without their cancer growing or spreading after starting treatment – by seven months compared to placebo plus erlotinib (N=225) [19.4 months in the Cyramza-containing arm compared to 12.4 months in the placebo-containing arm (HR=0.59; 95% CI, 0.46, 0.76; p<0.0001)]. The PFS treatment effect was consistent across exon 19 and exon 21 subgroups. At the time of the final analysis of PFS, OS data were not mature as only 26 percent of planned events for the final analysis had occurred (HR=0.83, 95% CI: 0.53, 1.30). A final OS analysis is planned when at least 300 events have occurred.

Treatment discontinuation of all study drugs due to adverse reactions occurred in 13 per cent of Cyramza with erlotinib-treated patients, with increased alanine aminotransferase (1.4%) and paronychia (1.4%) being the most common. The most common adverse reactions leading to treatment discontinuation of Cyramza were proteinuria (8.6%) and hyperbilirubinemia (6%).

In the US, Cyramza (ramucirumab) has six FDA approvals to treat four different types of cancers. Cyramza is being investigated in a broad global development program that has enrolled more than 15,000 patients across more than 100 trials worldwide. These include several studies investigating Cyramza in combination with other anti-cancer therapies for the treatment of multiple tumor types. To date, more than 150,000 patients have been treated with Cyramza.

Cyramza is an antiangiogenic therapy. It is a vascular endothelial growth factor (VEGF) Receptor 2 antagonist that binds specifically to VEGFR-2, thereby blocking the binding of the receptor ligands (VEGF-A, VEGF-C, and VEGF-D) – which may slow tumor growth. Cyramza inhibited angiogenesis in an in vivo animal model.

Angiogenesis is the process of making new blood vessels. In a person with cancer, angiogenesis creates new blood vessels that give a tumor its own blood supply, allowing it to grow and spread.

Some tumors create proteins called VEGF. These proteins attach to the VEGF receptors of blood vessel cells causing new blood vessels to form around the tumors, enabling growth. Blocking the VEGF protein from binding to the receptors located on the surface of blood vessels helps to inhibit tumor growth by slowing angiogenesis and the blood supply that feeds tumors. Of the three known VEGF receptors, VEGF Receptor 2 is linked most closely to VEGF-induced tumor angiogenesis.


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