FDA Approves Lilly's Retevmo® (selpercatinib), the First and Only RET Inhibitor for Adults with Advanced or Metastatic Solid Tumors with a RET Gene Fusion, Regardless of Type

Tumor-agnostic data supporting approval demonstrated an overall response rate (ORR) of 44% across multiple tumor types

FDA simultaneously grants traditional approval in adults with locally advanced or metastatic non-small cell lung cancer (NSCLC) with a RET gene fusion, as detected by an FDA-approved test

INDIANAPOLIS, IN, USA I September 21, 2022 I Eli Lilly and Company ( NYSE: LLY) today announced the U.S. Food and Drug Administration (FDA) has granted approval to Retevmo® (selpercatinib, 40 mg & 80 mg capsules) for adult patients with locally advanced or metastatic solid tumors with a rearranged during transfection (RET) gene fusion that have progressed on or following prior systemic treatment or who have no satisfactory alternative treatment options. This indication is approved under accelerated approval based on ORR and duration of response (DOR). Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trial.

"In the LIBRETTO-001 trial, selpercatinib demonstrated clinically meaningful and durable responses across a variety of tumor types in patients with RET-driven cancers, including pancreatic, colon and other cancers in need of new treatment options," said Vivek Subbiah, M.D., associate professor of Investigational Cancer Therapeutics at The University of Texas MD Anderson Cancer Center and co-investigator for LIBRETTO-001. "These data and FDA approval of the tumor-agnostic indication underscore the importance of routine, comprehensive genomic testing for patients across a wide variety of tumor types."

In addition to the tumor-agnostic approval, the FDA has granted traditional approval for Retevmo in adult patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) with a RET gene fusion, as detected by an FDA-approved test. This FDA action broadens the Retevmo label to include patients with locally advanced disease and converts the May 2020 accelerated approval for NSCLC to a traditional approval.

The labeling for Retevmo contains warnings and precautions for hepatotoxicity (evidence of liver dysfunction), interstitial lung disease (ILD)/pneumonitis, hypertension, QT interval prolongation, hemorrhagic events, hypersensitivity, tumor lysis syndrome, risk of impaired wound healing, hypothyroidism, and embryo-fetal toxicity.

"Since its initial accelerated approval, Retevmo has shifted the treatment paradigm for patients with RET-altered cancers," said David Hyman, M.D., chief medical officer, Loxo@Lilly. "Retevmo is the first and only RET inhibitor to receive both tumor-agnostic accelerated approval and traditional approval in NSCLC, further supporting its ability to deliver meaningful clinical benefit for patients across diverse tumor types."   

The two approvals are supported by data from the pivotal LIBRETTO-001 trial, which is the largest clinical trial of patients with RET-driven cancers treated with a RET inhibitor. The multicenter, open-label, multi-cohort study enrolled patients with locally advanced or metastatic RET-driven solid tumors, including NSCLC. Major efficacy outcomes were ORR and DOR, assessed by a blinded independent review committee (BIRC). Prespecified secondary endpoints included central nervous system (CNS) ORR and CNS DOR.

RET Fusion-Positive Solid Tumors
Among the 41 patients in the tumor-agnostic data set, the most common cancers were pancreatic adenocarcinoma (27%), colorectal (24%), salivary (10%), and unknown primary (7%). Thirty-seven patients (90%) received prior systemic therapy (median 2 [range 0 – 9]; 32% received 3 or more). Efficacy results are summarized below:

  RET Fusion-Positive
Solid Tumors
No. of patients 41
Overall Response Rate1 (95% CI) 44 %(28, 60)
Complete response 4.9 %
Partial response 39 %
Duration of Response  
Median in months (95% CI) 24.5 (9.2, NE)
% with ≥ 6 months2 67 %
1   Confirmed overall response rate assessed by BIRC.
2   Based on observed duration of response.
NE = not estimable
 

Efficacy results by tumor type are summarized below:

Tumor Type

Patients

(n = 41)

ORR1,2

DOR

Range (months)

    n (%) 95% CI  
Pancreatic
adenocarcinoma
11 6 (55 %) (23, 83) 2.5, 38.3+
Colorectal 10 2 (20 %) (2.5, 56) 5.6, 13.3
Salivary 4 2 (50 %) (7, 93) 5.7, 28.8+
Unknown primary 3 1 (33 %) (0.8, 91) 9.2
Breast 2 PR, CR NA 2.3+, 17.3
Sarcoma (soft tissue) 2 PR, SD NA 14.9+
Xanthogranuloma 2 NE, NE NA NA
Carcinoid (bronchial) 1 PR NA 24.1+
Carcinoma of the skin 1 NE NA NA
Cholangiocarcinoma 1 PR NA 5.6+
Ovarian 1 PR NA 14.5+
Pulmonary
carcinosarcoma
1 NE NA NA
Rectal neuroendocrine 1 NE NA NA
Small intestine 1 CR NA 24.5
+ denotes ongoing response.
1   Confirmed overall response rate assessed by BIRC.
2   Best overall response for each patient is presented for tumor types with ≤2 patients.
CI = confidence interval, CR = complete response, DOR = duration of response, NA = not applicable, NE = not evaluable, ORR = overall response rate, PR = partial response, SD = stable disease.
 

"Today's announcement of Retevmo's expanded label reflects an opportunity to bring more targeted treatment options to a broader set of difficult-to-treat solid tumors, such as pancreatic cancer," said Julie Fleshman, president and chief executive officer, the Pancreatic Cancer Action Network (PanCAN). "This news further highlights the importance of broad biomarker testing, which may open the door to new therapy options for more patients."

Retevmo may affect both healthy cells and tumor cells, which can result in side effects, some of which can be serious.

RET Fusion-Positive NSCLC
Efficacy results for patients with both platinum chemotherapy treated and treatment-naïve RET fusion-positive NSCLC are summarized below:

  RET Fusion-Positive NSCLC
  Treatment-Naïve Platinum
Chemotherapy
Treated
No. of patients 69 247
Overall Response Rate1
(95% CI)
84% (73%, 92%) 61% (55%, 67%)
Complete response 5.8 % 7.3 %
Partial response 78 % 54 %
Duration of Response    
Median in months (95% CI) 20.2 (13, NE) 28.6 (20, NE)
% with ≥ 12 months2 50 % 63 %
1   Confirmed overall response rate assessed by BIRC.
2   Based on observed duration of response.
NE = not estimable
 

The activity of Retevmo in patients with CNS metastases was also evaluated. Among the 247 patients with previously treated RET fusion-positive NSCLC, 16 had measurable CNS metastases at baseline as assessed by BIRC. One patient received radiation therapy (RT) to the brain within two months prior to study entry. Responses in intracranial lesions were observed in 87.5% (14 of 16) of patients; 39% of responders had an intracranial DOR of 12 months or greater. Among the 69 patients with treatment-naïve RET fusion-positive NSCLC, five had measurable CNS metastases at baseline as assessed by BIRC. Two patients received RT to the brain within two months prior to study entry. Responses in intracranial lesions were observed in four of these five patients; 38% of responders had an intracranial DOR of 12 months or greater.

"Retevmo's accelerated approval played an important role in providing earlier access for patients who needed new treatment options. We are now pleased to see the conversion from an accelerated approval to a traditional approval," said Andrea Ferris, president and chief executive officer, LUNGevity Foundation. "As a targeted treatment, this traditional approval further reinforces the need for comprehensive biomarker testing for lung cancer patients, with the hope that as many patients as possible can benefit from receiving treatments tailored to their specific tumor mutations."

In the full LIBRETTO-001 safety population (n=796) with advanced solid tumors, the most common adverse reactions (≥25%) were edema, diarrhea, fatigue, dry mouth, hypertension, abdominal pain, constipation, rash, nausea, and headache. The most common Grade 3 or 4 laboratory abnormalities (≥5%) were decreased lymphocytes, increased alanine aminotransferase (ALT), increased aspartate aminotransferase (AST), decreased sodium, and decreased calcium. For more information, see "IMPORTANT SAFETY INFORMATION FOR RETEVMO® (selpercatinib)" below.

About LIBRETTO-001
The Phase 1/2 LIBRETTO-001 trial is the largest clinical trial of patients with RET-driven cancers treated with a RET inhibitor. The trial, which spans 16 countries and 85 sites, included a dose escalation phase (Phase 1) and a dose expansion phase (Phase 2). The primary objective was to determine ORR by blinded independent review committee (BIRC) and other objectives included DOR, CNS ORR & DOR, safety and PFS.

About Retevmo® (selpercatinib, 40 mg & 80 mg capsules)
Retevmo (selpercatinib, formerly known as LOXO-292) (pronounced ret-tév-mo) is a selective and potent RET kinase inhibitor. Retevmo may affect both tumor cells and healthy cells, which can result in side effects. RET-driver alterations are predominantly mutually exclusive from other oncogenic drivers. Retevmo is a U.S. FDA-approved oral prescription medicine, 120 mg or 160 mg dependent on weight (<50 kg or ≥50 kg, respectively), taken twice daily until disease progression or unacceptable toxicity.

Please see full Prescribing Information for Retevmo.

About Lilly
Lilly unites caring with discovery to create medicines that make life better for people around the world. We've been pioneering life-changing discoveries for nearly 150 years, and today our medicines help more than 47 million people across the globe. Harnessing the power of biotechnology, chemistry and genetic medicine, our scientists are urgently advancing new discoveries to solve some of the world's most significant health challenges, redefining diabetes care, treating obesity and curtailing its most devastating long-term effects, advancing the fight against Alzheimer's disease, providing solutions to some of the most debilitating immune system disorders, and transforming the most difficult-to-treat cancers into manageable diseases. With each step toward a healthier world, we're motivated by one thing: making life better for millions more people. That includes delivering innovative clinical trials that reflect the diversity of our world and working to ensure our medicines are accessible and affordable. To learn more, visit Lilly.com and Lilly.com/newsroom or follow us on Facebook, Instagram, Twitter and LinkedIn. P-LLY 

SOURCE: Eli Lilly

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