New approval based on Phase 3 KEYNOTE-189 results
INDIANAPOLIS, IN, USA I January 31, 2019 I Eli Lilly and Company (NYSE: LLY) today announced that the U.S. Food and Drug Administration (FDA) has granted approval for a new indication for ALIMTA® (pemetrexed for injection) in combination with KEYTRUDA® (pembrolizumab), developed and marketed by Merck (known as MSD outside the U.S. and Canada), and platinum chemotherapy for the first-line treatment of patients with metastatic nonsquamous non-small cell lung cancer (NSCLC), with no EGFR or ALK genomic tumor aberrations. This indication is approved based on data from Merck’s Phase 3 KEYNOTE-189 trial, which enrolled patients regardless of PD-L1 expression and had dual primary endpoints of overall survival (OS) and progression-free survival (PFS).
ALIMTA in combination with pembrolizumab and carboplatin was first approved in June 2018 under the FDA’s accelerated approval process for the first-line treatment of patients with metastatic nonsquamous NSCLC, based on tumor response rates and PFS data from the Phase 2 study KEYNOTE-021 (Cohort G1). In accordance with the accelerated approval process, continued approval was contingent upon verification and description of clinical benefit, which has now been demonstrated in the KEYNOTE-189 trial and has resulted in the FDA converting the accelerated approval to full (regular) approval.
“KEYNOTE-189 demonstrated an exceptional effect of the ALIMTA-pembrolizumab-platinum chemotherapy combination in the first-line setting, offering significantly improved survival in patients with metastatic nonsquamous non-small cell lung cancer with no EGFR or ALK genomic tumor aberrations,” said Anne White, president, Lilly Oncology. “This new indication reinforces Lilly’s continued commitment to providing practice-changing treatment options that can make a meaningful difference for people living with lung cancer.”
ALIMTA is contraindicated in patients who have a history of severe hypersensitivity reaction to pemetrexed. See additional Important Safety Information below.
KEYNOTE-189 Trial Results
On August 20, 2018, Merck’s pembrolizumab was approved by the FDA for this indication, based on data from the KEYNOTE-189 study, which demonstrated that treatment with ALIMTA in combination with pembrolizumab plus platinum-based chemotherapy resulted in significantly longer OS and PFS than ALIMTA plus platinum chemotherapy with placebo.
Efficacy Results
| Endpoint |
ALIMTA Pembrolizumab Platinum Chemotherapy n=410 |
ALIMTA Placebo Platinum Chemotherapy n=206 |
||||||||
| OS | ||||||||||
| Number (%) of patients with event | 127 (31%) | 108 (52%) | ||||||||
| Median in months (95% CI) |
NR (NR, NR) |
11.3 (8.7, 15.1) |
||||||||
| Hazard ratio* (95% CI) | 0.49 (0.38, 0.64) | |||||||||
| p-Value† | <0.0001 | |||||||||
| PFS | ||||||||||
| Number (%) of patients with event | 244 (60%) | 166 (81%) | ||||||||
| Median in months (95% CI) | 8.8 (7.6, 9.2) | 4.9 (4.7, 5.5) | ||||||||
| Hazard ratio* (95% CI) | 0.52 (0.43, 0.64) | |||||||||
| p-Value† | <0.0001 | |||||||||
| ORR | ||||||||||
| Overall response rate‡ (95% CI) | 48% (43, 53) | 19% (14, 25) | ||||||||
| Complete response | 0.5% | 0.5% | ||||||||
| Partial response | 47% | 18% | ||||||||
| p-Value§ | <0.0001 | |||||||||
| Duration of Response | ||||||||||
| Median in months (range) | 11.2 (1.1+, 18.0+) | 7.8 (2.1+, 16.4+) | ||||||||
|
*Based on the stratified Cox proportional hazard model † Based on stratified log-rank test ‡ Response: Best objective response as confirmed complete response or partial response § Based on Miettinen and Nurminen method stratified by PD-L1 status, platinum chemotherapy and smoking status NR = not reached |
||||||||||
In the KEYNOTE-189 study, safety was evaluated in 405 patients who received ALIMTA in combination with pembrolizumab and platinum chemotherapy and 202 patients who received placebo, ALIMTA and platinum chemotherapy. ALIMTA was discontinued for adverse reactions in 23 percent of patients in the ALIMTA-pembrolizumab-platinum chemotherapy arm. The most common adverse reactions resulting in discontinuation of ALIMTA in this arm were acute kidney injury (3%) and pneumonitis (2%). Adverse reactions leading to the interruption of ALIMTA occurred in 49 percent of patients in the ALIMTA-pembrolizumab-platinum chemotherapy arm; the most common adverse reactions or laboratory abnormalities leading to interruption of ALIMTA in this arm (≥2%) were neutropenia (12%), anemia (7%), asthenia (4%), pneumonia (4%), thrombocytopenia (4%), increased blood creatinine (3%), diarrhea (3%), and fatigue (3%). Adverse reactions of any grade occurring in ≥20 percent of patients receiving ALIMTA in combination with pembrolizumab and platinum chemotherapy were nausea (56%), fatigue (56%), constipation (35%), diarrhea (31%), decreased appetite (28%), rash (25%), vomiting (24%), cough (21%), dyspnea (21%) and pyrexia (20%).
KEYNOTE-189 Trial Design
Conducted by Merck, the KEYNOTE-189 trial (ClinicalTrials.gov, NCT02578680), a randomized, double-blind, placebo-controlled, Phase 3 study, evaluated ALIMTA in combination with pembrolizumab and cisplatin or carboplatin compared with ALIMTA in combination with placebo and cisplatin or carboplatin, in 616 untreated patients with metastatic nonsquamous NSCLC, regardless of PD-L1 expression. Patients had no sensitizing EGFR or ALK genomic tumor aberrations, and had not previously received systemic therapy for advanced disease. This was a treat-to-progression protocol, with both ALIMTA and pembrolizumab being used until progression or unacceptable toxicity (or 35 cycles for pembrolizumab)1, and had dual primary endpoints of OS and PFS [assessed by blinded independent central review (BICR) per RECIST v1.1 (modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ)]; secondary endpoints include overall response rate (ORR) and duration of response (DOR). Patients were randomized 2:1 to one of two treatment groups, as follows:
- ALIMTA (500 mg/m2) (with vitamin supplementation) plus pembrolizumab (200 mg fixed dose every three weeks) plus cisplatin (75 mg/m2) or carboplatin AUC 5 mg/mL/min on day one every three weeks (Q3W) for four cycles, followed by ALIMTA (500 mg/m2) plus pembrolizumab 200 mg Q3W; or
- ALIMTA (500 mg/m2) (with vitamin supplementation) plus saline placebo plus cisplatin (75 mg/m2) or carboplatin AUC 5 mg/mL/min on day one every three weeks (Q3W) for four cycles, followed by ALIMTA (500 mg/m2) plus placebo Q3W.
Patients on the control arm who experienced disease progression, verified by central independent review, were permitted to undergo treatment assignment unblinding and crossover to receive open-label pembrolizumab. The KEYNOTE-189 study was conducted in collaboration with Lilly.
About Lung Cancer
Lung cancer is the leading cause of cancer death in the U.S. and most other countries, killing nearly 1.7 million people worldwide each year.2 In the U.S., lung cancer is responsible for approximately 25 percent of all cancer deaths, more than those from breast, colon and prostate cancers combined.3 Stage IV non-small cell lung cancer (NSCLC) is a very difficult-to-treat cancer and the prognosis is poor for metastatic NSCLC.4 NSCLC is much more common than other types of lung cancer and accounts for about 80 to 85 percent of all lung cancer cases.5 For those people afflicted with NSCLC, about 70 percent have nonsquamous cell carcinoma, while about 30 percent have squamous cell carcinoma.5
About ALIMTA® (pemetrexed for injection)
ALIMTA is indicated in combination with pembrolizumab and platinum chemotherapy for the initial treatment of patients with metastatic nonsquamous non-small cell lung cancer, with no EGFR or ALK genomic tumor aberrations. For all FDA-approved indications for ALIMTA, please see full Prescribing Information.
About Lilly Oncology
For more than 50 years, Lilly has been dedicated to delivering life-changing medicines and support to people living with cancer and those who care for them. Lilly is determined to build on this heritage and continue making life better for all those affected by cancer around the world. To learn more about Lilly’s commitment to people with cancer, please visit www.LillyOncology.com.
About Eli Lilly and Company
Lilly is a global healthcare leader that unites caring with discovery to create medicines that make life better for people around the world. We were founded more than a century ago by a man committed to creating high-quality medicines that meet real needs, and today we remain true to that mission in all our work. Across the globe, Lilly employees work to discover and bring life-changing medicines to those who need them, improve the understanding and management of disease, and give back to communities through philanthropy and volunteerism. To learn more about Lilly, please visit us at www.lilly.com and http://newsroom.lilly.com/social-channels. P-LLY
PP-PM-US-0690 01/2019 © Lilly USA, LLC 2019. ALL RIGHTS RESERVED.
ALIMTA® is a registered trademark owned by or licensed to Eli Lilly and Company, its subsidiaries, or affiliates.
KEYTRUDA® is a registered trademark of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc.
1 Gandhi L, Rodriguez-Abreu D, Gadgeel S, et al. Pembrolizumab plus Chemotherapy in Metastatic Non–Small-Cell Lung Cancer. N Engl J Med. 2018;378:2078-2092.
2 International Agency for Research on Cancer. 2018 Lung Cancer Fact Sheet. Available at: http://gco.iarc.fr/today/data/factsheets/cancers/15-Lung-fact-sheet.pdf. Accessed January 14, 2019.
3 American Cancer Society. Cancer Facts and Figures 2018. Available at: https://www.cancer.org/content/dam/cancer-org/research/cancer-facts-and-statistics/annual-cancer-facts-and-figures/2018/cancer-facts-and-figures-2018.pdf. Accessed January 14, 2019.
4 American Cancer Society. Non-Small Cell Lung Cancer Survival Rates, by Stage. Available at: http://www.cancer.org/cancer/lungcancer-non-smallcell/detailedguide/non-small-cell-lung-cancer-survival-rates. Accessed January 14, 2019.
5 American Cancer Society. What is non-small cell lung cancer? Available at: http://www.cancer.org/cancer/lungcancer-non-smallcell/detailedguide/non-small-cell-lung-cancer-what-is-non-small-cell-lung-cancer. Accessed January 14, 2019.
SOURCE: Eli Lilly
