FDA Expands Lilly's ALIMTA® (pemetrexed) Label to Include Combination with KEYTRUDA® (pembrolizumab) and Carboplatin as First-Line Treatment for Metastatic Nonsquamous Non-Small Cell Lung Cancer, Irrespective of PD-L1 Expression

New approval based on KEYNOTE-021, Cohort G1, results

INDIANAPOLIS, IN, USA I June 5, 2018 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 carboplatin and KEYTRUDA® (pembrolizumab) for the initial treatment of patients with metastatic nonsquamous non-small cell lung cancer (NSCLC), irrespective of PD-L1 expression status. Under the FDA's accelerated approval regulations, this indication is approved based on tumor response rate and progression-free survival (PFS). Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

Merck (known as MSD outside the U.S. and Canada) received accelerated approval for the combination of pembrolizumab with ALIMTA and carboplatin in May 2017. This is the first and only combination of chemotherapy and immunotherapy to earn FDA approval for the first-line treatment of metastatic nonsquamous NSCLC. This indication, now included in the ALIMTA prescribing information, is based on data from Merck's KEYNOTE-021 study, Cohort G1. 

"Lung cancer is the leading cause of cancer death in the U.S., and this approval represents the power of rational combinations and collaborations in bringing new treatments to these patients," said Sue Mahony, Ph.D., senior vice president and president of Lilly Oncology. "ALIMTA has been a long-standing, first-line treatment for locally advanced or metastatic nonsquamous non-small cell lung cancer. This combination with pembrolizumab continues to build on the robust body of evidence for ALIMTA in lung cancer."

The KEYNOTE-021, Part 2, Cohort G1, study included 123 previously untreated patients with locally advanced or metastatic nonsquamous NSCLC with no epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) genomic tumor aberrations and irrespective of PD-L1 expression status. The triplet combination of ALIMTA and carboplatin with pembrolizumab (n=60) demonstrated a statistically significant improvement in objective response rate (ORR) versus ALIMTA plus carboplatin alone (n=63) (55% vs 29%; all responses were partial) (estimated difference, 26%; 95% confidence interval [CI], range of 42-68 for triplet and range of 18-41 for ALIMTA plus carboplatin; P=0.0032), and PFS (HR=0.53; 95% CI, 0.31-0.91, P=0.0205). Median PFS was 13.0 months for triplet and 8.9 months for ALIMTA plus carboplatin (range of 8.3-NE for triplet and 4.4-10.3 for ALIMTA plus carboplatin).   

The labeling for ALIMTA contains warnings and precautions for myelosuppression and increased risk of myelosuppression without vitamin supplementation, renal failure, bullous and exfoliative skin toxicity, interstitial pneumonitis, radiation recall, increased risk of toxicity with ibuprofen in patients with renal impairment and also embryo-fetal toxicity. Initiate supplementation with oral folic acid and intramuscular vitamin B12 prior to and for 21 days after the last dose of ALIMTA. Determine creatinine clearance before each dose and periodically monitor renal function during treatment. Withhold ALIMTA in patients with a creatinine clearance of less than 45 mL/minute. The dosage of ALIMTA should be modified according to the full prescribing information when experiencing certain adverse reactions. The dosage of ibuprofen needs to be modified in patients with mild to moderate renal impairment receiving ALIMTA. Advise patients of the potential risk to a fetus and to use effective contraception. Please see Important Safety Information below and full Prescribing Information for more information.

About KEYNOTE-021
KEYNOTE-021, conducted by Merck, is a multi-cohort Phase 1/2 study evaluating the safety and preliminary efficacy of pembrolizumab with ALIMTA and carboplatin, immunotherapy or EGFR-targeted therapy for advanced nonsquamous NSCLC. Two of the eight cohorts included ALIMTA. Cohort G1 (n=123) is a Phase 2, randomized evaluation of the pembrolizumab-ALIMTA-carboplatin combination. The combination therapy is pembrolizumab at a fixed dose of 200 mg administered as an intravenous infusion over 30 minutes every three weeks in combination with ALIMTA 500 mg/m2 administered as an IV infusion over 10 minutes every three weeks and carboplatin AUC 5 mg/mL/min every three weeks for four cycles.

In the KEYNOTE-021, Cohort G1, trial, safety was evaluated in 59 patients who received pembrolizumab with ALIMTA and carboplatin and 62 patients who received ALIMTA and carboplatin alone. KEYNOTE-021 was not designed to demonstrate a statistically significant difference in adverse reaction rates for pembrolizumab with ALIMTA and carboplatin, as compared to ALIMTA and carboplatin alone. ALIMTA was discontinued for adverse reactions in nine percent of patients receiving pembrolizumab with ALIMTA and carboplatin.

The most common adverse reaction resulting in discontinuation of ALIMTA (≥2%) was acute kidney injury (3.4%). Adverse reactions leading to interruption of ALIMTA occurred in 36 percent of patients; the most common (≥2%) were fatigue (9%), neutrophil count decreased (9%), anemia (7%), dyspnea (3.4%) and pneumonitis (3.4%).

About Lung Cancer
Lung cancer is the leading cause of cancer death in the U.S. and most other countries, killing nearly 1.6 million people worldwide each year.1 In the U.S., lung cancer is responsible for approximately 26 percent of all cancer deaths, more than those from breast, colon and prostate cancers combined.2 Stage IV NSCLC is a very difficult-to-treat cancer and the prognosis is poor for metastatic NSCLC.3 NSCLC is much more common than other types of lung cancer and accounts for about 85 percent of all lung cancer cases.4 For those people afflicted with NSCLC, about 70 percent have nonsquamous cell carcinoma, while about 30 percent have squamous cell carcinoma.4 Approximately half of patients with metastatic NSCLC who begin first-line therapy will move on to second-line treatment.5 

About ALIMTA® (pemetrexed for injection)
In 2004, ALIMTA received consecutive approvals: it was the first agent to be approved in combination with cisplatin as an initial treatment for patients with malignant pleural mesothelioma, whose disease is unresectable or who are otherwise not candidates for curative surgery, and then as a single agent for the treatment of patients with locally advanced or metastatic NSCLC after prior treatment.

In 2008, ALIMTA, in combination with cisplatin, was approved as an initial chemotherapy treatment for locally advanced or metastatic NSCLC for patients with nonsquamous histology. At the time of this initial treatment approval, the FDA also approved a change to the indication for subsequent treatment. As a result, ALIMTA was also indicated as a single agent for the treatment of patients with recurrent, metastatic nonsquamous NSCLC after prior therapy.

In 2009, ALIMTA was approved as a maintenance therapy for locally advanced or metastatic NSCLC, specifically for patients with a nonsquamous histology whose disease has not progressed after four cycles of platinum-based initial chemotherapy.

In 2012, ALIMTA was approved by the FDA as maintenance therapy for locally advanced or metastatic NSCLC, following initial ALIMTA-plus-cisplatin treatment for locally advanced or metastatic nonsquamous NSCLC.

In 2018, ALIMTA received an additional indication for the combination with carboplatin plus pembrolizumab in first-line treatment for metastatic nonsquamous NSCLC, irrespective of PD-L1 expression status. This approval was based on Merck's KEYNOTE-021, Cohort G1, study.

ALIMTA is not indicated for treatment of patients with squamous cell NSCLC.

Indications for ALIMTA® (pemetrexed for injection)
ALIMTA (pemetrexed for injection) is indicated in combination with cisplatin therapy for the initial treatment of patients with locally advanced or metastatic nonsquamous non-small cell lung cancer.

ALIMTA is indicated as a single agent for the maintenance treatment of patients with locally advanced or metastatic nonsquamous non-small cell lung cancer whose disease has not progressed after four cycles of platinum-based first-line chemotherapy.

ALIMTA is indicated as a single agent for the treatment of patients with recurrent, metastatic nonsquamous non-small cell lung cancer after prior chemotherapy.

ALIMTA is indicated in combination with carboplatin and pembrolizumab for the initial treatment of patients with metastatic nonsquamous non-small cell lung cancer. This indication is approved under accelerated approval based on tumor response rate and progression-free survival. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.  

Limitation of Use: ALIMTA is not indicated for the treatment of patients with squamous cell non-small cell lung cancer.

ALIMTA in combination with cisplatin is indicated for the initial treatment of patients with malignant pleural mesothelioma whose disease is unresectable or who are otherwise not candidates for curative surgery.

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 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 www.lilly.com/newsroom/social-channels. P-LLY

1 International Agency for Research on Cancer. GLOBOCAN 2012. Lung Cancer Estimated Incidence, Mortality and Prevalence Worldwide in 2012. http://globocan.iarc.fr/Pages/fact_sheets_cancer.aspx. Accessed April 24, 2018.  
2 American Cancer Society. Cancer Facts and Figures 2017. https://www.cancer.org/content/dam/cancer-org/research/cancer-facts-and-statistics/annual-cancer-facts-and-figures/2017/cancer-facts-and-figures-2017.pdf. Accessed April 24, 2018.
3 American Cancer Society. Non-Small Cell Lung Cancer Survival Rates, by Stage. http://www.cancer.org/cancer/lungcancer-non-smallcell/detailedguide/non-small-cell-lung-cancer-survival-rates. Updated May 16, 2016. Accessed April 24, 2018.
4 American Cancer Society. What is non-small cell lung cancer? http://www.cancer.org/cancer/lungcancer-non-smallcell/detailedguide/non-small-cell-lung-cancer-what-is-non-small-cell-lung-cancer. Updated May 16, 2016. Accessed April 24, 2018. 
5 Stinchcombe TE, Socinski MA. Considerations for Second-Line Therapy of Non-Small Cell Lung Cancer. The Oncologist. 2008;13:28-36. 

SOURCE: Eli Lilly

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