Medical World News: Managed Care Updates, June 2018

FDA Grants Priority Review for Pembrolizumab, Chemotherapy Combination in NSCLC

The FDA granted priority review to Merck’s supplemental biologics license application (BLA) for pembrolizumab (Keytruda) in combination with pemetrexed (Alimta) and platinum chemotherapy as first-line treatment for patients with metastatic nonsquamous non—small cell lung cancer (NSCLC), the company announced April 16, 2018.

The Prescription Drug User Fee Act action date has been set for September 23, 2018. The FDA’s acceptance of the application is based on overall survival (OS) and progression-free survival (PFS) data from the phase 3 KEYNOTE-189 trial. The trial is the confirmatory trial for KEYNOTE-021, a phase 2 study that led to pembrolizumab being the first FDA-approved anti—PD-1 therapy in combination with chemotherapy for the first-line treatment of patients with metastatic nonsquamous NSCLC, regardless of PD-L1 expression.

In the double-blind, phase 3 KEYNOTE-189 trial,1 616 patients with NSCLC without EGFR or ALK mutations who had no previous treatment were randomized 2:1 to receive pemetrexed and a platinum-based drug plus either 200 mg of pembrolizumab or placebo every 3 weeks for 4 cycles, followed by pembroli- zumab or placebo for up to 35 cycles plus pemetrexed maintenance therapy.

After a median follow-up of 10.5 months, the estimated rate of OS at 12 months was 69.2% in the pembrolizumab cohort compared with 49.4% in the placebo cohort. Median PFS in the pembrolizumab cohort (8.8 months) was nearly double that of the placebo cohort (4.9 months).

“Keytruda is the first immunotherapy to significantly extend [the] survival of patients with NSCLC in combination with chemotherapy as a first-line treatment, including in patients whose tumors are either PD-L1 negative

or are untested,” said Roger M. Perlmutter, MD, president, Merck Research Laboratories, in a statement.²

If approved by the FDA, this would represent the third indication for pembrolizumab in metastatic NSCLC in the United States based on OS data.

In early April, pembrolizumab monotherapy as first-line treatment in locally advanced or metastatic NSCLC met its primary endpoint of overall survival in the phase 3 KEYNOTE-042 trial compared with platinum-based chemotherapy.³

Outside of NSCLC, the anti—PD-1 therapy has indications for melanoma, head and neck cancer, classical Hodgkin lymphoma, urothelial carcinoma, and gastric cancer. In March, the FDA accepted a new supplemental BLA and granted a priority review to pembrolizumab as treatment for advanced cervical cancer, which marked the first filing acceptance and priority review granted for an anti–PD-1 therapy in cervical cancer.⁴

References:

1. Gandhi L, Rodriguez-Abreu D, Gadgeel S, et al; KEYNOTE-189 Investigators. Pembrolizumab plus chemo- therapy in metastatic non-small-cell lung cancer [published online April 16, 2018]. N Engl J Med. doi: 10.1056/ NEJMoa1801005.
2. 2. FDA grants priority review to Merck’s sBLA for Keytruda (pembrolizumab) in combination with pemetrexed (Alimta) and platinum chemotherapy based on results from phase 3 KEYNOTE-189 trial as first-line treatment of metastatic nonsquamous NSCLC [press release]. Kenilworth, NJ: BusinessWire; April 30, 2018. businesswire. com/news/home/20180430005480/en/FDA-Grants-Priority-Review-Merck%E2%80%99s-sBLA-KEYTRUDA%C2%AE. Accessed May 1, 2018.
3. Keytruda (pembrolizumab) monotherapy met primary endpoint in phase 3 KEYNOTE-042 study, significant- ly improving OS as first-line therapy in locally advanced or metastsatic NSCLC patients expressing PD-L1 in at least 1 percent of tumor cells [press release]. Kenilworth, NJ: Merck; April 9, 2018. mrknewsroom.com/news-re-lease/oncology-newsroom/keytruda-pembrolizumab-monotherapy-met-primary-endpoint-phase-3-keyno. Accessed May 1, 2018.
4. Rosenberg J. Pembrolizumab granted priority review for treatment of cervical cancer. The American Journal of Managed Care^® website. ajmc.com/newsroom/pembrolizumab-granted-priority-review-for-treatment-of-cervical-cancer. Published March 13, 2018. Accessed April 16, 2018.

Researchers Identify New Gene That Predisposes People to ALL

Researchers have identified a fourth gene that may predispose individ- uals to develop acute lymphoblastic leukemia (ALL), according to findings of a study published in Cancer Cell.¹ IKZF1 joins 3 other genes—TP53, ETV6, and PAX5—which have been identified as predisposing carriers to develop B-cell ALL.

In addition to IKZF1 indicating individuals who have an increased susceptibility to ALL, variants in the gene can influence patient response to treatment.

“This finding adds to the growing body of evidence that, while germline variations still account for a small percentage of pediatric ALL cases overall, more children than previously recognized inherit a predisposition to develop ALL,” Charles Mullighan, MBBS, MD, a member of the St. Jude Department of Pathology, said in a statement.²

A decade ago, Mullighan and colleagues first reported that IKZF1 was often mutated in leukemic cells, which indicated that the individual would have poor treatment outcomes.

Although not everyone carrying a germline IKZF1 variant will develop ALL, the findings mean families can be informed about the potential risk to develop leukemia, added co-author Kim Nichols, MD, director of the St. Jude Cancer Predisposition Division.

The history of research into IKZF1 includes 3 generations of a German family with a germline variation of the gene and a family history of B-cell ALL. Researchers found that 2 of the 5 family members with the variant developed ALL as children and died.

“In IKZF1 and the other ALL predisposition genes, cells may require an additional cooperating mutation to develop into leukemia,” Mullighan said. “While familial ALL is rare, these cases can point to genes and novel biology to examine in a larger patient population.

References:

1. Churchman ML, Qian M, Kronnie G, et al. Germline genetic IKZF1 variation and predisposition to childhood acute lymphoblastic leukemia [published online April 19, 2018]. Cancer Cell. doi: 10.1158/2159-8290.CD- RW2018-073.
2. Discovery adds to evidence that some children are predisposed to develop leukemia [press release]. Memphis, TN: St. Jude Children’s Research Hospital; April 19, 2018. stjude.org/media-resources/news-releases/2018-med- icine-science-news/discovery-adds-to-evidence-that-some-children-are-predisposed-to-develop-leukemia. html. Accessed May 1, 2018.

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