ALIMTA® (pemetrexed): Use With Pembrolizumab and Platinum Chemotherapy

Detailed Information

The safety and efficacy of pemetrexed in combination with pembrolizumab and platinum chemotherapy was investigated in KEYNOTE-189 (NCT02578680), a randomized, multicenter, double-blind, active-controlled trial conducted in patients with previously untreated, metastatic nonsquamous NSCLC with no EGFR or ALK genomic tumor aberrations, regardless of PD-L1 tumor expression status.¹

Patients were ineligible for the trial if they had

• an autoimmune disease that required systemic therapy within 2 years of treatment

• a medical condition that required immunosuppression, or

• received >30 Gy of thoracic radiation within the prior 26 weeks.¹

Patients were randomized in a 2:1 ratio to one of 2 treatment arms in the study.¹

• In the pembrolizumab-containing arm, patients received pemetrexed 500 mg/m², pembrolizumab 200 mg, and investigator’s choice of cisplatin 75 mg/m² or carboplatin AUC 5 mg/mL/min IV on day 1 of each 21-day cycle for 4 cycles followed by pemetrexed 500 mg/m² and pembrolizumab 200 mg IV Q3W. Pemetrexed was administered after pembrolizumab and prior to platinum chemotherapy on day 1.¹

• In the placebo arm, patients received placebo, pemetrexed 500 mg/m², and investigator’s choice of cisplatin 75 mg/m² or carboplatin AUC 5 mg/mL/min IV on day 1 of each 21-day cycle for 4 cycles followed by placebo and pemetrexed 500 mg/m² IV Q3W.¹

Treatment with pemetrexed continued until progression of disease as determined by the investigator or unacceptable toxicity. Patients randomized to the placebo arm were offered pembrolizumab at the time of disease progression. A total of 85 patients in the placebo, pemetrexed, and chemotherapy arm received an anti-PD-1/PD-L1 monoclonal antibody at the time of disease progression.¹

Efficacy Results of KEYNOTE-189

A significant improvement in OS and PFS was observed for patients randomized to the pemetrexed, pembrolizumab, and platinum chemotherapy arm compared with placebo, pemetrexed, and platinum chemotherapy¹ (see Table 1. KEYNOTE-189 Survival and Response Summary ).

Table 1. KEYNOTE-189 Survival and Response Summary¹

Endpointa	Pemetrexed Pembrolizumab Platinum Chemotherapy (N=410)	Placebo Pemetrexed Platinum Chemotherapy (N=206)
OS (1° endpoint)
Patients with event, n (%)	127 (31)	108 (52)
Median in months (95% CI)	NR (NR-NR)	11.3 (8.7-15.1)
HRb (95% CI)	0.49 (0.38-0.64)
P valuec	<.0001
PFS (1° endpoint)
Patients with event, n (%)	244 (60)	166 (81)
Median in months (95% CI)	8.8 (7.6-9.2)	4.9 (4.7-5.5)
HRb (95% CI)	0.52 (0.43-0.64)
P valuec	<.0001
ORRd
ORR, % (95% CI)	48 (43-53)	19 (14-25)
CR, %	0.5	0.5
PR, %	47	18
P valuee	<.0001
DoR
Median in months (range)	11.2 (1.1+, 18.0+)	7.8 (2.1+, 16.4+)

Abbreviations: BICR = blinded, independent central radiologic review; CR = complete response; DoR = duration of response; HR = hazard ratio; NR = not reached; ORR = overall response rate; OS = overall survival; PD-L1 = programmed death-ligand 1; PFS = progression-free survival; PR = partial response; RECIST = Response Evaluation Criteria in Solid Tumors.

^a Assessed by the BICR according to RECIST v1.1.

^b Based on the stratified Cox proportional hazard model.

^c Based on stratified log-rank test.

^d Response: best objective response as confirmed CR or PR.

^e Based on Miettinen and Nurminen method stratified by PD-L1 status, platinum chemotherapy, and smoking status.

Figure 1. Kaplan-Meier Curve for Overall Survival in KEYNOTE-189¹

A+P+C = Alimta + pembrolizumab + platinum chemotherapy.
A+C = Alimta + platinum chemotherapy + placebo.

Safety Results of KEYNOTE-189

The median duration of exposure to pemetrexed was 7.2 months (range: 1 day to 1.7 years). The most common AEs of pemetrexed when administered in combination with pembrolizumab and platinum chemotherapy are shown in Table 2. Adverse Reactions Occurring in ≥20% of Patients in KEYNOTE-189 . Additional details regarding laboratory abnormalities that worsened from baseline as well as AEs that led to pemetrexed dose interruptions/discontinuations can be found in the prescribing information.¹

Table 2. Adverse Reactions Occurring in ≥20% of Patients in KEYNOTE-189¹

Adverse Reactiona	All Grades (%)	Grade 3 or 4 (%)	All Grades (%)	Grade 3 or 4 (%)
	Pemetrexed Pembrolizumab Platinum Chemotherapy (n=405)		Placebo Pemetrexed Platinum Chemotherapy (n=202)
Gastrointestinal Disorders
Nausea	56	3.5	52	3.5
Constipation	35	1.0	32	0.5
Diarrhea	31	5	21	3.0
Vomiting	24	3.7	23	3.0
General Disorders and Administration Site Conditions
Fatigueb	56	12	58	6
Pyrexia	20	0.2	15	0
Metabolism and Nutrition Disorders
Decreased appetite	28	1.5	30	0.5
Skin and Subcutaneous Tissue Disorders
Rashc	25	2.0	17	2.5
Respiratory, Thoracic, and Mediastinal Disorders
Cough	21	0	28	0
Dyspnea	21	3.7	26	5

Abbreviation: NCI CTCAE = National Cancer Institute Common Toxicity Criteria for Adverse Events.

^a Graded per NCI CTCAE version 4.03.

^b Includes asthenia and fatigue.

^c Includes genital rash, rash, rash generalized, rash macular, rash maculo-papular, rash papular, rash pruritic, and rash pustular.

Pemetrexed was discontinued for AEs in 23% of patients in the pemetrexed, pembrolizumab, and platinum arm. The most common AEs resulting in discontinuation of pemetrexed in this arm were acute kidney injury (3%) and pneumonitis (2%).¹

Enclosed Prescribing Information

ALIMTA® (pemetrexed for injection), for intravenous use, Lilly

Reference

1. Alimta [package insert]. Indianapolis, IN: Eli Lilly and Company; 2019.

Glossary

AE = adverse event

ALK = anaplastic lymphoma kinase 

AUC = area under the curve

EGFR = epidermal growth factor receptor

Gy = gray

IV = intravenous

NSCLC = non-small cell lung cancer

OS = overall survival

PD-1 = programmed death-1

PD-L1 = programmed death-ligand 1

Pembrolizumab = KEYTRUDA® (pembrolizumab), Merck & Co., Inc.

PFS = progression-free survival

Q3W = every 3 weeks