Cyramza® (ramucirumab): Postdiscontinuation Therapy in RELAY

Study Design

The RELAY trial was a phase 3, global, multicenter, randomized, double-blind, placebo-controlled trial in patients (N=449) with previously untreated EGFR mutation-positive, metastatic NSCLC. All patients had an EGFR mutation of exon 19 deletion or exon 21 L858R and an ECOG PS of 0 or 1. Patients were randomly assigned in a 1:1 ratio (stratified by sex, region, EGFR status, and EGFR testing method) to receive treatment with erlotinib (150 mg/day) plus ramucirumab (10 mg/kg every 2 weeks; n=224) or placebo (10 mg/kg every 2 weeks; n=225) until disease progression or unacceptable toxicity.¹

Postdiscontinuation Therapy

At the time of data cutoff, 107 (23.8%) patients were still receiving study treatment.  Of those patients in the RELAY ITT population who discontinued study treatment, 36 (16.1%) patients in the ramucirumab-erlotinib arm and 25 (11.1%) patients in the placebo-erlotinib arm received no PDT.¹ 

Per protocol, all study treatment was stopped for RECIST progression. Treatment beyond the point of RECIST progression was not allowed even if there was continued benefit per investigator assessment. Subsequent therapy was at the discretion of the investigator.¹

Anticancer PDT for the ITT population is summarized in Table 1

Table 1. Postdiscontinuation Anticancer Therapy in the RELAY ITT Population²

Postdiscontinuation Therapy	Ramucirumab + Erlotinib (N=224) n (%)	Placebo + Erlotinib (N=225) n (%)
Radiotherapy	22 (9.8)	33 (14.7)
Surgical procedure	5 (2.2)	4 (1.8)
Selected systemic therapy	120 (53.6)	156 (69.3)
ALK inhibitor
Crizotinib	0 (0.0)	2 (0.9)
Chemotherapy
Amrubicin	2 (0.9)	0 (0.0)
Carboplatin	24 (10.7)	44 (19.6)
Carboplatin; Etoposide	1 (0.4)	0 (0.0)
Carboplatin; Gemcitabine	0 (0.0)	1 (0.4)
Carboplatin; Pemetrexed	1 (0.4)	1 (0.4)
Cisplatin	26 (11.6)	30 (13.3)
Cisplatin; Pemetrexed	0 (0.0)	2 (0.9)
Docetaxel	12 (5.4)	21 (9.3)
Etoposide	0 (0.0)	3 (1.3)
Fluorouracil; Folinic Acid; Irinotecan	1 (0.4)	0 (0.0)
Gemcitabine	3 (1.3)	2 (0.9)
Gemcitabine; Vinorelbine	1 (0.4)	0 (0.0)
Gimeracil; Oteracil; Tegafur	3 (1.3)	6 (2.7)
Paclitaxel	7 (3.1)	10 (4.4)
Pemetrexed	42 (18.8)	73 (32.4)
Vinorelbine	3 (1.3)	1 (0.4)
Immunotherapy/PD-(L)1 inhibitor
Atezolizumab	1 (0.4)	1 (0.4)
Durvalumab	0 (0.0)	1 (0.4)
Nivolumab	5 (2.2)	9 (4.0)
Pembrolizumab	3 (1.3)	8 (3.6)
Spartalizumab	0 (0.0)	1 (0.4)
Immunotherapy/CTLA-4
Ipilimumab	1 (0.4)	0 (0.0)
Immunotherapy/CD73-inhibitor
Oleclumab	0 (0.0)	1 (0.4)
EGFR antagonist
Lazertinib	2 (0.9)	0 (0.0)
EGFR-TKI
Afatinib	11 (4.9)	22 (9.8)
EGF816	0 (0.0)	1 (0.4)
Erlotinib	62 (27.7)	58 (25.8)
Gefitinib	11 (4.9)	13 (5.8)
VEGF antibody
Bevacizumab	16 (7.1)	32 (14.2)
Ramucirumab	4 (1.8)	10 (4.4)
c-Met inhibitor
Savolitinib	1 (0.4)	2 (0.9)

Abbreviations: ALK = anaplastic lymphoma kinase; CD73 = ectonucleotidase 73; CLTA-4 = cytotoxic T-lymphocyte-associated protein 4; c-Met = hepatocyte growth factor; EGFR = epidermal growth factor receptor; ITT = intent-to-treat; N = number of subjects in ITT population part B; n = number of subjects in the specified category; PD(L)1 = programmed death-ligand 1; TKI = tyrosine kinase inhibitor; VEGF = vascular endothelial growth factor.

Consistent with international guidelines, treatment with a TKI beyond the point of RECIST progression is common clinical practice if there is continued benefit as judged by the treating physician; a practice that may have contributed to the relatively high usage of erlotinib as first subsequent therapy.²

Erlotinib was the most frequently used initial PDT. Fifty-one percent and 35% of patients in the ramucirumab-erlotinib arm vs. placebo-erlotinib arm, respectively, received erlotinib as first PDT. Chemotherapy was the most frequently used subsequent PDT.¹

References

1. Nakagawa K, Garon EB, Seto T, et al. Ramucirumab plus erlotinib in patients with untreated, EGFR-mutated, advanced non-small-cell lung cancer (RELAY): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2019;20(12):1655-1669. https://doi.org/10.1016/S1470-2045(19)30634-5

2. Data on file, Eli Lilly and Company and/or one of its subsidiaries.

Glossary

ECOG = Eastern Cooperative Oncology Group

EGFR = epidermal growth factor receptor

HR = hazard ratio

ITT = intent-to-treat

NSCLC = non-small cell lung cancer

OS = overall survival

PDT = postdiscontinuation therapy

PS = performance status

RECIST = Response Evaluation Criteria in Solid Tumors

TKI = tyrosine kinase inhibitor