Efficacy and safety of maintenance pemetrexed in patients with advanced nonsquamous non-small cell lung cancer following pemetrexed plus cisplatin induction treatment: A cross-trial comparison of two phase III trials

Abstract

Highlights•Compared advanced NSCLC phase III trials: pemetrexed-cisplatin with or without pem maintenance.•4 cycles pem-cis followed by pem maintenance improves survival over 6 cycles pem-cis.•Longer exposure to pem-cis or maintenance pem increases some toxicities, but overall incidence low. Abstract ObjectivesTwo phase III trials of advanced NSCLC patients were compared to examine relative efficacy and safety of differing treatment regimens. The JMDB trial investigated first-line pemetrexed-cisplatin (pemetrexed 500 mg/m 2 plus cisplatin 75 mg/m 2 every 21 days; maximum: 6 cycles). The PARAMOUNT phase III trial compared maintenance pemetrexed versus placebo after patients with nonsquamous NSCLC completed 4 cycles of first-line pemetrexed-cisplatin without disease progression. MethodsOverall survival (OS) and progression-free survival (PFS), analyzed by Kaplan-Meier and Cox methods, and toxicity rates were compared between the PARAMOUNT arms and a selected homogeneous population from JMDB: 346 patients with disease and prior treatment characteristics matching the PARAMOUNT population. ResultsOutcomes for the PARAMOUNT placebo arm were similar to the JMDB homogeneous group (median PFS: 5.6 versus 6.2 months, p = 0.117, HR = 1.16; median OS: 14.0 versus 14.2 months, p = 0.979, HR = 1.00). The PARAMOUNT maintenance pemetrexed group had statistically superior efficacy compared with the JMDB homogeneous group (median PFS: 7.5 versus 6.2 months, p < 0.00001, HR = 0.66; median OS: 16.9 versus 14.2 months, p = 0.003, HR = 0.75). Patients who received pemetrexed maintenance (median 4 cycles, range 1-44) following 4 cycles of pemetrexed-cisplatin exhibited a higher incidence of drug-related serious adverse events compared with JMDB patients (median 6 cycles of pemetrexed-cisplatin) (10.6% versus 2.9%); grade 3/4 fatigue and renal toxicity were also higher in the pemetrexed arm of PARAMOUNT. ConclusionsThe across-trial comparison of a relevant JMDB study population with the two arms of the PARAMOUNT study supported the efficacy of the pemetrexed continuation maintenance strategy and suggested the results are not influenced by limiting the pemetrexed-cisplatin induction treatment to four cycles. Although longer exposure to pemetrexed-cisplatin or maintenance pemetrexed increased some toxicities, the overall incidence remained low, underscoring the relative safety of these treatment regimens.

Final results from a Phase II study of pemetrexed and cisplatin with concurrent thoracic radiation after Pem-Cis induction in patients with unresectable locally advanced non-squamous non-small cell lung cancer (NSCLC)

“…The toxicity profile during Pem-Cis induction CT was similar to the known profile from Phase-III-studies evaluating Pem-Cis in advanced non-squamous NSCLC [10,20]. The only G3 hematologic toxicity reported during induction CT was neutropenia (2 patients), the only G3/4 non-hematologic toxicities reported were hyponatremia and syncope (1 patient each).…”

Nivolumab in Combination With Platinum‐Based Doublet Chemotherapy for First-Line Treatment of Advanced Non–Small-Cell Lung Cancer

“…[1][2][3][4][5][6] Bevacizumab and maintenance chemotherapy, most commonly with pemetrexed, have improved clinical outcomes (median PFS: maintenance bevacizumab, 3.7 to 6.9 months; maintenance pemetrexed, 7.5 months; maintenance bevacizumab plus pemetrexed, 7.4 to 8.6 months). [7][8][9] However, resistance to chemotherapeutic agents invariably develops, and all patients eventually experience progression. 10 Although conventional chemotherapy directly targets tumor cell replication strategies, preclinical evidence demonstrates that chemotherapeutic agents are less effective in immunodeficient hosts, suggesting the antitumor effects of cytotoxic chemotherapy also occur through modulation of the immune system.…”

Néphrotoxicité du pemetrexed

“…Certains auteurs rapportent une faible dégradation de la fonction rénale lors d'exposition courte au pemetrexed contrairement à une exposition prolongée responsable d'une IR par une toxicité cumulée due à l'accumulation intracellulaire de polyglutamate [34]. Deux essais randomisés de phase III (PARAMOUNT et JMDB) incluant des patients atteints de cancer du poumon avancés ont été comparés notamment sur leur toxicité rénale (tableau I) [35][36][37]. L'essai PARAMOUNT comportait une phase d'induction (4 cycles de pemetrexed-cisplatine) avant la randomisation pour la phase d'entretien (absence de progression de la maladie et/ou intolérance).…”

“…L'étude de phase III JMDB a porté sur une phase d'induction pemetrexed-cisplatine (pemetrexed 500 mg/m 2 + cisplatine 75 mg/m 2 tous les 21 jours, maximum 6 cycles). La toxicité rénale était plus élevée dans le bras pemetrexed de l'essai PARAMOUNT [36] et chez les patients ayant reçu le traitement d'entretien (médiane de 4 cycles, écart 1-44) après le traitement d'induction [35][36][37]. Au cours du traitement d'entretien, l'incidence de la toxicité rénale de grade 1 s'était accrue avec le nombre de cycles [36].…”