Phase III Non-inferiority Study Evaluating Efficacy and Safety of Low Dose Gemcitabine Compared to Standard Dose Gemcitabine With Platinum in Advanced Squamous Lung Cancer

Abstract

Background Prolonged infusion of low dose gemcitabine (PLDG) in combination with platinum has shown promising activity in terms of improved response rate and progression free survival (PFS); especially in squamous non-small cell lung cancer (NSCLC). Hence, we conducted a phase 3 randomized non-inferiority study with the primary objective of comparing the overall survival (OS) between PLDG and standard dose of gemcitabine with platinum. Methodology Adult subjects (age ≥ 18 years), with stages IIIB–IV, NSCLC (squamous) and ECOG performance status of ≤ 2 were randomized 1:1 into either carboplatin with standard dose gemcitabine (1000 mg/m 2 intravenous over 30 min, days 1 and 8) (STD-G arm) or carboplatin along with low dose gemcitabine (250 mg/m 2 intravenous over 6 h, days 1 and 8) (LOW-G arm) for a maximum of 6 cycles. Tumor response was assessed by RECIST criteria version 1.1 every 2 cycles till 6th cycle and thereafter at 2 monthly intervals till progression. The primary endpoint was overall survival. 308 patients were randomized, 155 in STD-G arm and 153 in LOW-G arm, respectively. Results The median overall survival in STD-G arm was 6.8 months (95%CI 5.3–8.5) versus 8.4 months (95%CI 7–10.3) in the LOW-G arm (HR-0.890 (90%CI 0.725–1.092). The results with per protocol analysis were in line with these results. There was no statistical difference in progression free survival (HR-0.949; 90%CI 0.867–1.280) and adverse event rate between the 2 arms. Conclusion This study suggests that PLDG is an alternative to the standard gemcitabine schedule in squamous NSCLC, and either of these can be selected subject to patient convenience.

Sintilimab Plus Platinum and Gemcitabine as First-Line Treatment for Advanced or Metastatic Squamous NSCLC: Results From a Randomized, Double-Blind, Phase 3 Trial (ORIENT-12)

“…Overall, sintilimab in combination with GP therapy was well tolerated, with relatively lower frequencies of dose discontinuation (14.5% versus 16.3%) and death events (4.5% versus 6.7%) caused by TEAEs, compared with GP alone. The AE profile observed in the current study was consistent with those known to be associated with gemcitabine, cisplatin, carboplatin, and sintilimab, 4,6,[29][30][31] with no new safety signals identified. In both groups, the most frequently reported TEAEs included anemia, decreased white blood cell count, decreased neutrophil count, and decreased platelet count, and they were also the common TEAEs of grade 3 or worse; these are expected hematological AEs associated with gemcitabine and platinum, 30,32 and they were manageable.…”

“…The previously reported median OS with GP was 6.8 to 10.8 months for sqNSCLC. [2][3][4] Our results revealed the survival benefit with sintilimab plus GP chemotherapy.…”

“…In the absence of driver gene mutations, chemotherapy is the mainstay of treatment for advanced sqNSCLC, which is associated with shorter overall survival (OS) than nonsqNSCLC. [2][3][4] Immune checkpoint inhibitors provide a new clinical approach for treating sqNSCLC [5][6][7][8] ; a phase 3 study confirmed the clinical benefit of an antiprogrammed cell death-protein 1 (PD-1) antibody (pembrolizumab) plus carboplatin and paclitaxel. 5 Nevertheless, paclitaxel could induce severe toxicities, such as neuropathy, limiting its clinical use.…”

Leptomeningeal metastasis from non-small cell lung cancer – a post-hoc analysis from four randomised clinical trials

“…Patients who were diagnosed with squamous cell carcinoma of the lungs were enrolled in a 1:1 fashion in the low-dose gemcitabine with platinum versus standard-dose gemcitabine with the platinum trial (May 2013–March 2018) [ 11 ]. OS was the primary end point.…”

Optimized Dosing: The Next Step in Precision Medicine in Non-Small-Cell Lung Cancer

“…Indeed, administration of gemcitabine 250 mg/m 2 over 6 h showed efficacy similar to that with 1000 mg/m 2 over 30 min [139]. Studies to test this prolonged infusion duration of low-dose gemcitabine in combination with 75 mg/ m 2 cisplatin found beneficial efficacy results and a different toxicity profile for gemcitabine compared with historical cohorts [140,141].…”