Second-line Activity Research Articles

International, open-label phase 2 study of regorafenib plus pembrolizumab in patients with advanced hepatocellular carcinoma (HCC) previously treated with immune checkpoint inhibitors (ICI).

4007 Background: The optimal second-line treatment for HCC after ICI is not established. Regorafenib is approved for treatment of advanced HCC after sorafenib. The primary aim of this study was to evaluate the activity of regorafenib plus pembrolizumab in patients with advanced HCC who progressed on only one prior ICI regimen. Methods: Patients aged ≥18 years, CP Class A, BCLC stage B or C, and ECOG PS of 0 or 1 received oral regorafenib 90 mg once daily 3 weeks (wk) on/1 wk off plus i.v. pembrolizumab 400 mg every 6 wk. The daily regorafenib dose could be escalated to 120 mg after the first 4-wk cycle of regorafenib if tolerated. Pembrolizumab dose reductions were not allowed. Cohorts were defined by prior treatment: Cohort 1 = atezolizumab + bevacizumab; Cohort 2 = any other ICI regimen (alone or combination). Primary endpoint was overall response rate (ORR) by independent central review (RECIST 1.1). Results: 95 patients were treated in 8 countries; Cohort 2 appeared to have more favorable disease characteristics (Table). Most common prior ICIs in Cohort 2 were durvalumab (30%), nivolumab (30%), ipilimumab (22%), and pembrolizumab (19%). Overall, median follow up was 7.1 months (mo). Median duration of regorafenib/pembrolizumab treatment (including interruptions, delays) was shorter in Cohort 1 vs Cohort 2 (11.0/9.4 wk vs 21.4/24.1 wk). ORR was 5.9% in Cohort 1 and 11.1% in Cohort 2; stable disease rates were 48.5% and 63.0%, respectively. Median PFS was 2.8 mo in Cohort 1 and 4.2 mo in Cohort 2. Overall, treatment-emergent adverse events (TEAE) were grade 3 in 56% of patients and grade 4 in 5%; drug-related grade 3 and 4 TEAE occurred in 37% and 3%, respectively. One patient (Cohort 1) had a grade 5 drug-related TEAE (cardiac arrest). Most common drug-related TEAE were palmar-plantar erythrodysesthesia syndrome (39%), asthenia (33%), decreased appetite (32%), diarrhea (28%), and hypertension (20%). Biomarkers assessed in paired biopsies (baseline and wk 6/day 1) showed on-treatment reductions in macrophages and angiogenesis RNA signatures. Conclusions: To our knowledge, this is the first prospective evaluation of a kinase inhibitor plus an ICI following first-line ICI therapy for HCC. Regorafenib plus pembrolizumab had modest activity in second line after first-line ICI regimens. The safety profile of the combination was consistent with those of either drug. Optimal treatment for patients with advanced HCC who progress after an ICI regimen remains an unmet need. Biomarker findings will be detailed in presentation. Clinical trial information: NCT04696055 . [Table: see text]

Impact of First Line Antiangiogenic Therapy Duration on Nivolumab Outcome in Metastatic Renal Cell Carcinoma Patients Treated in the GETUG—AFU 26 NIVOREN

BackgroundIn metastatic renal clear cell carcinoma (ccRCC), vascular endothelial growth factor receptor (VEGFR) and immune checkpoint are 2 main therapeutic targets. We investigated the impact of duration exposure to antiangiogenic on immunotherapy clinical outcomes in metastatic ccRCC. MethodsPatients from NIVOREN trial who received nivolumab after only 1 prior antiangiogenic therapy were included. Response rate, clinical benefit, progression free survival (PFS) and overall survival (OS) were prospectively analyzed depending on the duration of the first line (< 6 months, ≥6 months) and exploratory in patients with long first line exposure (≥18 months). The circulating levels of 8 plasma proteins and cytokines at baseline were collected and compared according to first line antiangiogenic duration. ResultsAmong 354 patients, 127 (36%) and 227 (64%) patients had received first line antiangiogenic for < 6months and ≥ 6months respectively. Respective duration of first line therapy was not associated with objective response to nivolumab (20.5% vs. 23.9%, P = .50), or PFS (HR 0.92; P = .421). Median OS was respectively 16.6 and 31.3 months in the <6 and ≥6 months subgroups respectively. Adjusted on international metastatic renal cell carcinoma database consortium risk, age and metastatic site, OS was longer in patients with longer treatment duration in the first line setting (HR 0.73; P = .017). Duration of first line VEGFR TKI was independent from circulating levels of 8 proteins and cytokines at nivolumab baseline. ConclusionNivolumab activity in second line is independent from first-line duration of VEGFR TKI. However, first line VEGFR TKI duration ≥ 6 months is associated with longer OS.

Efficacy and safety of chronomodulated irinotecan, oxaliplatin, 5-fluorouracil and leucovorin combination as first- or second-line treatment against metastatic colorectal cancer: Results from the International EORTC 05011 Trial.

The triplet combination of irinotecan, oxaliplatin and fluorouracil is an active frontline regimen in metastatic colorectal cancer, but scarce data exist on its use as salvage treatment. We aimed at assessing its safety and efficacy profiles with its circadian‐based administration (chronoIFLO5) as either first‐ or second‐line treatment, within the time‐finding EORTC 05011 trial. Five‐day chronoIFLO5 was administered every 3 weeks in patients with PS 0, 1 or 2. It consisted of chronomodulated irinotecan (180 mg/sqm), oxaliplatin (80 mg/sqm) and fluorouracil‐leucovorin (2800 and 1200 mg/sqm, respectively). For our study, toxicity and antitumour activity were evaluated separately in first‐ and second‐line settings. Primary endpoints included Grade 3‐4 toxicity rates, best objective response rate (ORR), progression‐free survival (PFS) and overall survival (OS). One‐hundred forty‐nine and 44 patients were treated in first‐line and second‐line settings, respectively, with a total of 1138 cycles with median relative dose intensities of about 90%. Demographics were comparable in the two groups. Thirty‐six (24.7%) and 10 (22.2%) patients experienced at least one episode of severe toxicity in first line and second line, respectively. Frontline chronoIFLO5 yielded an ORR of 62.3% [95% CI: 54.2‐70.4] and resulted in median PFS and OS of 8.7 months [7.5‐9.9] and 19.9 months [15.4‐24.5]. Corresponding figures in second line were 37.5% [22.5‐52.5], 6.7 months [4.8‐8.9] and 16.3 months [11.8‐20.8]. International and prospective evaluation revealed the favourable safety and efficacy profiles of chronoIFLO5, both as frontline and as salvage treatment against metastatic colorectal cancer. In particular, encouraging activity in second line was observed, with limited haematological toxicity.