A multicenter, randomized, phase II trial of anlotinib plus docetaxel versus docetaxel in EGFR-negative NSCLC patients after progression on first-line platinum-base chemotherapy: ALTER-L018.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e21186-e21186
Author(s):  
Lin Wu ◽  
Zhijun Wu ◽  
Zemin Xiao ◽  
Zhongsha Ma ◽  
Jie Weng ◽  
...  
Keyword(s):  
Adverse Events ◽  
Immune Checkpoint Inhibitors ◽  
Advanced Nsclc ◽  
Phase Ii Trial ◽  
Checkpoint Inhibitors ◽  
Second Line ◽  
First Line ◽  
Group A ◽  
Group B ◽  
Nsclc Patients

e21186 Background: Docetaxel is one of the standard second-line treatments for advanced non-small cell lung cancer (NSCLC), but the effect is limited. The combination of docetaxel and antiangiogenic drug (ramucirumab/nintedanib) has demonstrated antitumor activity as second-line therapy in advanced NSCLC. Anlotinib, an oral multi-target angiogenesis TKI targeting the VEGFR, FGFR, PDGFR and c-Kit, can prolong both PFS and OS of refractory advanced NSCLC patients in phase III trial (ALTER0303). We conducted ALTER-L018 to evaluate improvement of the efficacy and safety of anlotinib plus docetaxel in EGFR-negative refractory advanced NSCLC. Methods: ALTER-L018 (NCT03624309) is an ongoing, open-label, multicenter, randomized, controlled comparative, phase II trial, which was performed at 10 sites in China. Eligible EGFR-negative NSCLC patients (pts), who has been assessed progression after first-line platinum-based chemotherapy (combined with or without Immune checkpoint inhibitors), were randomly assigned (in a 1:1 ratio) to group A (anlotinib: 12mg QD from day 1 to 14 of a 21-day cycle +docetaxel: 75mg/m2 Q3W) and group B (docetaxel: 75mg/m2 Q3W). The primary end point was PFS, and secondary end points included OS, ORR, DCR and safety. Results: Between Jan 14, 2019, and Feb 7, 2021, 73 patients (pts.) were enrolled and 8 pts. were excluded from the safety and efficacy analysis set (n = 65) due to inclusion violations. 65 pts characteristics (28 pts in group A / 37 pts in group B): median age: 55(40-71)/57(39-74); male: 82% / 78%; non-squamous NSCLC: 75% / 65%; Immunotherapy in the front line: 18% / 22%. Median PFS were 4.03 months (95%CI: 2.98-5.08) in group A and 1.7 months (95%CI: 0.45-2.95) in group B (HR 0.40; 95% CI :0.21-0.77; p = 0.004); In group A and B, ORR and DCR were 32.14% versus 8.11%(p = 0.042), 82.12% versus 54.05%(p = 0.29), respectively. The adverse events that possibly or definitely related to therapy occurred in 26 (93%) of pts. experienced total of 52 grade 1-2 adverse events in group A, and in 25 (68%) of pts. experienced total of 25 grade 1-2 adverse events in group B. The most common grade ≥3 TRAE were leukopenia (5, 18%), neutropenia (5, 18%) and thrombocytopenia (3, 11%) in group A, and leukopenia (3, 8%), neutropenia (2, 5%) and thrombocytopenia (1, 3%) in group B. Conclusions: This combination of anlotinib and docetaxel showed clinical benefit in EGFR-negative NSCLC patients in terms of PFS, ORR, and with manageable safety profile. It is a viable option for relapsed NSCLC, who has been assessed progression on first-line platinum-base chemotherapy combined with/without Immune checkpoint inhibitors, or who can’t tolerate Immunotherapy. Clinical trial information: NCT03624309.

scholarly journals Comparative Safety of Immune Checkpoint Inhibitors and Chemotherapy in Advanced Non-Small Cell Lung Cancer: A Systematic Review and Network Meta-Analysis

2021 ◽  
Author(s):  
Ching-Yi Chen ◽  
Chi-Hsien Huang ◽  
Wang-Chun Chen ◽  
Ming-Shyan Huang ◽  
Yu-Feng Wei
Keyword(s):  
Lung Cancer ◽  
Immune Checkpoint Inhibitors ◽  
Advanced Nsclc ◽  
Checkpoint Inhibitors ◽  
Small Cell ◽  
Small Cell Lung ◽  
First Line ◽  
Grade 3 ◽  
Nsclc Patients ◽  
Combination Regimens

Abstract Backgrounds: Immune checkpoint inhibitors (ICIs) alone or in combination with chemotherapy (CT) are the standard of care for first-line therapy in metastatic non-small cell lung cancer (NSCLC) patients without actionable mutations. The safety ranking of different ICI and CT combination regimens has not been investigated. This study was aimed to provide a toxicity profile and safety ranking of different ICI and CT combination regimens.Methods: We performed comprehensive searches of phase 2 and 3 randomized clinical trials (RCTs) comparing different ICI regimens (alone or combination) or CT for the first-line treatment of advanced NSCLC. Outcomes of interest were the cumulative incidence of any treatment-related adverse events (TRAEs), grade 3-5 TRAEs (grade 3-5), any immune-related adverse events (irAEs), and grade 3-5 irAEs (grade 3-5). Odds ratios and 95% credible intervals were calculated as summary statistics to quantify the effect of different ICI combination regimens. Results: We included 23 RCTs from 2016 to 2021 with a total of 14,378 patients. The incidence of any TRAEs and grade 3-5 TRAEs ranked from high to low were ICI-CT (probability: 74.88%), ICI-ICI-CT (50.60%), CT alone (74.79%), ICI-ICI (98.37%), and ICI monotherapy (99.37%). Adding CT to ICI regimens resulted in a higher incidence of any grade or grade 3-5 TRAEs compared to ICI-ICI combinations or ICI monotherapy. However, ICI-ICI-CT combinations did not result in a higher incidence of TRAEs than ICI-CT combinations. For any irAEs and grade 3-5 irAEs, the ranking was ICI-ICI (probability: 97.38), ICI monotherapy (96.98%), ICI-CT (99.44%), and CT alone (99.98%). Notably, the incidence of any grade and grade 3-5 irAEs was lower when adding CT to ICI monotherapy. Conclusion: Lack of head-to-head comparisons, these findings provide evidence for clinical decision-making when considering different ICI combination regimens for advanced NSCLC patients.

A randomized phase II multi-institutional trial of anlotinib plus docetaxel versus docetaxel in EGFR-wild-type non-small cell lung cancer (NSCLC) patients after progression on first-line platinum-base chemotherapy: ALTER-L018.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e21703-e21703
Author(s):  
Lin Wu ◽  
Zhijun Wu ◽  
Zemin Xiao ◽  
Jie Weng ◽  
Zhongsha Ma ◽  
...  
Keyword(s):  
Advanced Nsclc ◽  
Phase Iii ◽  
Wild Type ◽  
First Line ◽  
End Points ◽  
Phase Iii Trial ◽  
Platinum Based Chemotherapy ◽  
Group A ◽  
Group B ◽  
Nsclc Patients

e21703 Background: Anlotinib is an oral VEGFR, FGFR, PDGFR and c-Kit tyrosine kinase inhibitor, which can prolong both PFS and OS of refractory advanced NSCLC patients in phase III trial: ALTER0303. The combination of docetaxel and ramucirumab/nintedanib had been demonstrated activity in the second line therapy setting for NSCLC. We performed ALTER-L018 to assessed the safety and efficacy of anlotinib with docetaxel in EGFR-wild type refractory advanced NSCLC (NCT03624309). Methods: Patients (pts) with EGFR-wild type refractory advanced NSCLC, who failed to first-line platinum-based chemotherapy, were randomized to group A(anlotinib: 12mg QD from day 1 to 14 of a 21-day cycle +docetaxel: 75mg/m2 Q3W) and group B(docetaxel: 75mg/m2 Q3W). The primary end points is PFS, and secondary end points include OS, ORR, DCR and safety. Results: Between January and December 2019, 36 pts were enrolled at 10 institutions in Hunan China, with 31(15 in group A, 16 in group B) of these individuals being evaluable for treatment efficacy and safety. Pt characteristics(group A/ group B): median age: 55(39-70)/57(44-67); male: 73%/81%; non-squamous NSCLC: 86%/75%. Median PFS were 5.3 months (95%CI:2.76-7.85) in group A and 2.3 months (95%CI, 1.14-3.46) in group B (HR 0.42; 95% CI:0.16-1.13; p = 0.047); In group A and B, ORR and DCR were 26.67% versus 0%(p = 0.043), 60.00% versus 31.25%(p = 0.16), respectively. Among 31 pts, 89% of treatment-related AEs (TRAEs) were grade 1 or 2, and the most common TRAEs in group A were hand-foot syndrome, pruritus and insomnia of 13%(2/15) each; in group B were alopecia, constipation and anemia of 12%(1/16) each. Toxicities≥grade 3(TRAEs) included: neutropenia, leukopenia, diarrhea and hrombocytopenia, 6.6%(1/15) each in group A. There was 1 grade 5 AE in group A. Conclusions: This combination of anlotinib and docetaxel with significant difference PFS prolonging and manageable safety profile, is a viable option in relapsed NSCLC, should be considered following progression on platinum-based chemotherapy. It will be further explored in a randomized phase III trial. Clinical trial information: NCT03624309.

scholarly journals Cancer immunotherapy-associated hypophysitis

2019 ◽  
Vol 15 (27) ◽  
pp. 3159-3169 ◽  
Author(s):  
Franklin Castillero ◽  
Omar Castillo-Fernández ◽  
Geiner Jiménez-Jiménez ◽  
José Fallas-Ramírez ◽  
Marco P Peralta-Álvarez ◽  
...  
Keyword(s):  
Adverse Event ◽  
Adverse Events ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Current Data ◽  
Second Line ◽  
First Line ◽  
Second Line Therapy ◽  
Line Therapy

The advances in cancer therapy have included the development of drugs that inhibit immune checkpoint ligands. Two types of immune checkpoint inhibitors, both antibodies that target CTLA-4 and PD-1, have been approved for its use in NSCLC and melanoma as first-line or second-line therapy. Sadly, not desirable consequences of immunotherapy are immune-related adverse events. immune-related hypophysitis is the most common endocrine adverse event after thyroid disfunction. The particularity of endocrine immune-related adverse events is their non-reversibility, with incidence and prevalence destined to increase in the coming years, particularly if this form of therapy is used in the future for earlier stages of cancer. Therefore, hypophysitis represents a challenge for the physician, sometimes occurring without specific symptomatology and which should be considered for clinical management. In this review, we describe the current data regarding the pathophysiology and management for immune-related hypophysitis.

scholarly journals The Landscape of Immunotherapy in Advanced NSCLC: Driving Beyond PD-1/PD-L1 Inhibitors (CTLA-4, LAG3, IDO, OX40, TIGIT, Vaccines)

2021 ◽  
Vol 23 (11) ◽  
Author(s):  
Andrea De Giglio ◽  
Alessandro Di Federico ◽  
Giacomo Nuvola ◽  
Chiara Deiana ◽  
Francesco Gelsomino
Keyword(s):  
Immune Checkpoint Inhibitors ◽  
Advanced Nsclc ◽  
State Of The Art ◽  
Checkpoint Inhibitors ◽  
Driver Mutations ◽  
First Line ◽  
Comprehensive Overview ◽  
Actual Knowledge ◽  
Nsclc Patients ◽  
First Line Treatment

Abstract Purpose of Review In this review, we analyzed the current landscape of non-PD-(L)1 targeting immunotherapy. Recent Findings The advent of immunotherapy has completely changed the standard approach toward advanced NSCLC. Inhibitors of the PD-1/PD-L1 axis have quickly taken place as first-line treatment for NSCLC patients without targetable “driver” mutations. However, a non-negligible portion of patients derive modest benefit from immune-checkpoint inhibitors, and valid second-line alternatives are lacking, pushing researchers to analyze other molecules and pathways as potentially viable targets in the struggle against NSCLC. Summary Starting from the better characterized CTLA-4 inhibitors, we then critically collected the actual knowledge on NSCLC vaccines as well as on other emerging molecules, many of them in their early phase of testing, to provide to the reader a comprehensive overview of the state of the art of immunotherapy in NSCLC beyond PD-1/PD-L1 inhibitors.

scholarly journals Development of nomogram based on immune-related gene FGFR4 for advanced non-small cell lung cancer patients with sensitivity to immune checkpoint inhibitors

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Li Wang ◽  
Zhixuan Ren ◽  
Bentong Yu ◽  
Jian Tang
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Advanced Nsclc ◽  
Cancer Genomics ◽  
Checkpoint Inhibitors ◽  
Small Cell ◽  
Small Cell Lung ◽  
Nsclc Patients

Abstract Introduction Immune checkpoint inhibitors (ICIs) have become a frontier in the field of clinical technology for advanced non-small cell lung cancer (NSCLC). Currently, the predictive biomarker of ICIs mainly including the expression of PD-L1, TMB, TIICs, MMR and MSI-H. However, there are no official biomarkers to guide the treatment of ICIs and to determine the prognosis. Therefore, it is essential to explore a systematic nomogram to predict the prognosis of ICIs treatment in NSCLC Methods In this work, we obtained gene expression and clinical data of NSCLC patients from the TCGA database. Immune-related genes (IRGs) were downloaded from the ImmPort database. The detailed clinical annotation and response data of 240 advanced NSCLC patients who received ICIs treatment were obtained from the cBioPortal for Cancer Genomics. Kaplan–Meier survival analysis was used to perform survival analyses, and selected clinical variables to develop a novel nomogram. The prognostic significance of FGFR4 was validated by another cohort in cBioPortal for Cancer Genomics. Results 3% of the NSCLC patients harbored FGFR4 mutations. The mutation of FGFR4 were confirmed to be associated with PD-L1, and TMB. Patients harbored FGFR4 mutations were found to have a better prolonged progression-free survival (PFS) to ICIs treatment (FGFR4: P = 0.0209). Here, we built and verified a novel nomogram to predict the prognosis of ICIs treatment for NSCLC patients. Conclusion Our results showed that FGFR4 could serve as novel biomarkers to predict the prognosis of ICIs treatment of advanced NSCLC. Our systematic prognostic nomogram showed a great potential to predict the prognosis of ICIs for advanced NSCLC patients.

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