Non-squamous Non-small Cell Lung Cancer Research Articles

86P Adjusting ORIENT-11 trial (O-11) results to a US patient population

O-11 demonstrated that adding sintilimab, a highly selective fully human IgG4 mAb that blocks the binding site of PD-1, to pemetrexed+platinum (SPP) improved progression free survival (PFS) in Chinese patients (pts) with advanced/metastatic nonsquamous NSCLC. To estimate the applicability of O-11 results to US pts, this post hoc retrospective study assesses the effect of SPP v placebo+pemetrexed+platinum (PPP) on PFS, after adjusting the O-11 population to reflect a target US population that would have been eligible for O-11.

94P Patient-reported outcomes (PROs) following sintilimab (sint) plus pemetrexed (pem) and platinum (plt) based chemotherapy as first-line therapy for locally advanced or metastatic nonsquamous NSCLC: A randomized, double-blind, phase III study (Orient-11)

In ORIENT-11, sint + pem + plt provided meaningful improvement in PFS and OS over pbo + pem + plt as first-line therapy in Chinese patients with locally advanced or metastatic nonsquamous NSCLC. This abstract summarized PRO results from ORIENT-11.

148P A phase II study of tislelizumab plus chemotherapy in EGFR mutated advanced non-squamous NSCLC patients failed to EGFR TKI therapies: First analysis

BackgroundAlthough EGFR tyrosine kinase inhibitors (TKI) have improved the survival of EGFR mutated NSCLC pts, drug resistance inevitably develops in almost all pts. Tislelizumab (tis), an anti-PD-1 mAb, has shown improved efficacy when combined with chemotherapy in pts with advanced EGFR-wt NSCLC with a tolerable safety profile. This study aims to evaluate the efficacy and safety of tis plus chemotherapy in EGFR-mut nsq-NSCLC pts failed to EGFR TKI therapies.MethodsThis multicenter, single-arm, phase II study enrolled pts with EGFR sensitizing mutations who have failed prior EGFR-TKI therapies. Pts were treated with tis plus carboplatin and nab-paclitaxel Q3W for up to 4 cycles, followed by tis plus pemetrexed maintenance therapy. Primary endpoint was 1-year PFS rate, and secondary endpoints included ORR, DCR and safety, etc. First analysis is planned at 7 weeks after 50% planned enrollment (33 pts) for early efficacy and safety.ResultsTable: 148PResponseTotal (N=32)EGFR mutation#Prior EGFR TKI treatmentprior anti-angiogenesis treatmentExon 19del (N=17)Exon 21 L858R (N=14)1/2nd and 3rd TKI (N=17)1/2nd or 3rd TKI (N=15)Yes (N=10)No (N=22)BoR, n (%)PR19 (59.4%)∗12 (70.6%)6 (42.9%)10 (58.8%)9 (60.0%)7 (70.0%)12 (54.6%)SD10 (31.3%)3 (17.7%)7 (33.3%)5 (29.4%)5 (33.3%)1 (10.0%)9 (40.9%)PD3 (9.4%)2 (11.8%)1 (7.1%)2 (11.8%)1 (6.7%)2 (20.0%)1 (4.6%)ORR19 (59.4%)12 (70.6%)6 (42.9%)10 (58.8%)9 (60.0%)7 (70.0%)12 (54.6%)DCR29 (90.6%)15 (88.2%)13 (92.9%)15 (88.2%)14 (93.3%)8 (80.0%)21 (95.5%)BOR, best overall response; PR, partial response; SD, stable disease; PD, progressive disease; ORR, objective response rate; DCR, disease control rate*Including 4 unconfirmed PR;#1 pts with exon 18 G719X was PR. Open table in a new tab ConclusionsTislelizumab plus chemotherapy has preliminarily shown a promising anti-tumor efficacy with manageable safety profile for EGFR TKI failure pts. Efficacy and safety of the combination will be continuously monitored.Clinical trial identificationNCT04405674.Legal entity responsible for the studyThe authors.FundingBeiGene (Beijing), Co. Ltd.DisclosureAll authors have declared no conflicts of interest. BackgroundAlthough EGFR tyrosine kinase inhibitors (TKI) have improved the survival of EGFR mutated NSCLC pts, drug resistance inevitably develops in almost all pts. Tislelizumab (tis), an anti-PD-1 mAb, has shown improved efficacy when combined with chemotherapy in pts with advanced EGFR-wt NSCLC with a tolerable safety profile. This study aims to evaluate the efficacy and safety of tis plus chemotherapy in EGFR-mut nsq-NSCLC pts failed to EGFR TKI therapies. Although EGFR tyrosine kinase inhibitors (TKI) have improved the survival of EGFR mutated NSCLC pts, drug resistance inevitably develops in almost all pts. Tislelizumab (tis), an anti-PD-1 mAb, has shown improved efficacy when combined with chemotherapy in pts with advanced EGFR-wt NSCLC with a tolerable safety profile. This study aims to evaluate the efficacy and safety of tis plus chemotherapy in EGFR-mut nsq-NSCLC pts failed to EGFR TKI therapies. MethodsThis multicenter, single-arm, phase II study enrolled pts with EGFR sensitizing mutations who have failed prior EGFR-TKI therapies. Pts were treated with tis plus carboplatin and nab-paclitaxel Q3W for up to 4 cycles, followed by tis plus pemetrexed maintenance therapy. Primary endpoint was 1-year PFS rate, and secondary endpoints included ORR, DCR and safety, etc. First analysis is planned at 7 weeks after 50% planned enrollment (33 pts) for early efficacy and safety. This multicenter, single-arm, phase II study enrolled pts with EGFR sensitizing mutations who have failed prior EGFR-TKI therapies. Pts were treated with tis plus carboplatin and nab-paclitaxel Q3W for up to 4 cycles, followed by tis plus pemetrexed maintenance therapy. Primary endpoint was 1-year PFS rate, and secondary endpoints included ORR, DCR and safety, etc. First analysis is planned at 7 weeks after 50% planned enrollment (33 pts) for early efficacy and safety. ResultsTable: 148PResponseTotal (N=32)EGFR mutation#Prior EGFR TKI treatmentprior anti-angiogenesis treatmentExon 19del (N=17)Exon 21 L858R (N=14)1/2nd and 3rd TKI (N=17)1/2nd or 3rd TKI (N=15)Yes (N=10)No (N=22)BoR, n (%)PR19 (59.4%)∗12 (70.6%)6 (42.9%)10 (58.8%)9 (60.0%)7 (70.0%)12 (54.6%)SD10 (31.3%)3 (17.7%)7 (33.3%)5 (29.4%)5 (33.3%)1 (10.0%)9 (40.9%)PD3 (9.4%)2 (11.8%)1 (7.1%)2 (11.8%)1 (6.7%)2 (20.0%)1 (4.6%)ORR19 (59.4%)12 (70.6%)6 (42.9%)10 (58.8%)9 (60.0%)7 (70.0%)12 (54.6%)DCR29 (90.6%)15 (88.2%)13 (92.9%)15 (88.2%)14 (93.3%)8 (80.0%)21 (95.5%)BOR, best overall response; PR, partial response; SD, stable disease; PD, progressive disease; ORR, objective response rate; DCR, disease control rate*Including 4 unconfirmed PR;#1 pts with exon 18 G719X was PR. Open table in a new tab BOR, best overall response; PR, partial response; SD, stable disease; PD, progressive disease; ORR, objective response rate; DCR, disease control rate *Including 4 unconfirmed PR; #1 pts with exon 18 G719X was PR. ConclusionsTislelizumab plus chemotherapy has preliminarily shown a promising anti-tumor efficacy with manageable safety profile for EGFR TKI failure pts. Efficacy and safety of the combination will be continuously monitored. Tislelizumab plus chemotherapy has preliminarily shown a promising anti-tumor efficacy with manageable safety profile for EGFR TKI failure pts. Efficacy and safety of the combination will be continuously monitored.

Tailoring maintenance chemotherapy upon response to induction chemotherapy as compared with pemetrexed continuation maintenance in advanced non-squamous NSCLC patients: Results of the IFCT-GFPC-1101 multicenter randomized phase III trial

BackgroundBenefit from maintenance in advanced non-squamous non-small cell lung cancer (NS-NSCLC) might favor switch maintenance after disease stabilization (SD) and continuation after objective response (OR). This trial assessed a maintenance strategy conditioned by response to cisplatin-gemcitabine (CG) with G continuation for patients with OR or switch to pemetrexed (P) for patients with SD as compared with a control arm based on the Paramount regimen. MethodsEligibility criteria: age 18–70 years, ECOG PS 0–1, untreated stage IV NS-NSCLC without EGFR or ALK alteration, ineligibility to bevacizumab. Patients were randomized 1:1 to receive either CG (4 cycles) followed by G maintenance in case of OR followed by P at progression, or switch to P for patients with SD, or 4 cycles of CP followed by P (control arm). Primary endpoint: overall Survival. ResultsBetween 2012 and 2016, 932 patients were randomized (CG: 467, CP: 465) with well-balanced characteristics. 257 patients (56.7%) in the CG arm received maintenance (G: 142, P: 113) versus 277 patients (59.7%) in the CP arm. Median number of maintenance cycles was 5 for G and P (CG induction) and 4 for P (CP induction). OS adjusted HR was 0.97 (95% CI 0.84, 1.13; p = 0.71) with a median of 10.9 months (CG) versus 10.4 (CP). HR for PFS was 0.95 (95% CI 0.83, 1.09; p = 0.45) with a median of 4.8 months for CG versus 4.5 for CP. Safety profile was as expected. ConclusionsAdapting maintenance strategy according to response to induction chemotherapy does not improve patient outcome. Clinical trial information: NCT01631136.

Deepening the Knowledge of ROS1 Rearrangements in Non-Small Cell Lung Cancer: Diagnosis, Treatment, Resistance and Concomitant Alterations.

ROS proto-oncogene 1 (ROS1) rearrangements are reported in about 1–2% of non-squamous non-small-cell lung cancer (NSCLC). After efficacy of crizotinib was demonstrated, identification of ROS1 translocations in advanced disease became fundamental to give patients the chance of specific and effective treatment. Different methods are available for detection of rearrangements, and probably the real prevalence of ROS1 rearrangements is higher than that reported in literature, as our capacity to detect gene rearrangements is improving. In particular, with next generation sequencing (NGS) techniques, we are currently able to assess multiple genes simultaneously with increasing sensitivity. This is leading to overcome the “single oncogenic driver” paradigm, and in the very near future, the co-existence of multiple drivers will probably emerge more frequently and represent a therapeutic issue. Since recently, crizotinib has been the only available therapy, but today, many other tyrosine kinase inhibitors (TKI) are emerging and seem promising both in first and subsequent lines of treatment. Indeed, novel inhibitors are also able to overcome resistance mutations to crizotinib, hypothesizing a possible sequential strategy also in ROS1-rearranged disease. In this review, we will focus on ROS1 rearrangements, dealing with diagnostic aspects, new therapeutic options, resistance issues and the coexistence of ROS1 translocations with other molecular alterations.

Cost-Effectiveness Analysis of Pembrolizumab Plus Pemetrexed and Platinum Versus Chemotherapy Alone as First-Line Treatment in Metastatic Non-Squamous Non-Small Cell Lung Cancer: A Reconstruction of Partitioned Survival Model Based on Time Dependent Pricing Mechanism of Patient Assistance Program.

ObjectivesA new patient assistance program (PAP) for pembrolizumab was started in China in 2021. The researchers aimed to evaluate the economic outcomes of pembrolizumab plus pemetrexed and platinum versus chemotherapy alone in the first-line treatment of patients with metastatic non-squamous non-small cell lung cancer, based on the pricing mechanism of PAP.Material and MethodsSurvival analysis and partitioned survival model were performed to evaluate the incremental cost-effectiveness ratio (ICER) in the pembrolizumab group compared with the chemotherapy group. Survival probabilities were extracted from the data of the KEYNOTE-189 trial. Cost and utility data were gathered from published literature. The pricing mechanism of PAP was set in each cycle in the partitioned survival model, according to the progression-free survival (PFS) data of the KEYNOTE-189 trial, which included PFS-1 and PFS-2. Deterministic sensitivity analysis and probabilistic sensitivity analysis were conducted.ResultsThe ICER of the pembrolizumab group versus chemotherapy group was $65,272/quality-adjusted life year (QALY), which still exceeded the willingness-to-pay threshold of three times per capita gross domestic product (GDP) of China ($33,581.22), although PAP was calculated. Sensitivity analysis implied that the price of chemotherapeutic drugs combined with pembrolizumab was one of the main influencing factors of ICER.ConclusionsDue to various prices set by PAP and the payment for combined chemotherapy, the economic advantage of pembrolizumab plus chemotherapy in the first-line treatment of non-small cell lung cancer (NSCLC) is still not achieved in China.

Anti-EGFR monoclonal antibody plus chemotherapy for treating advanced non-small cell lung cancer: A meta-analysis.

Background:The use of standard cytotoxic chemotherapy seems to have reached a “treatment plateau”. The application of anti-epidermal growth factor receptor (EGFR) monoclonal antibodies (mAbs) is a new strategy for non-small-cell lung cancer (NSCLC) therapy. We aimed to comprehensively assess the efficacy and safety of anti-EGFR-mAbs plus chemotherapy as first-line therapy for advanced NSCLC.Methods:According to inclusion and exclusion criteria, we conducted a comprehensive literature search of electronic databases. From the included trials, information on overall survival (OS), progression-free survival (PFS), objective response rate (ORR), and adverse events (AEs) was extracted.Results:The research showed that compared with chemotherapy alone, anti-EGFR-mAb plus chemotherapy combinations significantly improved OS (HR = 0.88, 95%CI: 0.83-0.94, P < .0001), PFS (HR = 0.89, 95%CI: 0.83-0.95, P = 0.0004) and ORR (OR = 1.39, 95%CI: 1.13-1.69, P = .001). Meta subgroup analyses manifested that the OS of patients with squamous NSCLC treated with anti-EGFR-mAb plus chemotherapy combinations was notably better than that of patients with non-squamous NSCLC treated with the same combinations (HR = 0.82, 95%CI: 0.73-0.92, P = .0005). Compared with the chemotherapy group, combination of chemotherapy and anti-EGFR mAb showed increase in incidences of severe AEs (> = grade 3) that mainly include, leukopenia (OR = 1.53, 95%CI: 1.28-1.82, P < .00001), febrile neutropenia (OR = 1.35, 95%CI: 1.06-1.71, P = .02), hypomagnesemia (OR = 5.68, 95%CI: 3.54-9.10, P < .00001), acneiform rash (OR = 35.88, 95%CI: 17.37-74.10, P < .00001), fatigue (OR = 1.24, 95%CI: 1.02-1.49, P = .03), diarrhea (OR = 1.69, 95%CI: 1.16-2.47, P = .006), and infusion-related reactions (OR = 3.78, 95%CI: 1.93-7.41, P = .0001).Conclusion:Adding an anti-EGFR-mAb to the standard platinum-based chemotherapy regimens used for the first-line treatment of advanced NSCLC resulted in statistically notable improvements in OS, PFS, and ORR. In particular, anti-EGFR-mAb and chemotherapy combinations achieved greater survival benefits in patients with squamous NSCLC than in those with non-squamous NSCLC. In addition, the safety profile of chemotherapy plus anti-EGFR-mAb combinations was acceptable compared to that of chemotherapy alone.

Efficacy and safety of MIL60 compared with bevacizumab in advanced or recurrent non-squamous non-small cell lung cancer: a phase 3 randomized, double-blind study.

BackgroundWe compared the efficacy, safety, and immunogenicity of MIL60 with reference bevacizumab as first-line treatment in patients with advanced or recurrent non-squamous non-small cell lung cancer (NSCLC) in this phase 3, randomized, double-blind study.MethodsPatients with untreated advanced or recurrent NSCLC were randomized (1:1 ratio) to receive either MIL60 or bevacizumab in combination with paclitaxel/carboplatin. Patients with non-progressive disease continued maintenance single-agent MIL60 until disease progression, or intolerable toxicity. The primary endpoint was the 12-week objective response rates (ORR12) by independent review committee (IRC) using RECIST 1.1. Bioequivalence was established if the ORR ratio located between 0.75 and 1/0.75. The trial was registered with clinicaltrials.gov (NCT03196986).FindingsBetween Aug 23, 2017, and May 8, 2019, 517 patients were randomly assigned to MIL60 group (n=257) and bevacizumab group (n=260). In the full analysis set (FAS) population including all randomized and evaluable patients who received at least one dose of MIL60 or bevacizumab, the ORR12 in MIL60 group and bevacizumab group were 48.6% and 43.1%, respectively. The ORR ratio of these two groups were 1.14 (90% CI 0.97-1.33), which fell within the pre-specified equivalence boundaries (0.75-1/0.75). The median DOR was 5.7 months (95% CI 4.5-6.2) for MIL60 and 5.6 months (95% CI 4.3-6.4) for bevacizumab. No significant difference was noted in median PFS (7.2 vs. 8.1 months; HR 1.01, 95% CI 0.78-1.30, p=0.9606) and OS (19.3 vs. 16.3 months; HR 0.81, 95% CI 0.64-1.02, p=0.0755). Safety and tolerability profiles were similar between the two groups. No patient detected positive for Anti-drug antibody (ADA).InterpretationThe efficacy, safety and immunogenicity of MIL60 were similar with bevacizumab, providing an alternative treatment option for advanced or recurrent non-squamous NSCLC.FundingThis study was sponsored by Betta Pharmaceutical Co., Ltd.

VP9-2021: ORIENT-31: Phase III study of sintilimab with or without IBI305 plus chemotherapy in patients with EGFR mutated nonsquamous NSCLC who progressed after EGFR-TKI therapy

Treatment option for nonsquamous non-small cell lung cancer (nsqNSCLC) with epidermal growth factor receptor mutations (EGFRm) is limited upon progression after tyrosine kinase inhibitors (TKIs). ORIENT-31 is a randomized, double-blind, phase 3 study of sintilimab (sint, anti-PD-1 antibody) with or without IBI305 (bevacizumab biosimilar) plus chemotherapy (chemo) in patients (pts) with EGFRm nsqNSCLC who progressed after EGFR TKI therapy (NCT03802240). Pts with EGFRm nsqNSCLC who had progressed afterEGFR-TKI therapy were randomized (1:1:1) to Arm A (sint + IBI305 + chemo), Arm B [sint + placebo 2 (pb2) + chemo] or Arm C (pb1 + pb2 + chemo), stratified by sex (male vs female) and brain metastasis (yes vs no). Sint / pb1 (200 mg), IBI305 / pb2 (15 mg/kg), pemetrexed (500 mg/m2) and cisplatin (75 mg/m2) were administered IV Q3W for 4 cycles, followed by maintenance treatment of sint / pb1, IBI305 / pb2 and pemetrexed. Conditional crossover to sint monotherapy was allowed for pts in Arm C. Primary endpoint is progression-free survival (PFS) by independent radiographic review committee (IRRC). By data cutoff (31 Jul, 2021, median follow up of 9.8m) of first interim analysis, 444 pts were randomized (Arm A / B / C 148 / 145 / 151). Median age was 57 y. 36.0% pts had brain metastasis. Previously, 63.7% pts received 1st or 2nd generation (G) TKI with T790M-, 28.2% pts received 1st or 2nd and then 3rd G TKI with T790M+, 8.1% pts received first-line 3rd G TKI. Median PFS (95%CI) by IRRC was 6.9m (6.0, 9.3) in Arm A, 5.6m (4.7, 6.9) in Arm B, 4.3m (4.1, 5.4) in Arm C. PFS was significantly prolonged in Arm A vs. Arm C (HR 0.464, 95%CI: 0.337, 0.639; p<0.0001). Arm B showed trend of PFS benefit vs. Arm C (HR 0.750, 95%CI: 0.555, 1.013; p=0.0584). The futility analysis of Arm A vs. B did not cross the futility boundary (HR 0.726, 95%CI: 0.528, 0.998). Confirmed ORR were 43.9%, 33.1% and 25.2% in Arm A, B and C respectively. Incidence of grade ≥3 treatment-emergent AEs were 54.7%, 39.3% and 51.0% respectively. In pts with EGFRm nsqNSCLC who progressed after EGFR-TKIs, sint combined with IBI305 and chemo has significantly improved PFS compared with chemo alone.

Initial treatment and survival in Danish patients diagnosed with non-small-cell lung cancer (2005-2015): SCAN-LEAF study.

Aim: To describe initial treatment patterns and survival of patients diagnosed with non-small-cell lung cancer (NSCLC) in Denmark, before immune checkpoint inhibitor and later-generation tyrosine kinase inhibitor use. Patients & methods: Adults diagnosed with incident NSCLC (2005-2015; follow-up: 2016). Initial treatments and overall survival (OS) are reported. Results: 31,939 NSCLC patients (51.6% stage IV) were included. Increasing use of curative radiotherapy/chemoradiation for stage I, II/IIIA and IIIB NSCLC coincided with improved 2-year OS. Systemic anticancer therapy use increased for patients with stage IV non-squamous NSCLC(53.0-60.6%) but not squamous NSCLC (44.9-47.3%). 1-year OS improved in patients with stage IV non-squamous NSCLC (23-31%) but not squamous NSCLC (22-25%). Conclusion: Trends indicated improved OS as treatments evolved between 2005 and 2015, but the effect waslimited to 1-year OS in stage IV disease.

Real-World Data on the Prevalence of Anaplastic Lymphoma Kinase-Positive Non-Small-Cell Lung Cancer in the Middle East and North Africa.

PURPOSEAnaplastic lymphoma kinase (ALK) gene alterations are potent oncogenic drivers in non–small-cell lung cancer (NSCLC). Tyrosine kinase inhibitors targeting the ALK pathway are effective in treating ALK-positive NSCLC. Around 5% of Asian and White patients with NSCLC have ALK-positive tumors, but ALK rearrangement prevalence data in the Middle East and North Africa (MENA) region are limited.METHODSIn this noninterventional epidemiology study, histologically confirmed nonsquamous NSCLC samples retained for < 5 years in tissue banks at six centers in MENA were retrospectively analyzed for ALK rearrangement using the VENTANA immunohistochemistry (IHC) method. Patient characteristics obtained were analyzed for association with ALK rearrangement. Concordance between IHC and Vysis fluorescence in situ hybridization (FISH) ALK detection methods was assessed in a subset of samples.RESULTSFour hundred forty-eight tissue samples were analyzed using IHC: 137 (30.6%) in Lebanon, 104 (23.2%) in Saudi Arabia, 97 (21.7%) in Egypt, 80 (17.9%) in the United Arab Emirates, and 30 (6.7%) in Morocco. On the basis of IHC, the prevalence was 8.7% (95% CI, 6.3 to 11.7) for ALK-positivity and 91.3% (95% CI, 88.3 to 93.7) for ALK-negativity. On the basis of FISH (n = 148), the prevalence was 5.4% positivity and 81.8% negativity (12.8% nonevaluable). Concordance between IHC and FISH (n = 129) was 98.4% (95% CI, 94.2 to 99.8) for negative agreement and 98.5% (95% CI, 94.5 to 99.8) for overall agreement. Univariate analysis showed that ALK rearrangement was significantly associated with epidermal growth factor receptor wild-type status (P = .03) but was not significantly associated with sex, race, smoking history, or histologic subtype.CONCLUSIONOur findings suggest that ALK rearrangements are more prevalent in MENA than other geographic regions. High concordance was found between FISH and IHC. Except for epidermal growth factor receptor wild-type status, no clinicopathologic characteristics were associated with ALK-positive NSCLC.

Risk factors of nephrotoxicity of maintenance pemetrexed in patients with metastatic non-squamous non-small cell carcinoma of lung

BackgroundNephrotoxicity is one of the concerns of prolonged maintenance therapy with pemetrexed. No reversible risk factors for pemetrexed-induced nephrotoxicity have been identified in previous studies. Identification of such factors would be clinically meaningful to maximize the chemotherapeutic benefits by avoiding premature termination of maintenance therapy which might otherwise result from the development of renal impairment. MethodsThis was a retrospective single-center cohort study conducted in Queen Mary Hospital in Hong Kong. The study included 134 patients with advanced stage non-squamous NSCLC that received first line pemetrexed-platinum doublets followed by maintenance pemetrexed. The primary endpoint was the occurrence of nephrotoxicity. The risk factors of nephrotoxicity were identified. ResultsPresence of non-evacuated third-space fluid during treatment course (OR 4.185, 95% CI = 1.150–15.191, p-value 0.030), the use of cisplatin (instead of carboplatin) during the induction phase (OR 8.761, 95% CI = 1.684–45.577, p-value 0.010) and receiving more than 15 cycles of maintenance pemetrexed (OR 3.839, 95% CI = 1.022–14.413, p-value 0.046) were identified as independent risk factors to the development of nephrotoxicity associated with maintenance pemetrexed use. ConclusionsIn order to reduce the risk of development of nephrotoxicity in NSCLC patient receiving first-line pemetrexed-platinum doublets, third-space fluid should be evacuated and carboplatin should be chosen over cisplatin whenever possible.

A Pilot Study to Evaluate Early Predictive Value of Thorax Perfusion-CT in Advanced NSCLC.

Simple SummaryThe use of targeted drugs has brought about the development of new imaging techniques which are able to assess in vivo processes and changes in vascularization parameters can be captured as part of the antitumor response to antiangiogenic therapies. This pilot study (IMPACT trial, NCT02316327) aimed to explore the capacity of Perfusion-Computed Tomography (pCT) to detect early changes in tumor vascularization in non-small cell lung cancer (NSCLC) patients treated with an antiangiogenic-based therapy. Our results confirm the feasibility of pCT to capture early changes in tumor vasculature and suggest the potential of blood volume (BV) to early identify differential tumor responses to antiangiogenic therapy.Background: The role of perfusion computed tomography (pCT) in detecting changes in tumor vascularization as part of a response to antiangiogenic therapy in non-small cell lung cancer (NSCLC) remains unclear. Methods: In this prospective pilot study (IMPACT trial, NCT02316327), we aimed to determine the ability of pCT to detect early changes in blood flow (BF), blood volume (BV), and permeability (PMB), and to explore whether these changes could predict the response at day +42 in patients with advanced, treatment-naive, non-squamous NSCLC treated with cisplatin and gemcitabine plus bevacizumab. Results: All of the perfusion parameters showed a consistent decrease during the course of treatment. The BV difference between baseline and early assessment was significant (p = 0.013), whereas all perfusion parameters showed significant differences between baseline and day +42 (p = 0.003, p = 0.049, and p = 0.002, respectively). Among the 16 patients evaluable for efficacy, a significant decline in BV at day +7 from baseline was observed in tumors with no response (p = 0.0418). Conclusions: Our results confirm that pCT can capture early changes in tumor vasculature. A substantial early decline of BV from baseline might identify tumors less likely responsive to antiangiogenic-drugs.

Impact of thymosin α1 as an immunomodulatory therapy on long-term survival of non-small cell lung cancer patients after R0 resection: a propensity score-matched analysis.

Background:There is limited information about thymosin α1 (Tα1) as adjuvant immunomodulatory therapy, either used alone or combined with other treatments, in patients with non-small cell lung cancer (NSCLC). This study aimed to evaluate the effect of adjuvant Tα1 treatment on long-term survival in margin-free (R0)-resected stage IA–IIIA NSCLC patients.Methods:A total of 5746 patients with pathologic stage IA-IIIA NSCLC who underwent R0 resection were included. The patients were divided into the Tα1 group and the control group according to whether they received Tα1 or not. A propensity score matching (PSM) analysis was performed to reduce bias, resulting in 1027 pairs of patients.Results:After PSM, the baseline clinicopathological characteristics were similar between the two groups. The 5-year disease-free survival (DFS) and overall survival (OS) rates were significantly higher in the Tα1 group compared with the control group. The multivariable analysis showed that Tα1 treatment was independently associated with an improved prognosis. A longer duration of Tα1 treatment was associated with improved OS and DFS. The subgroup analyses showed that Tα1 therapy could improve the DFS and/or OS in all subgroups of age, sex, Charlson Comorbidity Index (CCI), smoking status, and pathological tumor-node-metastasis (TNM) stage, especially for patients with non-squamous cell NSCLC and without targeted therapy.Conclusion:Tα1 as adjuvant immunomodulatory therapy can significantly improve DFS and OS in patients with NSCLC after R0 resection, except for patients with squamous cell carcinoma and those receiving targeted therapy. The duration of Tα1 treatment is recommended to be >24 months.

Cost-Effectiveness of Domestic PD-1 Inhibitor Camrelizumab Combined With Chemotherapy in the First-Line Treatment of Advanced Nonsquamous Non–Small-Cell Lung Cancer in China

Objective: Camrelizumab is the first domestic PD-1inhibitor approved to be combined with chemotherapy as a first-line therapy for advanced nonsquamous non–small-cell lung cancer (NSCLC) in China. The purpose of this study was to determine whether using camrelizumab in the first-line setting is cost-effective in China when compared with traditional chemotherapy or the imported PD-1inhibitor pembrolizumab. Material and Methods: A Markov model was built to simulate 3-week patient transitions over a 30-year horizon from the perspective of the Chinese healthcare system. Health states included stable disease, first progression, second progression, and death. A direct comparison between first-line camrelizumab in combination with pemetrexed and carboplatin (CPC) and pemetrexed plus carboplatin (PC) was performed by calculating transition probabilities from the CameL trial. An indirect comparison between first-line CPC and pembrolizumab in combination with pemetrexed and platinum (PPP) was performed by calculating transition probabilities using a network meta-analysis. Costs in the Chinese setting were collected from the local public database and literatures. Sensitivity analyses explored the uncertainty around model parameters. Results: In the primary analysis, first-line CPC gained an additional 0.41 quality-adjusted life-years (QALYs) with an incremental cost of $3,486 compared with PC, resulting in an incremental cost-effectiveness ratio (ICER) of $8,378 per QALY gained. In the secondary analysis, first-line PPP yielded an additional 0.10 QALYs at an incremental cost of $6,710, resulting in an ICER of $65,563 per QALY gained. Conclusion: For Chinese patients with advanced nonsquamous NSCLC without targetable genetic aberrations, our primary analysis results supported first-line CPC as a cost-effective treatment compared with traditional PC chemotherapy. The findings of our secondary analysis suggested that first-line PPP would not be a cost-effective option compared with first-line CPC. This analysis provided strong evidence for promoting the widespread use of first-line CPC in China and, to some extent, stimulated the enthusiasm for the development of domestic cancer drugs.

Real-world Overall Survival Using Oncology Electronic Health Record Data: Friends of Cancer Research Pilot.

In prior work, Friends of Cancer Research convened multiple data partners to establish standardized definitions for oncology real‐world end points derived from electronic health records (EHRs) and claims data. Here, we assessed the performance of real‐world overall survival (rwOS) from data sets sourced from EHRs by evaluating the ability of the end point to reflect expected differences from a previous randomized controlled trial across five data sources, after applying inclusion/exclusion criteria. The KEYNOTE‐189 clinical trial protocol of platinum doublet chemotherapy (chemotherapy) vs. programmed cell death protein 1 (PD‐1) in combination with platinum doublet chemotherapy (PD‐1 combination) in first‐line nonsquamous metastatic non‐small cell lung cancer guided retrospective cohort selection. The Kaplan‐Meier product limit estimator was used to calculate 12‐month rwOS with 95% confidence intervals (CIs) in each data source. Cox proportional hazards models estimated hazard ratios (HRs) and associated 95% CIs, controlled for prognostic factors. Once the inclusion/exclusion criteria were applied, the five resulting data sets included 155 to 1,501 patients in the chemotherapy cohort and 36 to 405 patients in the PD‐1 combination cohort. Twelve‐month rwOS ranged from 45% to 58% in the chemotherapy cohort and 44% to 68% in the PD‐1 combination cohort. The adjusted HR for death ranged from 0.80 (95% CI: 0.69, 0.93) to 1.15 (95% CI: 0.71, 1.85), controlling for age, gender, performance status, and smoking status. This study yielded insights regarding data capture, including ability of real‐world data to precisely identify patient populations and the impact of criteria on end points. Sensitivity analyses could elucidate data set–specific factors that drive results.

A phase I study of the tyrosine kinase inhibitor anlotinib combined with platinum/pemetrexed-based chemotherapy in untreated nonsquamous non-small-cell lung cancer

SummaryBackground. Anlotinib hydrochloride is an oral small molecule inhibitor of multiple tyrosine kinases, and it has been approved as a third-line therapy for patients with advanced non-small-cell lung cancer (NSCLC) in China. This dose-exploration study was designed to investigate the feasibility of anlotinib in combination with other chemotherapy regimens in patients with nonsquamous NSCLC. Methods. This phase I study followed a 3 + 3 dose reduction design with three doses of anlotinib (12 mg, 10 mg, and 8 mg). Anlotinib was given at an initial dose of 12 mg with pemetrexed (500 mg/m2) plus cisplatin (75 mg/m2) or carboplatin (AUC = 5) on 21-day cycles for 4 cycles. The primary goal of the study was to identify the maximum tolerated dose (MTD), and secondary endpoints included progression-free survival (PFS) and overall survival (OS). Results. A total of eight participants were enrolled. Dose-limiting toxicities (DLTs) were observed in two patients (pts) at anlotinib 12 mg (grade 3 hand-foot syndrome and grade 3 appetite loss). No DLTs occurred with 10 mg anlotinib, and the MTD was 10 mg. Among seven evaluable pts, four achieved a confirmed partial response (PR), and three had stable disease (SD). With a median follow-up of 10.05 months, the median PFS was 7.00 months (95% CI: 2.76 to NE). Grade 3 treatment-related adverse events (TRAEs) included appetite loss (n = 2), hypertension (n = 2), thrombocytopenia (n = 1), diarrhea (n = 1) and hand-foot syndrome (n = 1). No grade 4 or grade 5 TRAEs were observed during the treatment. Conclusion. The feasible dose of anlotinib in combination with platinum/pemetrexed-based chemotherapy as a first-line regimen was 10 mg, which was well tolerated and showed promising antitumor activity in advanced nonsquamous NSCLC.

Overall Survival and Safety With Pemetrexed/Platinum ± Anti-VEGF Followed by Pemetrexed ± Anti-VEGF Maintenance in Advanced Nonsquamous Non–Small-Cell Lung Cancer: A Pooled Analysis of 4 Randomized Studies

BackgroundBefore immune checkpoint blockade therapy, chemotherapy with pemetrexed maintenance was the standard of care for patients with advanced nonsquamous non–small-cell lung cancer (NSQ-NSCLC) and remains such where immunotherapy is not applicable. This pooled analysis aimed to characterize overall survival (OS) and safety of pemetrexed ± anti-VEGF maintenance, by treatment duration. Patients and MethodsData from 4 randomized clinical trials (PARAMOUNT, PRONOUNCE, PointBreak, JVBL) of patients with NSQ-NSCLC receiving pemetrexed ± anti-VEGF maintenance therapy were pooled as 2 groups (Group A: pemetrexed-only maintenance, n = 486; and Group B: pemetrexed + anti-VEGF maintenance, n = 329). OS and treatment-emergent adverse events (TEAEs) were analyzed in both groups by treatment duration. ResultsBaseline characteristics were well balanced between both groups. Median OS did not significantly differ between Group A (16.1 months) and Group B (18.4 months; hazard ratio: 1.17, P= .1417). A correlation between median OS and treatment duration was numerically stronger in Group A (r = 0.72) versus B (r = 0.62). Across treatment groups, TEAEs were largely grade 1 to 2 and, with few exceptions, did not increase with increased treatment duration. ConclusionThere was no significant OS difference between pemetrexed-only and pemetrexed ± anti-VEGF maintenance in patients with NSQ-NSCLC. Patients receiving pemetrexed + anti-VEGF experienced a slightly less favorable safety profile with more reported TEAEs compared to pemetrexed monotherapy. Pemetrexed ± anti-VEGF maintenance therapy may be considered in NSQ-NSCLC, based on an individualized patient approach, particularly where immunotherapy is not clinically indicated.

XX (a PD-1 Inhibitor), Stereotactic Body Radiotherapy and Granulocyte-Macrophage Colony Stimulating Factor as Second-Line Therapy for Advanced Non-Small Cell Lung Cancer: Safety Run-In Results of a Prospective, Multicenter, Phase II Trial

<h3>Purpose/Objective(s)</h3> Several PD-1/PD-L1 inhibitors have been approved, with or without chemotherapy, in advanced non-small cell lung cancer (NSCLC). However, the objective response rate (ORR) remains limited in unselected population. Accumulating data indicated that adding SBRT to PD-1/PD-L1inhibitors could improve treatment efficacy in NSCLC and the anti-tumor immune response induced by SBRT may be enhanced by GM-CSF, which plays a pivotal role in dendritic cell differentiation and maturation. Nevertheless, the safety and efficacy of triple combination of XX (a PD-1 inhibitor), SBRT and GM-CSF in advanced NSCLC remain unknown. <h3>Materials/Methods</h3> This is a prospective, multicenter, phase II study. Eligible patients (pts) were advanced EGFR/ALK negative NSCLC pts who had failed first-line standard chemotherapy. Pts received SBRT (8 Gy*3) to one lesion, followed by XX (200 mg d1, every 3 weeks) and GM-CSF (125 μg/m2 d1-d14, cycle 1) within 3 weeks after SBRT. XX would be given continuously until disease progression, unacceptable toxicity, or up to 35 cycles. To determine the tolerability of the triple combination therapy, a safety run-in phase was conducted in the first 20 enrolled pts by monitoring the dose-limiting toxicities (DLTs). Primary end point is ORR. Secondary end points are safety, out-of-field response rate, overall survival (OS), progression free survival (PFS). Here, we report the preliminary results of the safety run-in phase. <h3>Results</h3> From 2019/10/16 to 2020/8/8, 20 pts were enrolled from 3 academic centers. The majority of pts were male, smoker, ECOG 1 and non-squamous NSCLC, with a median age of 61 (range, 32-71). Baseline brain, liver and bone metastasis were present in 2, 4 and 8 pts, respectively. All of the pts had more than 5 lesions at baseline, and the sites of SBRT included lung (n = 11), mediastinal lymph node (n = 5), liver (n = 1), abdominal lymph node (n = 1), pleural nodule (n = 1) and vertebra (n = 1). There were no DLTs. Treatment-related adverse event (TRAE) occurred in 18 pts. The most common TRAEs were fatigue (50%), fever (30%), and ostealgia (20%), and all were grade1. Only 2 grade 3 TRAEs were observed. 1 pt had G3 ALT and AST elevation, and the other experienced transient (recovered within 7 days) acute heart failure which was considered GM-CSF related. No grade 4 or 5 AE occurred. Median follow-up was 7.9 (range,1.6-16.5) months by data cut-off (2021/02/28). Partial response occurred in 7 and stable disease in 5 pts, the confirmed ORR was 35%. Median PFS was 6.9 (95% CI, 2.76-NA) months with 12 events and 1-year OS rate was 75.0% (95% CI, 58.2%-96.6%). <h3>Conclusion</h3> Triple combination of XX, SBRT and GM-CSF is safe and shows promising efficacy as a novel second-line treatment for advanced EGFR/ALK negative NSCLC. The trial continues to recruit participants.

Crizotinib efficacy in advanced non-squamous NSCLC patients with ALK or ROS1 rearrangement

In patients with advanced non-small cell lung cancer (NSCLC), comprehensive genetic diagnostics is currently carried out in order to qualify for molecularly targeted therapies and immunotherapy. The aim of the study was to assess the usefulness of the reverse transcriptase (RT-PCR) method in the diagnosis of gene rearrangements, the effectiveness of EGFR, ALK, ROS1, and PD-L1 inhibitors in first-line treatment in NSCLC patients. We enrolled 95 non-squamous NSCLC patients with known status of EGFR, ALK, ROS1, MET and RET genes and PD-L1 protein expression. We used the real time PCR, fluorescence in situ hybridization (FISH), immunohistochemistry (IHC) and RT-PCR techniques for determination of predictive factors. In patients with ALK and ROS1 genes alteration, the median overall survival was 34 months in crizotinib treated patients and 6 months in patients who received chemotherapy (HR = 0.266, p = 0.0056). The risk of death was lower in patients treated with molecularly targeted therapies or immunotherapy compared to patients with predictive factors without personalized treatment (HR = 0.265, 95% CI 0.116–0.606) and to patient without predictive factors who received chemotherapy (HR = 0.42, 95% CI 0.162–1.09). Diagnosis of predictive factors and implementation of personalized treatment are key to prolonging the survival in advanced NSCLC patients.