bluuebunny/crossref_metadata_2025 huggingface dataset:
Safety and efficacy of nivolumab plus recombinant human endostatin in previously treated advanced non-small cell lung cancer: A prospective and multicenter phase 2 trial.
Authors: Lv Weize , Zhong Beilong , Zhao Wenhua , Lin Zhong , Pei Xiaofeng , Wang Zhihui
Published: June 2021

e21079

Background: Although the administration of immune checkpoint inhibitors (ICIs) and antiangiogenic agents in advanced non–small-cell lung cancer (NSCLC) has been well established, evidence supporting the combination of immune checkpoint inhibitors plus antiangiogenic drugs in previous treatment patients with advanced NSCLC is insufficient. We aimed to investigate the efficacy and safety of nivolumab combined with recombinant human endostatin (rh-Endostatin) as second-line or later treatment for advanced NSCLC. Methods: In this prospective and multicentre phase 2 trial we enrolled patients with advanced NSCLC who had not responded to standardized first-line treatment regimen from two cancer centres in China. Eligible patients were those aged 18-75 years without ICIs in first-line treatment who received nivolumab (3mg/kg, intravenous drip, day 1) every 2 weeks and rh-Endostatin (30 mg, 24-hour continous intravenous infusion，day 1–7) every 4 weeks till disease progression or discontinuation. The primary end points were objective response rate and safety. This study is registered with Chinese Clinical Trial Registry, number ChiCTR1900023664. Results: A total of 35 patients (median age, 60 years; range, 37-72 years) received nivolumab and rh-Endostatin. Median previous treated line of eligible patients was 2 lines (range, 1-7 lines). Patients received a median of 2 cycles of therapy (range, 1-14 cycles). Eleven of 33 evaluable patients achieved confirmed partial response with an objective response rate of 33.3% (11/33, 95% confidence interval [CI]: 17.2% – 49.4%) and disease control rate of 60.6% (20/33,95%CI:43.9%–77.3%). Median follow-up was 8.2 months (range: 0.9 –17.1). Median progression-free survival was 7.1 months (95% CI: 1.2m–13.0m), median overall survival was not reached and the 6-month overall survival rate was 54.5% (95% CI:37.6%–71.4%). The predominant grade 1-2 adverse events were thyroiditis, arrhythmia, hypertension. The grade 3 treatment-related adverse events were pneumonitis (3/35, 8.6%), hypertension (1/35, 2.9%) and atrial fibrillation (1/35, 2.9%), respectively. No grade 4 or 5 treatment-related adverse events were observed. Conclusions: To the best of our knowledge, this is the first prospective study that assessed nivolumab combined with rh-Endostatin as second-line or later treatment in pretreated patients with advanced NSCLC. In view of its encouraging efficacy and safety profile, nivolumab plus rh-Endostatin represents a promising treatment regimen in this patient population. Clinical trial information: ChiCTR1900023664.
Efficacy of weekly paclitaxel-bevacizumab combination in advanced nonsquamous non-small cell lung cancer (NSCLC): AVATAX, a retrospective multicentric study.
Authors: Bilger Geoffroy , Toffart Anne-Claire , Darasson Marie , Duruisseaux Michaël , Ulmer Lucie , Wang Pascal , Giroux Leprieur Etienne , Girard Nicolas , Massiani Marie Ange , Bore Paul , Descourt Renaud , Pinsolle Julian , Valery Solene , Monnet Isabelle , Swalduz Aurélie , Tissot Claire , Fournel Pierre , Baranzelli Anne , Cortot Alexis , Decroisette Chantal
Published: June 2021

e21086

Background: With the growing role of immunotherapy (ICI) as first-line setting for advanced NSCLC, strategies must be redefined after failure. The combination paclitaxel-bevacizumab showed in the ULTIMATE trial a significant superiority versus docetaxel as second or third-line treatment. Limited restropective studies has demonstrated unexpected efficacy of chemotherapy after prior progression on ICI. This combination could be use as salvage treatment following ICI. Methods: This multi-centric retrospective study identifies patients treated with the combination paclitaxel-bevacizumab in metastatic non-squamous NSCLC as second-line therapy or beyond. Main objectives were to describe safety and efficacy of this combination, with a special attention to the sub-group treated just after ICI. Results: From January 2010 to February 2020, 314 patients started the paclitaxel-bevacizumab combination : 55% male, with a median age of 60 years, 27% with a performance status ≥2, 45% with brain metastases. A majority of patients were treated in second (20%) and third-line (39%), and 28% were treated just after ICI failure (88/314). Objective response rate (ORR) was 40% and disease control rate was 77 %. Median progression-free survival (PFS) and overall survival (OS) were 5,7 months [IQ,3,2–9,6] and 10,8 months [IQ,5,3–19,6] respectively. All grades adverse events concerned 82% of patients, including 53% asthenia and 39% neurotoxicity, and 25% of patients continued a monotherapy alone due to toxicity. Median PFS for patients treated after ICI failure (ICI+) was significantly superior compare to those not previously treated with ICI (ICI-) : 7,0 months [IQ,4,2–11,0] vs 5,2 months [IQ,2,9–8,8] p (log-rank) = 0,01. There was not statistically significant difference in term of OS between this two groups. In multivariate analysis, factors associated with superior PFS were previous ICI treatment (ICI+) and performance status. Conclusions: This study confirms an acceptable toxicity profile associated with interesting efficacy of the combination paclitaxel-bevacizumab as second-line treatment or beyond for non–squamous NSCLC patients, particularly after progression with ICI.
Population pharmacokinetics (Pop PK) of MYL-1402O (a proposed biosimilar to bevacizumab) and reference product (Avastin) in patients with nonsquamous non-small cell lung cancer (nsNSCLC).
Authors: Owen Joel , Rackley Russell J. , Hummel Matthew A. , Roepcke Stefan , Huang Hannah , Liu Mark S. , Idris Tazeen A. , Nainar Murugesan Sundara Moorthi , Vishweswaramurthy Ashwini , Loganathan Subramanian , Ranganna Gopinath , Barve Abhijit J. , Waller Cornelius , Socinski Mark A.
Published: June 2021

e21087

Background: MYL-1402O (MYL) is a proposed biosimilar to bevacizumab reference product. A multicenter, double blind randomized, phase 3 study compared the efficacy, safety, PK, and immunogenicity of MYL and Avastin in patients with Stage IV metastatic nsNSCLC. Patients received either MYL or reference product, in combination with carboplatin-paclitaxel up to 18 weeks (6 cycles) followed by monotherapy for up to an additional 24 weeks (8 cycles). The objective was to develop a Pop PK model based on data from a phase 3 study pooled with a single dose healthy volunteer phase 1 study data; to assess PK linearity across the dose levels of 1 mg/kg to 15 mg/kg in 2 clinical studies; to assess the PK similarity of MYL and reference product in patients with nsNSCLC; and to explore potential covariates to account for variability in Pop PK model parameters. Methods: A Pop PK model was developed based on preliminary analyses of MYL phase 1 data and published population analyses of reference product using a 2-compartment linear model (Han K et al., 2016). Individual empiric Bayesian parameter estimates of nsNSCLC patients were used to predict PK measures reflecting exposure to drug and were compared qualitatively between treatments. Results: The data subset used for model development consisted of 8724 records from 771 subjects. Population PK analyses indicated no differences between PK profiles of patients in the MYL and reference product arms. Importantly, treatment was not a significant covariate of clearance ( P = 0.453) or volume of the central compartment ( P = 0.161) using the likelihood ratio χ2 test. Model-based steady state exposure measures, predicted based on the final model for all patients, were also similar between treatment arms (Table). Conclusions: The model supported linear PK at clinical doses in patients with nsNSCLC; there were no clinically relevant/significant differences between the PK of MYL and reference product; and the findings were consistent with the PK study in normal, healthy volunteers. Bayesian Parameter Clinical trial information: 2015-005141-32. [Table: see text]
The very early tumor regression rate and safety of anlotinib combined with sintilimab and chemotherapy for advanced non-small cell lung cancer without driver mutations.
Authors: Jiang Jian , Jia Yuming , Ren Yue , Li Ting , Du Lei-Ya , Jiang Mao-Qiong , Qiu Ye , Chen Jie , Yan Jun , Li Li
Published: June 2021

e21090

Background: Unlike bevacizumab, anlotinib, which is also an anti-angiogenic drug, is indicated for lung squamous cell carcinoma(LSCC). A phase IB study showed that the first-line therapy with anlotinib and sintilimab for stage IIIB to IV NSCLC with negative driver genes has the objective response rate of 72.7%. Regardless of the PD-1 expression level, this combination method has consistent therapeutic benefit. According to the IMpower150 study, the four-drug combination therapy has a synergistic effect and prolong the survival time. It is necessary to further explore the efficacy and safety of anlotinib combined with sintilimab and chemotherapy for NSCLC without driver mutations. Methods: We retrospectively analyzed the patients of newly diagnosed unresectable stage IIIA-IVB NSCLC who received platinum-containing dual-drug chemotherapy combined with anlotinib and sintilimab in our hospital from January 2019 to December 2020. Patients receive at least one cycle of treatment, and the efficacy can be evaluated. The main observation indicators are the very early tumor regression rate and the safety. Results: This study included 11 patients with stage IIIA-IVB NSCLC with no driver mutations that were not resectable. Ten patients (90.9%) were male, with a median age of 65 years. The pathological types were LSCC (7, 63.6%), lung adenocarcinoma (3, 27.3%), and poor differentiated carcinoma (1, 9.1%). Six patients were with stage ⅢA-ⅢB, 4 patient with ⅢC-IVB. Eleven patients received an average of 1.63 cycles of treatment. In order to evaluate the efficacy of multi-drug combination therapy in a timely manner, and effectively avoid the risk of hemoptysis caused by anlotinib-induced pulmonary cavity, all patients were evaluated for efficacy after receiving one cycle of treatment. Eight patients achieved very early tumor regression (defined as tumor shrinkage ≥30% after receiving one cycle of treatment in the evaluation of efficacy), 2 patients achieved stable disease, and 1 patients achieved disease progression. The very early tumor regression rate was 72.7%. Three patients with locally advanced (ⅢA-ⅢB) NSCLC underwent radical R0 resection and the downstage rate reached 100%; 2 patients underwent radical radiotherapy. At the last follow-up time in February 2021, one patient died, the remaining patients were alive. No treatment-related grade 3-4 adverse reactions were observed. Conclusions: The high rate of very early tumor regressions in inoperable locally advanced NSCLC provided opportunities for radical surgery and radiotherapy in a short period of time. And the safety is satisfactory. Therefore, our research group has registered the prospective study of anlotinib combined with sintilimab and chemotherapy for the neoadjuvant downstage treatment of stage III NSCLC (Registration number: ChiCTR1900026631).
Efficacy of EGFR-TKIs monotherapy versus TKI plus chemotherapy as first-line treatment in EGFR mutant lung adenocarcinoma with liver metastases.
Authors: Wang Huijuan , Li Mengmeng , Zhang Mina , guo Wei Zhang , Yan Xiangtao , Ma Zhiyong , Xing Ruyue
Published: June 2021

e21099

Background: Liver metastasis is one of the most reasons for the poor prognosis of patients with advanced lung cancer. Seeking for active and effective treatment measures is very important for these patients. At present, the first-line standard treatment of the advanced NSCLC with EGFR mutation is EGFR-TKIs monotherapy. However, its efficacy is poor in the advanced non-small cell lung cancer with EGFR mutation and liver metastases. The objective of this study is to evaluate the efficacy of EGFR-TKIs plus chemotherapy in patients with EGFR mutation of advanced non-small cell lung cancer with liver metastases. Methods: The clinical data of a total of 384 advanced NSCLC patients with EGFR mutation positive who were admitted to The Affiliated Cancer Hospital of Zhengzhou University/Henan Cancer Hospital from February 2017 to June 2020 were retrospectively analyzed. There were 75 patients with liver metastases. Patients were divided into two groups, and accepted EGFR-TKIs monotherapy or EGFR-TKIs plus chemotherapy, respectively. All patients treatment response were evaluated by the RECIST1.1 Response evaluation criteria in solid tumors.Progression free-survival (PFS) were also analyzed. Results: In the study, 75 patients were finally screened. There were 37 patients in the EGFR-TKIs monotherapy group and 38 patients in the TKI plus chemotherapy group. The median follow-up time was 23.0 months. At the latest follow-up date (2021-01-01), 57 patients had disease progression and 35 patients had died. Comparing with EGFR-TKIs monotherapy,the first-line PFS of EGFR-TKI plus chemotherapy group was longer, and the median PFS was 12.7 months VS 7.4 months (P = 0.018).The ORR of primary lung lesions was no significant difference between these two groups（65.8%VS 51.4% P = 0.204), and DCR (97.4% VS 94.6% P = 0.981) also had no difference between two groups（P > 0.05）. ORR of liver metastases in the EGFR-TKIs plus chemotherapy group was significantly higher than EGFR-TKIs monotherapy group ORR (65.8%VS 40.5%，P = 0.028). Conclusions: In advanced NSCLC patients with EGFR mutation and liver metastases, comparing with EGFR-TKIs monotherapy, taking EGFR-TKIs plus chemotherapy as first-line treatment had longer PFS, and better efficacy on liver lesions.
Economic evaluation of crizotinib, alectinib, ceritinib, and brigatinib in treatment naïve anaplastic lymphoma kinase positive (ALK+) non-small cell lung cancer (NSCLC).
Authors: Choi Briana , Alkhatib Nimer S. , Halawah Hala , Calamia Matthias , Gulick Dexter , Manasrah AlMothana , Alkhdour Odai , McBride Ali , Abraham Ivo
Published: June 2021

e21102

Background: Crizotinib was approved by the FDA (2011) as the first ALK inhibitor for ALK+ NSCLC as the first line drug. This was followed by the approval as second line treatment of ceritinib (2014), alectinib (2015) and brigatinib (2017); and, following more data, now also as first line therapies in ALK+ NSCLC. With varying costs and clinical benefits for progression free survival (PFS), cost effectiveness/utility analyses were conducted. Methods: A 3 state Markov model was built including progression free, progression and death. PFS and overall survival curves were digitized and exponential functions were fit the curves for extrapolation beyond trial follow up. A lifetime horizon, US payer perspective, and a discount rate of 3% were applied. Drug costs were based on Redbook Wholesale Acquisition Cost while costs of adverse events, monitoring, disease progression were from literatures (US$ 2020). Adverse events reported at > 5% were included. Crizotinib was used as reference treatment. PFS life years (PFSLY), quality adjusted life years (PFSQALY), incremental cost-effectiveness and utility ratios (ICER/ICUR) of PFSLY and PFSQALY gained (PFSLYG, PFSQALYG) were estimated in base case (BCA) and probabilistic sensitivity analyses (PSA). Results: Crizotinib was the reference drug in the following estimations. For alectinib, at incremental cost of $7,789 (PSA $7,719), the incremental PFSLY of 1.10 (1.10) and PFSQALY 1.07 (1.07) yielded an ICER of $7,109 ($7,030) / PFSLYG and an ICUR of $7,278 ($7.197) / PFSQALYG. For ceritinib, at incremental cost of $88,688 ($88,450), the incremental PFSLY of 1.02 (1.02) and PFSQALY of 1.01 (1.01) resulted in an ICER of $86,970 ($86,729) / PFSLYG and an ICUR of $87,472 / PFSQALYG. For brigatinib, at incremental cost of $84,680 ($83,986), the incremental PFSLY of 1.01 (1.01) and PFSQALY of 1.02 yielded an ICER of $83,774 ($83,073) / PFSLYG and an ICUR of $82,666 ($81,976) / PFSQALYG. Conclusions: Ceritinib had the highest lifetime cost and comparable PFSLY and PFSQALY to brigatinib. However, alectinib reported the highest PFSLY and PFSQALY gained while having lower costs than ceritinib and brigatinib, therefore being the most cost-effective treatment for naïve ALK+ NSCLC.[Table: see text]
Integration of proteomic and clinical data for the prediction of response to immune checkpoint inhibitor therapy in non-small cell lung cancer.
Authors: Shaked Yuval , Harel Michal , Lahav Coren , Jacob Eyal , Sela Itamar , Yahalom Galit , Elon Yehonatan , Sharon Ofer , Kamer Iris , Bar Haim , Dicker Adam P. , Bar Jair , Katzenelson Rivka , Wolf Ido , Gottfried Maya , Abu-Amana Mahmud , Agbarya Abed , Nechushtan Hovav , Moskovitz Mor Tal , Zer Alona
Published: June 2021

e21110

Background: Immune checkpoint inhibitor (ICI) therapy represents one of the most promising cancer treatments to date. However, despite unprecedented rates of durable response, only a small proportion of patients benefits from this approach. Major efforts are therefore required to characterize treatment resistance mechanisms, as well as to identify reliable biomarkers for response. We have previously shown that in response to various types of cancer therapy, including ICIs, the host may induce pro-tumorigenic processes that can promote therapy resistance. Here we examined systemic host-response proteomic profiles in non-small cell lung cancer (NSCLC) patients, aiming to discover biomarkers for response to ICI therapy and to unravel underlying resistance mechanisms. Methods: As part of our ongoing PROPHETIC clinical trial (NCT04056247), plasma samples were obtained at baseline (T0) and early-on treatment (T1; following the first treatment) from 120 NSCLC patients receiving ICI therapy. Proteomic profiling of the plasma samples was performed using proximity-extension assay (PEA) technology; validation was carried out for a fraction of the samples using ELISA-based arrays. To identify a proteomic signature that predicts clinical outcome, machine learning algorithms were applied following a random separation of the cohort into a discovery set and a validation set. Results: A proteomic signature predictive of response to treatment was identified and validated. Bioinformatic analysis identified potential mechanisms of resistance based on differentially expressed proteins associated with pro-tumorigenic biological processes. Statistical analysis of the clinical data identified multiple novel differential clinical parameters between responders and non-responders, either at baseline or by comparing T0 to T1, which may suggest host-mediated effects. Conclusions: Our study demonstrates the potential clinical utility of analyzing the host response to ICI therapy, in particular for the discovery of novel predictive biomarkers for NSCLC patient stratification. Clinical trial information: NCT04056247.
Phase II, noncomparative, open label, multicenter, study of osimertinib, in patients with locally advanced or metastatic EGFR mutated, T790M undetectable or unknown non-small cell lung cancer (Stage IIIB-IV) after no immediate prior EGFR TKI (OSIRIS study).
Authors: Soto Parra Hector J. , Noto Laura , Verderame Francesco , Galetta Domenico , Barbieri Vito , Ferrau Francesco , Migliorino Maria Rita , Catino Annamaria , Aiello Marco M. , Capelletto Enrica , Ricciardi Serena , Spinnato Francesca , Tassone Pierfrancesco , Morelli Anna Maria , Latteri Fiorenza , Gozzo Lucia , Valerio Oriana , Avola Rossana , Novello Silvia
Published: June 2021

e21116

Background: Osimertinib (OSI) is a potent irreversible EGFR TKI approved for 1st line therapy advanced EGFR+ NSCLC and for 2nd line T790M+ pts. The AURA trial showed promising results even in pts with T790M- NSCLC after no immediate prior OSI in locally advanced or metastatic EGFR+ NSCLC, T790M undetectable or unknown, after 1st line EGFR TKI and subsequent chemotherapy. Methods: This phase II trial was performed to investigate the role OSI in locally advanced or metastatic EGFR+ NSCLC, T790M undetectable or unknown, after 1st line EGFR TKI (1 or 2 generation) and subsequent chemotherapy. Eligible pts (M or F, > 18 years, ECOG 0-2) received OSI (80 mg/day) until disease progression or unacceptable toxicity. Objective response rate (ORR) was the primary endopoint. Assuming a 10% attrition rate, 90 pts were planned to be enrolled according to the Optimal Simon’s 2 stage design. In the first stage, 32 pts were planned to be accrued, and if ≤ 3 responses were observed the study would be stopped. Otherwise, 49 additional pts were planned to be accrued. The null hypothesis would have been rejected if ≥ 12 responses were observed. This design yields a type I error rate of 0.05 and 80% power. Results: From May 2017 to October 2020, a total of 54 pts were enrolled (17 M and 37 F, mean age 66 years). The study was stopped early due to an extremely slow enrolment rate. However, the ORR of 31.5% (95% CI 19.5% - 45.5%) was significantly higher than the null hypothesis of 9% (p<0.0001). 17 pts obtained a partial response and 20 a stable disease with an overall disease control rate of 68.5%. Median PFS was 9 mos and median OS was 15 mos. Forty-one pts experienced at least 1 adverse event (51.8% treatment related), more than 90% Grade 1 or 2, the most common being diarrhea. Conclusions: Despite early termination and incomplete recruitment, the treatment with OSI in pts with undetectable or unknown T790M showed a significant ORR and a PFS in line with results in T790M+. Currently, OSI represents the preferred option in naïve pts with EGFR+ NSCLC, regardless of T790M status and for pts who progress the recommended subsequent therapies include local therapy, continuing OSI or chemotherapy; in this new scenario, our results confirm that OSI rechallenge in subsequent line after chemotherapy should be explored. This research was conducted with support from AstraZeneca. Clinical trial information: 2016-002555-17.
Feasibility of RECIST-based real-world tumor response assessment in metastatic non-small cell lung cancer patients.
Authors: Tran Nguyet , Fu Alan , Izano Monika A. , Toland Liz , Hilbelink Ryan , Tu Huakang , Hsu Hil , Sommers Chris , Rioth Matthew J. , Brown Thomas D.
Published: June 2021

e21121

Background: Treatment response to anti-cancer therapies for advanced lung cancer is usually assessed according to the Response Evaluation Criteria in Solid Tumors (RECIST), which is not generally applied in real-world settings. With real-world evidence increasingly being used to support promising treatment, this study evaluated the feasibility of assessing real-world lung cancer response by RECIST-based measurement of lesions on archived radiologic films and assessed its concordance with treatment response based on oncologist narratives in electronic health record (EHR). Methods: This retrospective study included 30 randomly selected metastatic non-small cell lung cancer (mNSCLC) patients diagnosed between January 2015 and December 2019 from the Syapse Learning Health Network of US community health systems. Eligible patients were ≥18 years, histologically confirmed mNSCLC; no other malignancy within 2 years prior to diagnosis; initiated index systemic treatment subsequent to progression on a platinum or anti-PD(L)-1-containing therapy; and had a baseline scan followed by at least one additional scan during the index period. Patients were followed from the initiation of index treatment until the initiation of a post-index line of treatment, death, or date of last contact, whichever occurred first. Tumor response was established using response documented in the medical oncologists’ narratives and compared to a radiologist’s assessment of archived images using RECIST v1.1 criteria. Best overall response was characterized as complete or partial response (CR/PR), stable disease (SD), progressive disease (PD), and not evaluable (NE). Results: The median age at mNSCLC diagnosis was 62 years; 22/30 (73%) were male; 28/30 (93%) were White and 2/30 (7%) were Black. Of the 22/30 (73%) patients with a documented Eastern Cooperative Oncology Group performance status, 21 (95%) had a status of 0 or 1. Patients had a median of 8 months follow-up with the majority surviving (63%) until the end of study. Table shows good concordance of best overall response between medical oncologist-reported and radiologist re-assessed responses; CR/PR was 67%, SD 79% and PD 80%. Causes of discordance were lack of CR/PR confirmation in medical oncologists’ narratives, absence of narratives, or presence of clinical symptoms. Conclusions: This study is an important step in demonstrating the potential to approximate real-world RECIST-based treatment response using EHR abstraction of oncologists’ documentation. Future studies should validate this approach, and improve upon it, by exploring additional real-world data elements as surrogates for clinically relevant responses to anti-cancer therapies. [Table: see text]
Albumin-bilirubin grade as a significant prognostic factor in patients with non-small cell lung cancer treated with anti-PD-1-based therapy: A multicenter retrospective study.
Authors: Takamori Shinkichi , Takada Kazuki , Shimokawa Mototsugu , Toyokawa Gouji , Shimamatsu Shinichiro , Hirai Fumihiko , Tagawa Tetsuzo , Okamoto Tatsuro , Hamatake Motoharu , Tsuchiya-Kawano Yuko , Otsubo Kohei , Inoue Koji , Yoneshima Yasuto , Tanaka Kentaro , Okamoto Isamu , Nakanishi Yoichi , Mori Masaki
Published: June 2021

e21125

Background: Albumin-bilirubin (ALBI) grade is calculated from albumin and bilirubin values as continuous variables, allowing an accurate evaluation of liver function. Some studies showed that ALBI grade was a prognostic and predictive biomarker for the efficacy of chemotherapy in cancer patients. However, no report has examined the association between ALBI grade and outcome in patients with non-small cell lung cancer (NSCLC) treated with anti-programmed cell death-1 (PD-1)-based therapy. Methods: We retrospectively enrolled 452 patients with advanced or recurrent NSCLC treated with anti-PD-1-based therapy (nivolumab or pembrolizumab monotherapy or pembrolizumab combination therapy) between 2016 and 2019 at three medical centers in Japan. With reference to previous reports, ALBI score was calculated using the formula (log10 (total bilirubin [mg/dL] x 17.1) x 0.66) + (albumin [g/dL] x 10 x −0.085), and the score was stratified as grade 1 (≤ −2.60), grade 2 (more than −2.60 to ≤ −1.39), and grade 3 (more than −1.39). We examined the clinical impact of ALBI grade on outcome in patients with NSCLC receiving anti-PD-1-based therapy using Kaplan–Meier survival analysis with the log-rank test and Cox proportional hazards regression analysis. Results: Of the 452 patients, 158 (35.0%) patients were classified as grade 1, 271 (60.0%) as grade 2, and 23 (5.0%) as grade 3. ALBI grade was strongly correlated with performance status (PS), clinical stage, and body mass index, and mutation status ( P < 0.0001, P = 0.0077, P = 0.0050, and P = 0.0302, respectively). The Kaplan–Meier curves showed that ALBI grade was significantly associated with progression-free survival (PFS) and overall survival (OS) ( P < 0.0001 and P < 0.0001, respectively). Multivariate analyses showed that PS ( P = 0.0044), combination therapy of anti-PD-1 and chemotherapy ( P = 0.0004), programmed cell death-ligand 1 (PD-L1) expression status ( P < 0.0001), and ALBI grade ( P < 0.0001) were independent prognostic factors for PFS. Multivariate analyses also showed that PS ( P = 0.0008), combination therapy of anti-PD-1 and chemotherapy ( P = 0.0066), PD-L1 expression status ( P = 0.0006), and ALBI grade ( P < 0.0001) were independent prognostic factors for OS. In the subgroup analysis, ALBI grade effectively stratified PFS and OS regardless of PD-L1 expression status. Conclusions: We report for the first time that ALBI grade was an independent prognostic factor for PFS and OS in patients with advanced or recurrent NSCLC receiving anti-PD-1-based therapy. These findings should be validated prospectively.
Impact of KRAS mutational variant on response to immunotherapy in metastatic NSCLC.
Authors: Kuang Shelley , Lau Sally C. M. , Sharma Kieran , Lee Juehea , Ryan Malcolm Isaiah , Schmid Sabine , Bradbury Penelope Ann , Liu Geoffrey , Shepherd Frances A. , Tsao Ming Sound , Leighl Natasha B. , Sacher Adrian G.
Published: June 2021

e21127

Background: KRAS alterations constitute the most common driver mutations in metastatic non-small cell lung cancers (mNSCLC) and occur in approximately 30% of patients. KRAS mutational subtype as well as the presence of co-mutations has been associated with altered activation of downstream signaling pathways in preclinical models. We hypothesize that different KRAS G12C mutational subsets will be associated with variable clinical outcome and response to therapy. To this end, we have performed a retrospective analysis of survival and treatment outcomes by KRAS mutation subtype (G12C vs non-G12C). Methods: A review of KRAS-mutated mNSCLC patients treated with immunotherapy between 2013 and 2020 was conducted. Patient demographics, smoking status, KRAS mutational subtype, co-mutations and PD-L1 status were collected. Overall response rate (ORR) and progression-free survival (PFS) were analyzed in each subgroup. Results: 98 KRAS mutant mNSCLC patients were treated with immune checkpoint inhibitors (ICI): 37% with a KRAS G12C mutation, 62% with a non-G12C mutation. Patients with a G12C mutation were more likely to be of Caucasian ancestry (86% vs 56%; p = 0.01) whereas all other characteristics were similar between the groups including smoking history, PD-L1 expression ≥50% (61% vs 40%) and the presence of a TP53 co-mutation (48% vs. 54%); all p > 0.05. Treatment patterns were similar between the groups, with PD-1 inhibitor monotherapy given in 86% vs 79% of KRAS G12C and non-G12C patients. Overall response rate was 51% vs 27% in G12C vs non-G12C (p = 0.03). PFS was superior in G12C mutants (19.6 months vs 4.0 months), even after adjusting for smoking history, TP53 co-mutation status and PD-L1 expression (adjusted HR 0.51; p = 0.02). In subgroup analyses, the superiority in PFS was driven by the G12C mutants with high PD-L1 expression (n = 19): 26.8 months in G12C, PD-L1 high vs 4.7 months in G12C, PD-L1 low vs. 4.7 months in KRAS transversion mutations, PD-L1 high vs 4.0 months in transversion mutations, PD-L1 low vs. 3.0 months in transition mutations; p < 0.001. Conclusions: The presence of a KRAS G12C mutation is associated with improved ORR and PFS after treatment with ICI compared to non-G12C mutations in mNSCLC. The greatest benefit in PFS was observed in the subgroup with G12C mutation and high PD-L1 expression. Differential activation of downstream signaling associated with specific KRAS codon 12 mutation variants may modulate the composition of the tumor immune microenvironment thereby contributing to the variable response to immunotherapy. Further understanding on these molecular mechanisms may direct the development of new treatment strategies in KRAS mutant lung cancers.
The low advanced lung cancer inflammation index to predict poor prognosis of patients with metastatic non-small cell lung cancer.
Authors: Lu Ping , Ma Yifei , Kai Jindan , Wang Jun , Yin Zhucheng , Xu Hongli , Li Xinying , Liang Xin , Wei Shaozhong , Liang Xinjun
Published: June 2021

e21132

Background: Inflammation plays a crucial role in cancers, in which the advanced lung cancer inflammation index (ALI) is considered to be a potential factor reflecting systemic inflammation. This work aimed to explore the prognostic value of ALI in metastatic non-small cell lung cancer (NSCLC) and classify patients according to their potential risks and different prognosis. Methods: Non-small cell lung cancer patients with stage IV were included in this retrospective study who were diagnosed pathologically in Hubei Cancer Hospital from June 2012 to December 2013. Combined with relevant imaging data and exfoliative cytology, patients with non-small cell lung cancer were staged according to the eighth edition of TNM staging criteria for non-small cell lung cancer. We screened 318 patients who met the inclusion and exclusion criteria requirements. The clinicopathological and therapeutic data of the patients were collected through medical records, including age, sex, smoking and drinking, tumor site, tumor family history, histology, metastatic site, chemotherapy, radiotherapy, anti-VEGF therapy and EGFR-TKI therapy. The formula of ALI is body mass index (BMI, Kg / m2) × serum albumin (Alb, g / dl) / neutrophil-lymphocyte ratio (NLR). Categorical variables were analyzed by chi-square test or Fisher’s exact test. The OS rates was analyzed by Kaplan–Meier method and plotted with R language. Multivariate Cox proportional hazard model was used to analyze the relationship between ALI and OS. The nomogram based on the Multivariable Cox regression was establish, and the Harrell consistency index (C-index) was used to evaluate the predictive performance of the Cox regression model. Results: According to the optimal cut-off value determined by X-tile software, patients were divided into two groups: ALI < 32.6 and ALI ≥ 32.6 and the median OS in the high ALI group were better than those in the low ALI group (39.97 vs 19.23 months, p < 0.01). Local or distant metastases and some distant metastasis sites are related to prognosis. Multivariable Cox regression model confirmed that ALI (HR: 1.39; 95%CI: 1.03-1.89; P = 0.03) and chemotherapy (HR: 0.67; 95%CI: 0.49- 0.91; P = 0.01) were independent prognostic factors for OS in patients with metastatic non-small-cell lung cancer. Conclusions: The results of our study indicates that patients with low ALI tend to have lower OS in metastatic NSCLC, and ALI can serve as an effective prognostic factor for metastatic NSCLC patients.
Role of capmatinib in MET exon 14-mutated advanced non-small cell lung cancer (NSCLC): A systematic review.
Authors: Khan Israr , Ahmed Faiza , Hanif Nazma , Haider Mobeen Zaka , Khalid Farhan , Mishra Sakshi , Garimella Radhika , Andrews Kim , Pakala Ramya , Gara Sirisha , Guntipalli Prathima , Pacha Faris , Mohan Karthik , Thompson Andre , Mouchli Mohamad , Enebong Nya Godsgift
Published: June 2021

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Background: Capmatinib is a selective inhibitor of MET receptor that got accelerated FDA approval in May 2020 to treat NSCLC with MET ex 14 mutation (METex14). Here, we proclaim the first review of capmatinib efficacy and safety profile in METex14 positive NSCLC patients. Methods: A systematic literature search was conducted using PubMed, Cochrane Library, Clinicaltrials.gov, and Google Scholar. We compiled and analyzed the original studies evaluating the clinical response of capmatinib in MET ex14 mutated advanced NSCLC. Results: The most recent results (as of January 6, 2020) of the GEOMETRY Mono-1 phase 2 study showed an overall response rate (ORR) of 41% (69/97; 95% CI, 29-53) with 41% partial response (PR), and 36% stable disease (SD) in patients who previously received 1-2 prior therapy lines (cohort 4). While the ORR, PR, and SD were 68% ( n = 29/97; 95% CI, 48-84), 64%, and 25%, respectively in treatment naïve patients (cohort 5b). Median progression-free survival (mPFS) and duration of response (DOR) were 5.4 months (mon) and 9.7 mon (95%CI, 5.6-13.0) in cohort 4 vs. 12.4 mon and 12.6 mon (CI, 5.6- not estimated), respectively in cohort 5b. Moreover, disease control was shown in n = 54/69 patients in cohort 4 (95% CI 78 (97-87) and n = 27/28 patients (95% CI 96 (82-100). A post-hoc analysis of 19 patients out of 69 who were pre-treated with immunotherapy demonstrated an ORR of 57.9% (n = 11/19; 95%CI 33.5-79.7) with capmatinib. In contrast, treatment-naive had an ORR of 34% (n = 17/50; 95%CI 21.2-48.8) as per the investigator. Median PFS was 3.29 mon noted on prior therapy. In the phase 1 retrospective analysis reported by Choi et al., ORR was 50% with a median duration of 16.1 (5.3-36.4) mon. Among 45 Japanese pts with MET ex 14 mutated or MET amplified status, the ORR was 36.4% (95% CI 10.9%-69.2%) with a PFS of 4.70 mon in the MET ex 14 mutated groups who had received a second or third line of therapy. Most commonly reported adverse events were peripheral edema, nausea, vomiting, and elevated creatinine across all studies and were mostly grade 1-2. Conclusions: Our results showed that capmatinib has promising anti-tumor activity in patients with NSCLC harboring MET exon 14 skipping mutation. The efficacy and tolerability profile of capmatinib is remarkable, particularly in treatment-naïve patients. Although the GEOMETRY Mono-1 trial is still ongoing, further clinical studies with long-term follow-up are needed.
The role of PTEN and TP53 co-mutations in immunotherapy of lung cancer.
Authors: Ma Xiaolong , Zhang Ding , Chen Shiqing
Published: June 2021

e21161

Background: Patients with non-small cell lung cancer (NSCLC) harboring PTEN mutations have a worse prognosis of immunotherapy in research with small sample size and case reports. However, the role of PTEN and TP53 co-mutations in immunotherapy of NSCLC has not been fully studied. Methods: Patients with NSCLC from our dataset were enrolled in this study. For the genomic profiling, only the pathogenic mutations and likely pathogenic mutations in clinical significance were rolled. The efficiency of immunotherapy was analyzed in a public cohort of 240 NSCLC patients by Rizvi. Patients with EGFR/ALK mutation were excluded in our analysis. Results: In our dataset, 1,428 patients were included in the analysis. 25 (1.75%) patients have PTEN mutations and 429 (30.04%) patients have TP53 mutations. In all patients with PTEN mutations, 84% with TP53 co-mutations. Median tumor mutational burden (TMB) was 12.29 mutations/MB (range, 3.35-36.87) and 6.98mutations/MB (range, 0.56-9.50) in patients harboring PTEN mutations with TP53 co-mutations and without TP53 co-mutations, respectively ( p= 0.02). In 240 NSCLC patients of Rizvi, the overall response rate (ORR) of the PTEN and TP53 co-mutations group, the PTEN mutations without TP53 mutations group and PTEN wild-type group was 33.33%, 0% and 20.26%, respectively. The disease control rate (DCR) was 83.33%, 0% and 54.74%, respectively. The median progression-free survival (PFS) in the PTEN and TP53 co-mutations group was the longest (7.5 months), while the median PFS in the PTEN mutations without TP53 mutations group was only 2.5 months. However, No significant differences of PFS were observed. Conclusions: Our findings suggested that patients with NSCLC harboring PTEN and TP53 co-mutations might benefit more from immunotherapy compare to those harboring PTEN mutation without TP53 mutations and PTEN wild-type. TMB may be an important factor that lead to the results. Further studies need to be explore in cohorts with larger sample sizes.
Association of TGFBR2 mutations with shorter survival in non-small cell lung cancer treated with immune checkpoint inhibitors.
Authors: Zheng Linxin , Yang Mengmei , Huang Mengli , Li Weifeng
Published: June 2021

e21166

Background: Transforming growth factor beta receptor 2 (TGFBR2) is a transmembrane receptor that plays an important role in both cellular functions and immune reaction, including cell proliferation, cell differentiation and extracellular matrix production. It forms a heterodimeric complex with TGF-beta receptor type-1 and binds TGF-beta. The association between TGFBR2 gene mutations and efficiency of immune checkpoint inhibitors (ICIs) has not been investigated in non-small cell lung cancer (NSCLC). Methods: Two published cohorts of NSCLC patients treat with ICIs were used to explore the immunotherapeutic predictive role of TGFBR2 gene mutations, including a discovery cohort (Gandara et al., Nature Genetics, 2018) and a validation cohort(Samstein et al. Nature Genetics, 2019). The Cancer Genome Altas (TCGA) Pan -Lung Cancer dataset was used for prognostic analysis. Results: TGFBR2 mutations were identified in 1.6% (7/429) and 2.3% (8/344) patients with NSCLC in the discovery and validation cohort, respectively. In the discovery cohort, patients with TGFBR2 mutations had shorter progression-free survival (PFS, median, 1.3 months vs 2.7 months; HR = 2.83; 95% CI, 1.33–6; p = 0.0046) and dramatically shorter overall survival (OS, median, 2.4 months vs 11.1 months; HR = 3.46; 95% CI, 1.63–7.35; p = 0.00058) than those with wild-type TGFBR2. Consistent with this, TGFBR2 mutations were significantly correlated with shorter OS (3 months vs 10 months; HR = 3.46; 95% CI, 1.63–7.35; p = 0.00058) in the validation cohort. In addition, no significant difference was found in OS between TGFBR2-mutant and TGFBR2-wild-type NSCLC patients with standard treatment in TCGA cohort (p = 0.821). Conclusions: TGFBR2 gene mutations are associated with shorter survival in NSCLC patients treated with ICIs, suggesting that TGFBR2 mutations be used as a potential biomarker of predicting the efficiency of immunotherapy and guiding NSCLC systemic treatment.
Immunotherapy in patients with lung cancer with driver mutations: A single center experience.
Authors: Vundemodalu Prathyush , Rauthan Amit , Patil Poonam , Aswath Rajashri
Published: June 2021

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Background: Immunotherapy has revolutionized treatment in metastatic non small cell lung cancer (NSCLC)without driver mutations. Trial data shows that programme death-1/ PDL1 blockade in epidermal growth factor receptor(EGFR) and other driver mutation positive lung cancers is not beneficial. Here we evaluated the efficacy of immune check point inhibitors in a series of patients with EGFR and other driver mutation positive advanced NSCLC. Methods: We retrospectively analysed 75 patients who received PD1/ PDL1 inhibitors for advanced NSCL between January 2017 to January 2020. 10 patients were detected to have driver mutations on either tumor tissue or blood by NGS. Results: Out of 10 patients, 7 were male and 3 were female. EGFR was detected in 6 patients (3 on tumor and 3 in blood NGS). We found MET exon 14 skip mutation in 2 and RAS in 2 patients. Immunotherapy combined with chemotherapy was given in 5(50%) patients, immunotherapy + bevacizumab+chemotherapy in 2(20%) and immunotherapy alone in 3 patients(30%). Immunotherapy was as started as first line in 4 patients as tumor tissue was negative for EGFR, ALK, ROS1 by single gene testing. On NGS testing at progression, EGFR mutation was detected in 1 patient, MET exon 14 skip mutation was detected in 2 and Ras mutation in 2 patients. Immunotherapy alone was used in 3 patients in view of advanced age and multiple comorbidities.The progression free survival(PFS) ranged between 2 to 11months. Conclusions: Single agent checkpoint inhibitors seem to have a limited impact in treatment in patients with driver mutations. Molecular testing by NGS is recommended either on tumor tissue or on blood by NGS if single gene testing for EGFR/ ALK/ ROS1 alterations is negative. We do see benefit in patients who received PD1/PDL1 inhibitors in combination with chemotherapy with/ without Bevacizumab. In conclusion, patients progressing on EGFR TKIs who are planned for immunotherapy should always be given in combination with chemotherapy+/- Bevacizumab.[Table: see text]
Algorithm to derive progression-based lines of therapy from a real-world non-small cell lung cancer (NSCLC) dataset.
Authors: Agrawal Smita , Priya Vandana , George Rohini , Manirevu Sai Vinod , Bhardwaj Tapasya , Prajapati Rambaksh , Chakkrapani Sangavai , Walker Mark S. , Vaidya Vivek Prabhakar , Narayanan Babu
Published: June 2021

e21172

Background: Analysis of Real World Data (RWD) from Electronic Health Records (EHR) for applications such as Health Economics and Outcomes Research (HEOR) or regulatory submissions requires identification of the lines of therapy (LoT) patients have received. LoTs are typically not captured in EHR and must be manually abstracted. As the use of RWD increases, there is a growing need to create algorithms that can work on RWD to extract LoT information in an automated manner with high accuracy. We present here the results of such an algorithm created on NSCLC RWD. Methods: 10950 advanced NSCLC patients from the ConcertAI Oncology RWD database who had received anti-neoplastic treatment after advanced diagnosis were used to build and validate this algorithm. These data were further enriched by expert nurse curators to fill in missing oral drug information and identify progression events. We developed a progression-based LoT (pLoT) model that identified LoT changes in sync with tumor progressions. If patients received multiple regimens before progression they were captured as nested regimens within the LoT. The algorithm uses complex rules to define combination of drugs as regimens (combination rule), identify resumption of regimens (gap rule) or dropping of drugs from regimens as new lines and to handle noisiness in RWD etc. Results: The LoT model accurately captures line changes triggered by progression events as well as any nested regimen changes due to adverse events etc. Patient level validation of LoT was carried out by clinical experts using an in-house tool and found to be consistent with literature & individual drug data. Cohort level analysis of top 3 combinations of therapies used in 1st & 2nd line treatment between 2015-2020 (8200 patients) are shown in Table. Sensitivity analysis on the combination rule showed that this parameter can be changed between 28-33 days without significantly impacting the LoT output (<1% impact). We use a 30 day combination rule as the default. Similarly, the gap rule parameter is quite robust and does not show significant variation between 45 – 90 days (<2% impact). We use 63 days. Conclusions: We have developed a robust algorithm to derive pLoT on RWD at scale assuming availability of curated progression data which can be used to support use cases such as HEOR, clinical development and regulatory submissions. pLoT is better suited for outcomes analysis compared to regimen based LoT since it distinguishes changes in treatment due to progression events from changes due to toxicity, drug availability, etc., and allows analysis on a more homogeneous patient population relating to their past clinical experience. [Table: see text]