Monotherapy In Non-small Cell Lung Cancer Research Articles

Abstract CT249: Results from KEYMAKER-U01 substudy 3: a phase 2 umbrella study of pembrolizumab plus investigational agents in patients with non-small-cell lung cancer (NSCLC) previously treated with anti-PD-(L)1 therapy

Abstract Background: The anti-PD-1 monoclonal antibody (mAB) pembrolizumab with or without chemotherapy is a standard of care for first-line advanced or metastatic NSCLC and as monotherapy for NSCLC with PD-L1 TPS ≥1% previously treated with chemotherapy. However, there are limited treatment options for patients whose disease progresses after anti-PD-(L)1 therapy. We present results from the KEYMAKER-U01 study (NCT04165798) substudy 3, which evaluated pembrolizumab in combination with investigational mAbs for patients with NSCLC previously treated with anti-PD-(L)1 therapy. Methods: This randomized, phase 2, rolling-arm, multicenter, open-label, adaptive-design study enrolled patients aged ≥18 y with ECOG PS of 0 or 1 and confirmed stage IV squamous or nonsquamous NSCLC (per current AJCC) who progressed on or after prior anti-PD-(L)1 therapy and platinum-based chemotherapy given sequentially or concomitantly. Patients were randomized to receive up to 35 cycles (~2 y) of pembrolizumab 200 mg Q3W plus either the anti-CD27 mAb boserolimab 30 mg Q3W (arm A), the anti-ILT4 mAb MK-4830 800 mg Q3W (arm B), or the anti-ILT3 mAb MK-0482 750 mg Q3W (arm C). The primary endpoint was ORR per RECIST version 1.1 by investigator review. Secondary endpoints were PFS per RECIST version 1.1 by investigator review and safety (AEs and treatment discontinuation due to AEs). Results: Overall, 127 patients received ≥1 dose of study treatment in arms A (n = 37), B (n = 45), and C (n = 45). At data cutoff (Nov 10, 2023), median study follow-up was 35 (range, 31-45) mo, 33 (range, 30-36) mo, and 23 (range, 18-25) mo, respectively. ORR (95% CI) was 8% (2%-22%; 1 CR, 2 PR) in arm A, 11% (4%-24%; 1 CR, 4 PR) in arm B, and 4% (1%-15%; 0 CR, 2 PR) in arm C. Median (95% CI) PFS was 2.4 (1.4-2.8) mo, 2.4 (1.5-2.7) mo, and 2.6 (1.4-4.7) mo, respectively. AEs of any cause occurred in 37 patients (100%) in arm A, 42 (93%) in arm B, and 41 (91%) in arm C. These were grade 3-5 in 21 (57%), 20 (44%), and 17 patients (38%), respectively. Treatment-related AEs occurred in 27 patients (73%; grade 3/4, 16%) in arm A, 25 patients (56%; grade 3/4, 9%) in arm B, and 23 patients (51%; grade 3/4, 11%) in arm C. Six (16%), 8 (18%), and 3 patients (7%) discontinued treatment due to any AE. Grade 5 AEs occurred in 2 (5%), 4 (9%), and 2 patients (4%), respectively; none were deemed to be treatment related. Conclusions: In the KEYMAKER-U01 substudy 3 evaluating novel treatment combinations of pembrolizumab plus boserolimab, MK-4830, or MK-0482 in patients with NSCLC that progressed on/after platinum-based chemotherapy and anti-PD-(L)1 therapy, modest antitumor activity was observed with all 3 treatment combinations. No new safety signals were observed for the treatment combinations investigated. Citation Format: Charu Aggarwal, James Stevenson, Dariusz M. Kowalski, Tibor Csőszi, Nir Peled, Byoung Chul Cho, Belén Rubio-Viqueira, Jiaxin Niu, David P. Carbone, Susanne M. Arnold, Mark M. Awad, Justin F. Gainor, Suman Rao, Anne S. Tsao, Heng Zhou, Omobolaji O. Akala, Elliot Chartash, Ernest Nadal. Results from KEYMAKER-U01 substudy 3: a phase 2 umbrella study of pembrolizumab plus investigational agents in patients with non-small-cell lung cancer (NSCLC) previously treated with anti-PD-(L)1 therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT249.

RBM17 Expression Is Associated With the Efficacy of ICI Monotherapy in NSCLC With Low PD-L1 Expression.

Immune checkpoint inhibitors (ICIs) are currently a standard treatment tool for non-small cell lung cancer (NSCLC). RNA-binding motif protein 17 (RBM17), a splicing factor, is frequently over-expressed in NSCLC, but little is known about the role of RBM17 in the efficacy of ICIs for NSCLC. Thus, we investigated the correlation between RBM17 expression and ICI efficacy in NSCLC. Biopsy or surgical specimens were collected from patients with advanced or recurrent NSCLC who received ICI monotherapy or chemo-immunotherapy in a first-line setting. RBM17 expression was examined using immunohistochemistry. The correlation between the efficacy of ICI monotherapy or chemo-immunotherapy and RBM17 expression was evaluated. Among the 218 cases, 115 (52.8%) cases were positive for RBM17 expression. RBM17 expression was not associated with the objective response rate (ORR) or progression-free survival (PFS) in either of the ICI monotherapy or chemo-immunotherapy groups. However, among those with a low PD-L1 expression level (PD-L1 <50%; n=86), RBM17 expression was significantly associated with a better ORR (p=0.045) and a better PFS (p<0.001) in the ICI monotherapy group, and was significantly associated with a poor ORR in the chemo-immunotherapy group (p=0.041). RBM17 might be a useful predictive marker for a higher efficacy of ICI monotherapy in NSCLC patients with a low PD-L1 expression level.

Challenges and knowledge gaps with immune checkpoint inhibitors monotherapy in the management of patients with non-small-cell lung cancer: a survey of oncologist perceptions

Immune checkpoint-inhibitors (ICIs) are changing outcomes in different cancer settings, notably for patients with non-small-cell lung cancer (NSCLC). There are, however, still important gaps of evidence for clinical practice when using these novel treatments. In this study, we assessed physicians' opinion and experience on challenges for clinical practice with ICIs monotherapy in NSCLC. A survey was conducted on experienced physicians treating patients with NSCLC with ICIs. Two rounds of pilot tests were carried out for validation among a group of experts. Topics under analysis were in relation to treatment of elderly populations, performance status, brain metastases, use of steroids or antibiotics, the effects of gut microbiome, autoimmune diseases, human immunodeficiency virus infection, solid organ transplants, use of anti-programmed cell death protein 1 versus anti-programmed death-ligand 1 drugs, atypical tumour responses, predictors of response, duration of treatment and a final open question on additional relevant challenges. Two hundred and twenty-one answers were collected, including 106 (48%) valid answers from experts for final analysis (physicians who have treated at least 20 patients with NSCLC with ICIs). The vast majority agreed that the selected topics in this study are important challenges ahead and more evidence is needed. Moreover, predictors of response, treating brain metastasis, shorter duration of treatment, the effects of gut microbiome and concomitant use of steroids were voted the most important topics to be further addressed in prospective clinical research. This survey contributed to understanding which are the main challenges for clinical practice with ICIs monotherapy in NSCLC. It can also contribute to guide further clinical research, considering the opinions and experience of those who regularly treat NSCLC patients with ICIs.

Landscape of Savolitinib Development for the Treatment of Non-Small Cell Lung Cancer with MET Alteration-A Narrative Review.

Non-small cell lung cancer (NSCLC) is increasingly being treated with targeted therapies. Savolitinib (Orpathys®) is highly selective mesenchymal epithelial transition (MET)-tyrosine kinase inhibitor (TKI), which is conditionally approved in China for advanced NSCLC with MET exon 14 skipping mutations (METex14). This article summarizes the clinical development of savolitinib, as a monotherapy in NSCLC with METex14 mutation and in combination with epidermal growth factor receptor (EGFR) inhibitor in post EGFR-TKI resistance NSCLC due to MET-based acquired resistance. Preclinical models demonstrated anti-tumor activities in MET-driven cancer cell line and xenograft tumor models. The Phase Ia/Ib study established an optimized, recommended phase II dose in Chinese NSCLC patients, while TATTON study of savolitinib plus osimertinib in patients with EGFR mutant, MET-amplified and TKI-progressed NSCLC showed beneficial efficacy with acceptable safety profile. In a pivotal phase II study, Chinese patients with pulmonary sarcomatoid carcinoma, brain metastasis and other NSCLC subtype positive for METex14 mutation showed notable responses and acceptable safety profile with savolitinib. Currently, results from ongoing clinical trials are eagerly anticipated to confirm the efficacious and safety benefits of savolitinib as monotherapy and in combination with EGFR-TKI in acquired resistance setting in advanced NSCLC and its subtypes with MET alterations.

EP08.01-043 Clinicopathologic and Genomic Factors Impacting Efficacy of First-Line Chemoimmunotherapy in Advanced Non-small Cell Lung Cancer (NSCLC)

While recent studies have examined the impact of clinicopathologic features on clinical outcomes to PD-(L)1 monotherapy in NSCLC, factors that influence chemoimmunotherapy efficacy are in need of further investigation.

1200TiP Phase Ia/Ib study of RS-0139, a novel tumor-targeted delivery of docetaxel, in patients with recurrent, locally advanced, or metastatic non-small cell lung cancer (NSCLC)

Docetaxel (DTX) is an anti-microtubule agent registered for multiple indications and is usually administered 3-weekly at doses of 60-100 mg/m2. Important limitations of DTX include acute hypersensitivity reactions, neutropenia, neuropathy, fatigue and nausea. RS-0139 is developed as a DTX-releasing, tumor-targeted prodrug. DTX is covalently bound to a polymer backbone, together with a targeting peptide, which shows high affinity to avb3, avb5 and avb6 integrin receptors highly expressed on tumor cell surface. Once RS-0139 is up-taken by the cell, the covalent bond is cleaved to release DTX in the cytoplasm. RS-0139 gains the investigational new drug status since DTX is covalently modified for the targeted treatment. The physical properties of RS-0139, pharmacokinetic profile and improved aqueous solubility may provide an advantage over the currently used taxanes. In preclinical studies, enzymatically cleavable covalent conjugation of DTX enabled sustained-release inside the tumor, reducing adverse effects due to limited circulating free DTX. Hence, RS-0139 showed superior tolerability than DTX in healthy animals. Besides, the dosing frequency decreased owing to the increased half-life. Preclinical data strongly support the clinical translation of this novel nanomedicine for the treatment of solid tumors. This is a phase Ia/Ib open-label, multicenter, dose-escalation and expansion study to evaluate the safety and tolerability of RS-0139 monotherapy in NSCLC. Patients who progressed after standard therapy are eligible for the study. In Phase Ia, patients receive RS-0139 (IV) at escalating doses (75-200 mg/m2). The protocol consists of an accelerated titration design until the recommended dose for Phase Ib is elicited and switched to standard 3+3 design in case of grade 2 toxicity. Phase Ib will be initiated following the determination of the recommended dose for RS-0139 upon evaluation of all available safety and PK data and 6 patients will receive 3 cycles in every 21 days. The primary endpoint is the determination of the MTD of RS-0139. The study is open for enrollment in 2 sites. Two of the planned 16 patients have been enrolled to date. NCT04261413. RS Research.

Tumor expression of cGAS, not STING, negatively impacts on the efficacy of PD-1/L1 inhibitors in non-small cell lung cancer with PD-L1 TPS ≥50.

e21048 Background: The cGAS/STING pathway is an innate immune pathway that promotes cytokine production in response to cytoplasmic DNA, and its activation is important for the induction of anti-tumor immunity. However, predictivity of cGAS/STING tumor expression on the efficacy of PD-1/L1 inhibitors and subsequent immune responses (e.g., changes in serum cytokines) remain to be elucidated. Non-small cell lung cancer with PD-L1 tumor proportion score (TPS) of 50% or higher respond well to immune checkpoint inhibitor (ICI) monotherapy, but there is still a poor response group among them, and the extraction of such patients is an urgent issue. Methods: This is a post hoc analysis of prospective biomarker study, which enrolled 106 patients with advanced non-small cell lung cancer (NSCLC) who were treated with ICI monotherapy between December 2015 and September 2018. We investigated in 68 patients with preserved evaluable tissue samples taken before start of ICI treatment. cGAS, STING, and PD-L1 expression in tumors were stained by immunohistochemistry. cGAS and STING were evaluated by H-score. Using peripheral blood which was collected by the observational study, 41 serum proteins at the time of PD-1/L1 inhibitors initiation and in 4 – 6 weeks later were quantified. Results: The median cGAS and STING H-SCORE were 220 (5 – 300) and 190 (0 – 300), respectively. There were no differences in cGAS or STING H-SCORE between PD-L1 high (TPS ≥50) and low (TPS &lt; 50) groups ( p= 0.990 and 0.283). Cases were divided into two groups according to median of the H-SCORE, respectively, and compared. Unexpectedly, cGAS high (H-SCORE ≥220) patients showed significantly shorter progression free survival of ICI when PD-L1 TPS ≥50 (median progression free survival (PFS); 143 days vs. not reached, p = 0.028) and progression free rate at 18 months was 7 and 53%, while no association was observed when PD-L1 TPS &lt; 50 (median PFS; 47 vs. 61 days, p= 0.798). STING tumor expression was not associated with PFS regardless of PD-L1 TPS. In cytokine analysis, cGAS high was associated with significantly higher serum concentrations of TGF-β1 and β2 before ICI initiation (47.5 vs. 22.3hg/l, p= 0.023; 2118 vs. 882rg/ml, p= 0.037), and H-SCORE of cGAS, not STING, were significantly correlated with TGF-β1 and β2 basal levels (r = 0.447, p= 0.009; r = 0.373, p= 0.033). Analysis about fold change from baseline to 4 – 6 weeks later of 41 cytokines revealed that leptin significantly increased in cGAS high tumor while no difference was seen in all of cytokines between STING high and low tumor. Conclusions: Tumor expression (H-Score) of cGAS, not STING, is a candidate for predictor of poor response to ICI monotherapy in NSCLC with PD-L1 high (TPS ≥50). cGAS tumor expression may be associated with TGF-β producing, immune-suppressive tumor microenvironment in NSCLC. Clinical trial information: UMIN000024414.

Evaluation of Programmed Death Ligand 1 (PD-L1) Gene Amplification and Response to Nivolumab Monotherapy in Non–small Cell Lung Cancer

Robust predictors for response to anti-programmed death 1 and its ligand (PD-1/PD-L1) immunotherapy in non-small cell lung cancer (NSCLC) are not fully characterized. To evaluate whether PD-L1 (CD274) copy number gains (CNGs), comprising amplification and polysomy, in pretreatment specimens assessed by fluorescence in situ hybridization are associated with response to nivolumab monotherapy in NSCLC. This multicenter cohort study enrolled 200 patients, of whom 194 had assessable tumors, with advanced or recurrent NSCLC who were treated with nivolumab after progression following prior treatment at 14 institutions in Japan between July 2016 and December 2018. Median (interquartile range) duration of follow-up was 12.6 (5.6-20.4) months. Data were analyzed from December 2019 to February 2020. Sequential nivolumab was given on day 1 of a 14-day cycle. Response was assessed every 4 cycles using Response Evaluation Criteria in Solid Tumors version 1.1. Overall response rate (ORR) according to the PD-L1 copy number status. Additional end points were progression-free survival, overall survival, and PD-L1 tumor proportion score (TPS) assessed by immunohistochemistry based on PD-L1 copy number status. A total of 6 of the 200 patients were excluded because of poor-quality tumor specimens for the biomarker study, resulting in 194 assessable patients. Of these, 155 (79.9%) were men, with a median (range) age of 69 (43-83) years. PD-L1 CNGs were identified in 32 patients (16.5%), including 5 (2.6%) with amplification and 27 (13.9%) with polysomy. The ORR among patients with and without PD-L1 CNGs was 28.1% (95% CI, 13.7%-46.7%) and 17.9% (95% CI, 12.3%-24.7%), respectively. Although patients with PD-L1 polysomy did not demonstrate improved ORR (18.5% [95% CI, 6.3%-38.1%]) compared with those without PD-L1 CNGs, 4 of 5 patients (80.0% [95% CI, 28.4%-99.5%]) with PD-L1 amplification showed response, among whom median duration of response was not reached. Patients with PD-L1 amplification showed excellent survival outcomes for progression-free and overall survival. Overall, 3 PD-L1-amplified tumors (60.0%) showed PD-L1 TPS of at least 80%, but 2 (40.0%) had PD-L1 TPS of 15% or less. In this study, tumor PD-L1 amplification but not polysomy was associated with response to nivolumab monotherapy among patients with NSCLC. External validation with a larger sample size is warranted.

Abstract 3180: Development of a fully automated immunoassay system for detection of serum NY-ESO-1 and XAGE1 antibodies as biomarkers predicting the clinical efficacy of anti-PD-1 therapy

Abstract Background: Programmed cell death-1 (PD-1) and PD-ligand1 (PD-L1) inhibitors have become standard therapies for advanced non-small-cell lung cancer (NSCLC) due to prolonged patient survival. However, extended survival with anti-PD-1/PD-L1 therapy is limited to a small subset of NSCLC patients. Therefore, predictive biomarkers are needed to determine which patients will benefit. Recently, we reported that serum antibodies (Abs) against NY-ESO-1 and/or XAGE1 cancer-testis antigens are useful biomarkers that predict the clinical efficacy of anti-PD-1 monotherapy for NSCLC. The serum Abs were measured with enzyme-linked immunosorbent assay (ELISA); however, the ELISA method has several technical limitations for clinical applications. To overcome limitations in Ab measurement, we have developed a fully automated immunoassay system (HISCLTM) using chemiluminescent magnetic immunoassay technology. HISCLTM is widely used in many clinical fields because it is superior to ELISA due to its rapid reaction (17 minutes), wide dynamic ranges, and high reproducibility. Patients and Methods: Sera of NSCLC patients were obtained before anti-PD-1 monotherapy (nivolumab or pembrolizumab) as a part of standard care. NY-ESO-1/XAGE1 serum Abs were measured by ELISA and HISCLTM and their clinical performance was evaluated. In HISCLTM system, serum Abs were captured by magnetic beads coated with antigens, and the antigen-Ab complex was incubated with anti-human IgG conjugated with alkaline phosphatase. The chemiluminescent intensity acquired was then used for analyses. Results: Twenty-eight NSCLC patients were selected as the initial cohort for this study. Half of the patients responded to anti-PD-1 monotherapy and the remaining half did not. There were strong correlations between HISCLTM chemiluminescence signal intensity and titers of NY-ESO-1 and XAGE1 serum Abs in ELISA (r&amp;gt;0.93 for both). Twelve of thirteen Ab-positive patients in HISCLTM responded to anti-PD-1 therapy, while only two of fifteen Ab-negatives did (92% vs. 13%, p&amp;lt;0.001). Notably, the signal intensities in HISCLTM correlated well with tumor reduction rates after anti-PD-1 therapy. Serum NY-ESO-1/XAGE1 Ab-positivity in HISCLTM predicted efficacy with an AUC of 0.898, resulting in a sensitivity of 86% and specificity of 93%. Conclusions: We have developed a rapid and highly reproducible immunoassay system for detecting the serum NY-ESO-1 and XAGE1 Abs as predictive biomarkers of clinical benefits with anti-PD-1 monotherapy in NSCLC. In the future, our system would be examined in large-scale clinical trials for various other cancers. Citation Format: Yumiko Sakai, Hirotaka Abo, Kanako Sakaeda, Yusuke Atarashi, Nobuyuki Ide, Takaaki Yamaoka, Koji Kurose, Kenta Noda, Toshiyuki Sato, Toru Oga, Mikio Oka. Development of a fully automated immunoassay system for detection of serum NY-ESO-1 and XAGE1 antibodies as biomarkers predicting the clinical efficacy of anti-PD-1 therapy [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3180.

Role of pleural and peritoneal metastasis in immune checkpoint inhibitors efficacy patients with non-small cell lung cancer: real-world data from a large cohort in France.

Checkpoint inhibitors (CKI) targeting PD-1 or PD-L1 are major therapies for the treatment of non-small cell lung cancer (NSCLC). Despite numerous studies of biological biomarkers, we currently lack a marker to predict CKI primary resistance. The aim of this study was to isolate clinical markers associated with the absence of efficacy of CKI used as monotherapy in NSCLC. We conducted a retrospective analysis of 172 patients treated with anti-PD1 or anti-PDL1 monoclonal antibodies (mAb) for advanced NSCLC at the Dijon Cancer Center. Baseline characteristics were compared using the Chi squared test between responders and non-responders. Survival curves were estimated by the Kaplan-Meier method and compared with the Log-rank test for univariate analysis. Cox regression models were used to determine hazard ratios and 95% confidence intervals for progression-free survival (PFS) and overall survival (OS). Among 172 patients included, 149 (86.5%) received CKI after platinum chemotherapy. Response rate (RR) was 16%, median progression-free survival (PFS) was 2.5months (95% CI 0.7-30months) and median overall survival (OS) was 10months (95% CI 0.7-46.8months). By univariate analysis, WHO performance status ≥ 1, presence of bone, liver and pleuroperitoneal metastasis were associated with poor PFS and OS. Multivariate analysis showed that only pleuroperitoneal metastasis was independently associated with PFS and OS. Patients with pleuroperitoneal metastasis and WHO performance status ≥ 1 had a < 10% chance of yielding a benefit from CKI. Our data support the hypothesis that pleuroperitoneal metastasis is a major predictive factor affecting CKI efficacy in NSCLC patients and may be used to avoid CKI monotherapy for such patients.

Abstract B38: Immunologic monitoring markers of clinical responses to anti-PD-1 therapy for non-small cell lung cancer

Abstract Background: Programmed cell death-1 (PD-1) and PD-ligand1 (PD-L1) inhibitors effectively treat advanced non-small cell lung cancer (NSCLC) and prolong patient survival, resulting in standard therapies of NSCLC. Clinical benefits of good response and long survival with anti-PD-1/L1 therapy are limited in a small population of NSCLC patients, although combinations with chemotherapy have been extensively developed. Tumor PD-L1 expression and mutation burden are well known as response biomarkers for these therapies. On the other hand, biomarkers monitoring clinical responses during anti-PD-1/L1 therapy have yet to be identified. Very recently, we reported robust biomarkers of NY-ESO-1 and XAGE1 serum antibodies (Abs) predicting clinical benefits with anti-PD-1 monotherapy for NSCLC. NY-ESO-1 and XAGE1 are major cancer-testis antigens in NSCLC and play important roles in the immune surveillance. Then, we investigated whether these Abs became monitoring markers of clinical responses to anti-PD-1 monotherapy in NSCLC. Patients and Methods: Patient sera were serially obtained during anti-PD-1 therapy (nivolumab or pembrolizumab) of the first or later line as a standard care, and serum Abs against NY-ESO-1 and XAGE1 antigens and mutant p53 (as neoantigen) were detected by ELISA. Ab-positive was defined for serum with extrapolated titers exceeding or equal to 100 (≥100). Objective responses to anti-PD-1 therapy were assessed according to the Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1. Results: In patients responding to anti-PD-1 therapy, NY-ESO-1/XAGE1 serum Ab titers were increased with several spikes within two to three months after therapy and were gradually decreased with tumor shrinkage. The increase of Ab titers showed rapid or gradual type, and the former reflected rapid tumor shrinkage and the latter did slow one. The Ab titers in patients with complete response (CR) were gradually decreased to an undetectable level, and these patients experienced no recurrence. However, the decreased titers in patients with partial response (PR) remained plateau or under 100, and some of these patients experienced recurrence or regrowth. The Ab titers in patients with progressive disease (PD) were gradually increased and not decreased. On the other hand, p53 serum Ab titers were gradually increased after the peaks of NY-ESO-1/XAGE1 serum Ab titers, suggesting antigen-spreading of neoantigens associated with tumor destruction. Conclusions: Our results suggest that NY-ESO-1 and/or XAGE1 serum Abs are robust monitoring biomarkers of clinical responses to immune checkpoint inhibitors and are useful for decision making regarding the continuation or discontinuation of therapy in clinical settings. Citation Format: Mikio Oka, Koji Kurose, Yoshihiro Ohue, Takahiro Karasaki, Junichiro Futami, Takeshi Masuda, Masaaki Fukuda, Akitoshi Kinoshita, Katsuhiko Shimizu, Masao Nakata, Noboru Hattori, Hiroyuki Yamaguchi, Minoru Fukuda, Toru Oga, Kazuhiro Kakimi. Immunologic monitoring markers of clinical responses to anti-PD-1 therapy for non-small cell lung cancer [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2019 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(3 Suppl):Abstract nr B38.

331P - A phase II study of abemaciclib in patients (pts) with brain metastases (BM) secondary to non-small cell lung cancer (NSCLC) or melanoma (MEL)

BackgroundAbemaciclib, a selective CDK4 & 6 inhibitor, demonstrated single-agent activity in NSCLC and melanoma (Patnaik et al., 2016). Clinical data demonstrate abemaciclib penetrates the blood brain barrier resulting in comparable concentrations in tissues and plasma (Sahebjam et al., 2016). MethodsStudy JPBO is a Simon 2-stage trial evaluating abemaciclib in 6pt cohorts with BM secondary to HR+ breast cancer, NSCLC, or melanoma. Here, we report NSCLC and melanoma cohorts. Pts with ≥1 new or not previously irradiated BM≥10mm or a progressive BM previously irradiated were eligible. Abemaciclib was orally administered BID on a continuous dosing schedule. Primary endpoint was objective intracranial response rate (OIRR; [confirmed CR+PR]) based on Response Assessment in Neuro-Oncology BM response assessment criteria (RANO-BM). Secondary endpoints included intracranial clinical benefit rate, PFS, OS, and safety. Results28 (NSCLC) and 23 (MEL) pts were enrolled and 23 (NSCLC) and 22 (MEL) were evaluable. Pts had a median of 2 prior systemic therapies in the metastatic setting. 35% (NSCLC) and 46% (MEL) of pts had prior whole brain radiotherapy. 35% (NSCLC) and 27% (MEL) pts had stereotactic radiotherapy. Median time from radiation to study enrollment was 4.8 (NSCLC) to 5.6 (MEL) months. No confirmed intracranial response was observed (OIRR 0% for both cohorts). 21.7% (NSCLC) and 13.6% (MEL) of pts showed a decrease in the sum of their intracranial target lesions. ICBR (CR+PR+SD persisting for > 6 months) was 26.1% (NSCLC) and 9.1% (MEL). Median PFS was 1.5 months (95% CI, 1.4-2.8) for NSCLC and 1.2 months (95% CI, 1.0-1.6) for MEL. Median OS was 7.1 months (95% CI, 3.7-9.4) for NSCLC and 2.9 months (95% CI, 1.2-4.3) for MEL. Based on efficacy results, enrollment closed at end of stage 1. Safety and tolerability were similar as previously reported for abemaciclib. ConclusionsThere was limited intracranial clinical activity for abemaciclib monotherapy in NSCLC and MEL pts in this study; OIRR and short median PFS suggest that no further studies for abemaciclib monotherapy are warranted in this pt population. Clinical trial identificationNCT02308020. Editorial acknowledgementMedical writing assistance was provided by Kristi Gruver, employee of Eli Lilly and Company. Legal entity responsible for the studyEli Lilly and Company. FundingEli Lilly and Company. DisclosureE. Le Rhun: Advisory / Consultancy, Research grant / Funding (institution), Oscar Lambert Center, Lille, FR: Mundipharma; Research grant / Funding (institution), University Hospital, Lille, FR: Amgen; Advisory / Consultancy, personal fees: Novartis; Advisory / Consultancy, personal fees: Daiichi Sankyo; Advisory / Consultancy, personal fees: Abbvie. G. Jerusalem: Advisory / Consultancy, Non-remunerated activity/ies, per patient investigator fee: Eli Lilly and Company; Research grant / Funding (self), Non-remunerated activity/ies, personal fees: Novartis; Research grant / Funding (self), Non-remunerated activity/ies, personal fees: Roche; Advisory / Consultancy, Non-remunerated activity/ies, personal fees: Pfizer; Advisory / Consultancy, personal fees: Celgene; Advisory / Consultancy, Non-remunerated activity/ies, personal fees: Amgen; Advisory / Consultancy, Non-remunerated activity/ies, personal fees: BMS; Advisory / Consultancy, personal fees: Puma Technology; Advisory / Consultancy, Non-remunerated activity/ies, personal fees: AstraZeneca; Advisory / Consultancy, personal fees: Daiichi Sankyo; Advisory / Consultancy, personal fees: Abbvie. D. Subramaniam: Advisory / Consultancy, personal fees: AstraZeneca; Advisory / Consultancy, personal fees: Takeda Oncology; Speaker Bureau / Expert testimony, Research grant / Funding (institution): Genentech. Y. Chen: Shareholder / Stockholder / Stock options, Full / Part-time employment, employee and stock options: Eli Lilly and Company. P.F. Conte: Research grant / Funding (self): Novartis; Travel / Accommodation / Expenses, travel grant: Eli Lilly and Company; Research grant / Funding (self): Roche; Research grant / Funding (self): AstraZeneca; Travel / Accommodation / Expenses, travel grant: Celgene; Travel / Accommodation / Expenses, travel grant: Tesaro. All other authors have declared no conflicts of interest.

Predictors of benefits to chemoimmunotherapy (CIT) in stage IV non-small-cell lung cancer (NSCLC): A meta-analysis.

e20595 Background: Immune checkpoint inhibitors (ICIs) have changed the landscape of NSCLC therapy. In previous study, gender, smoking history, and PD-L1 status were found to influence the efficacy of ICI monotherapy in NSCLC. This meta-analysis evaluated the clinical and molecular factors predictive of benefit from the addition of ICIs to first-line (1L) chemotherapy in metastatic NSCLC. Methods: Using the random effect model, we computed and compared the pooled hazard ratio (HR) of progression-free survival (PFS) and overall survival (OS) among the selected subgroups. The correlation between PD-L1 expression level and outcome was analyzed by meta-regression. Results: 7 phase III randomized trials comparing CIT vs. chemo in the 1L treatment of stage 4 NSCLC were included. CIT evenly improved the PFS irrespective of age, gender, histology, smoking history and ECOG performance status (PS). While patients (pts) with liver metastasis or ALK/EGFR aberration had greater PFS with the addition of ICI to Bevacizumab (BEV) based chemo regimen, the derived benefit was no longer statistically significant among pts treated with non-BEV-based regimens. Whereas the PFS superiority conferred by CIT was noticed across all PD-L1 expression subgroups, the benefit correlated with PD-L1 level and was more pronounced in the “PD-L1 high” subset. Except for pts with EGFR/ALK abnormalities, squamous histology or liver metastasis, CIT yielded a consistent amelioration of OS across the other selected subgroups. Conclusions: Survival advantage associated with 1L CIT in metastatic NSCLC was observed in different pts population including those for which single-agent ICI has limited therapeutic benefit. Our findings support the role of chemo +/- VEGF blockade as enhancer of ICIs activity even in “less immunogenic” context. [Table: see text]

Patient outcomes of monotherapy with hypofractionated three-dimensional conformal radiation therapy for stage T2 or T3 non-small cell lung cancer: a retrospective study.

BackgroundHypofractionated three-dimensional conformal radiation therapy (3D-CRT) is a treatment option for patients with early-stage non-small cell lung cancer (NSCLC) who are medically unable to tolerate surgery and who are not amenable to treatment with stereotactic body radiotherapy. This study assessed the efficacy and safety of 3D-CRT as a monotherapy in patients with localized stage T2 or T3 NSCLC.MethodsThis retrospective study consisted of 29 patients (20 males) aged 56–89 years (median, 76 years) with histologically confirmed NSCLC who underwent 3D-CRT between 2005 and 2014.ResultsThe median duration of patient observation was 17.0 months (range, 1.0–64.0 months). Complete and partial responses occurred in 13.8 and 44.8 % of patients, respectively, and the overall response rate was 58.2 %. Meanwhile, the 1- and 3-year survival rates were 65.8 and 33.8 %, respectively. In T2 NSCLC, the median survival time (MST) was 12 months, and the 1- and 3-year survival rates were 62.4 and 21.4 %, respectively. In T3 NSCLC, the MST was 17 months, and the 1- and 3-year survival rates were 72.9 and 48.6 %, respectively. Severe toxicities (Common Terminology Criteria Grade 3) were not observed. The mean biologically effective dose required to improve local control exceeded 80 Gy (range, 67.2–96.0 Gy).ConclusionThese findings support a role for 3D-CRT as a treatment option for patients who refuse or could not tolerate surgical therapy with early-stage NSCLC. Although this was a small, retrospective study, it may form the basis for future, larger controlled studies on 3D-CRT as a monotherapy for NSCLC.

Survival improvement in thoracic cancer: progress from the last decade and beyond

Lung cancer remains a major concern, being the most common cancer worldwide, and with the incidence continuing to increase in many countries. Survival following diagnosis of non-small cell lung cancer (NSCLC) remains relatively low, with 1-year overall survival being approximately 25%. However, the development of new drugs and innovative treatment approaches is improving the outlook for patients with NSCLC. Important contributions have been made to the treatment of NSCLC and continue to do so with the development of gemcitabine, and more recently, pemetrexed. Major advances in the understanding of cancer biology have identified many potential targets for rationally designed novel therapies. Many of these targets are components of signalling pathways or metabolic processes that contribute to one of the hallmarks of the cancer phenotype. The novel targeted therapy enzastaurin, which is a derivative of the prototypical protein kinase C inhibitor staurosporine, is currently being investigated as monotherapy in NSCLC following first- or second-line chemotherapy. Research into the use of pharmacogenomics to tailor therapy to the individual patient is another innovative field that is yielding promising results that may help to improve the clinical outcome for patients with NSCLC in the future.

Phase II trial of imatinib (I) and docetaxel (D) in recurrent non-small cell lung cancer (NSCLC)

18132 Background: Second line monotherapy for NSCLC produces a response rate of 9% and a median survival of 7–8 months, regardless of the agent used. Emerging data suggest that combining an approved agent with an anti-angiogenesis inhibitor may improve efficacy in the salvage setting. Platelet Derived Growth Factor Receptor alpha (PDGFR-alpha) is involved in angiogenesis and its expression has been reported in 100% of adenocarcinoma (11/11) and 89% of squamous cell (16/18) lung cancer specimens in a small group sample. Preclinical models have shown that I inhibits PDGFR and may subsequently inhibit angiogenesis. In addition, I + D have additive anticancer activity. We initiated a phase II trial of I +D to evaluate the efficacy and safety of this combination regimen in recurrent NSCLC. Methods: Patients (pts)with pathologically confirmed NSCLC, measurable disease, no more than 1 previous platinum-based chemotherapy regimen, PS 0–1, clinically stable brain metastases and adequate organ function were eligible. Tumor samples, when available, were tested for PDGFR expression by immunohistochemistry. All pts received D 30mg/m2 intravenously weekly x 3 every 4 weeks and oral I 600mg daily for 4 cycles. Non- progressors after 4 cycles continued with I alone for a total of 12 months or until progression. Tumor response was assessed every 2 cycles. The primary endpoint was response rate. A Simon two-stage design was used with 16 patients in the first stage and accrual of a total of 32 patients planned. Results: Currently 15/16 patients for stage I of the protocol have been enrolled. A total of 24 cycles of combined I+D were given. Patient characteristics and toxicity data are described in the table below. Efficacy data is premature. Conclusion : I +D combination has been well tolerated in this relapsed population. A detailed toxicity, efficacy and PDGFR analysis will be presented. [Table: see text] No significant financial relationships to disclose.

Gefitinib monotherapy in previously treated advanced non-small cell lung cancer (NSCLC): An immunohistochemical (IHC) analysis of EGFR and its downstream molecules

7096 Background: Gefitinib (ZD1839) monotherapy in NSCLC has shown meaningful antitumor activity with tolerable toxicity in previous studies and epidermal growth factor receptor (EGFR) expression status was not predictive of response. But its downstream molecules had not been examined in NSCLC. We analyzed efficacy and tolerability of gefitinib monotherapy in NSCLC and performed IHC analysis of EGFR and its downstream molecules and examined its correlation with response. Methods: Advanced NSCLC patients (pts) with ECOG PS 0–2 who had received two or more prior chemotherapy regimens were retrospectively analyzed. Patients received gefitinib 250mg daily as a part of expanded access program. Patients with evaluable paraffin embedded tissues obtained prior to any treatment had IHC determination of EGFR, phosphorylated(p)-EGFR, p-Erk expression. Their expression and correlation with response were analyzed. Results: Among 65 pts analyzed, we observed 14(21.5%) PR, 21(32.3%) SD, and 21(32.3%) PD. Nine patients were not evaluable. Median overall survival and time to progression was 6.7(95%CI 5.3–8.1) and 2.8(95% CI 1.9–3.7) months, respectively. Skin rash (31 pts, 47.6%) and diarrhea (20 pts, 31.8%) were most common adverse events. 34 patients had evaluable tissue specimen (9 operative specimen, 10 bronchoscopic biopsy(bx), 10 lung needle bx, 3 lymph node bx, 2 other site bx). EGFR expression was 0/1+/2+/3+ in 14/13/5/2 pts. p-EGFR expression was positive in 20.6%, p-Erk in 32.4%. None of the markers tested were correlated with response. Conclusions: Gefitinib monotherapy in previously treated advanced NSCLC showed efficacy and toxicity profile comparable to other studies. IHC determination of EGFR, p-EGFR, p-Erk failed to show correlation with response. No significant financial relationships to disclose.

Gefitinib monotherapy in previously treated advanced non-small cell lung cancer (NSCLC): An immunohistochemical (IHC) analysis of EGFR and its downstream molecules

7096 Background: Gefitinib (ZD1839) monotherapy in NSCLC has shown meaningful antitumor activity with tolerable toxicity in previous studies and epidermal growth factor receptor (EGFR) expression status was not predictive of response. But its downstream molecules had not been examined in NSCLC. We analyzed efficacy and tolerability of gefitinib monotherapy in NSCLC and performed IHC analysis of EGFR and its downstream molecules and examined its correlation with response. Methods: Advanced NSCLC patients (pts) with ECOG PS 0–2 who had received two or more prior chemotherapy regimens were retrospectively analyzed. Patients received gefitinib 250mg daily as a part of expanded access program. Patients with evaluable paraffin embedded tissues obtained prior to any treatment had IHC determination of EGFR, phosphorylated(p)-EGFR, p-Erk expression. Their expression and correlation with response were analyzed. Results: Among 65 pts analyzed, we observed 14(21.5%) PR, 21(32.3%) SD, and 21(32.3%) PD. Nine patients were not evaluable. Median overall survival and time to progression was 6.7(95%CI 5.3–8.1) and 2.8(95% CI 1.9–3.7) months, respectively. Skin rash (31 pts, 47.6%) and diarrhea (20 pts, 31.8%) were most common adverse events. 34 patients had evaluable tissue specimen (9 operative specimen, 10 bronchoscopic biopsy(bx), 10 lung needle bx, 3 lymph node bx, 2 other site bx). EGFR expression was 0/1+/2+/3+ in 14/13/5/2 pts. p-EGFR expression was positive in 20.6%, p-Erk in 32.4%. None of the markers tested were correlated with response. Conclusions: Gefitinib monotherapy in previously treated advanced NSCLC showed efficacy and toxicity profile comparable to other studies. IHC determination of EGFR, p-EGFR, p-Erk failed to show correlation with response. No significant financial relationships to disclose.

Docetaxel (Taxotere) - an update

The development of docetaxel, a member of the taxoid family, has been recent and rapid. Phase I studies recommend that a dose of 100 mg/m2 be administered every three weeks in a 1-h infusion. These studies have also demonstrated that the major dose-limiting toxicity is neutropenia. Major clinical research projects are now being carried out for breast cancer, non-small-cell lung cancer (NSCLC), squamous cell carcinoma of the head and neck (SCCHN) and gastric cancer. In advanced and metastatic NSCLC, Phase II studies have shown a response rate of 30 - 40%, and responses have been obtained in cis-platinum failures. In advanced and metastatic breast cancer, first-line treatment has yielded a response rate of 54 - 68%, and the rate for second-line response is only slightly lower, indicating an absence of cross-resistance. Phase II combination studies with docetaxel are in progress, and preliminary results are promising. The first Phase III study demonstrated preliminary response rates significantly higher than seen with doxorubicin, although survival data have not yet been published. Fewer results are available from SCCHN studies, but response rates have been encouraging (around 40%). Although further long-term data are needed to determine the precise role of docetaxel in combination with other drugs, it is apparent that this promising drug shows one of the best response rates for monotherapy in NSCLC and breast cancer.