Treatment Of Advanced NSCLC Patients Research Articles

Abstract 5390: High serum interleukin 6 level associates with early death after initiation of treatment with PD-1 inhibitor in advanced NSCLC

Abstract Anti-PD-1 therapy has been the standard treatment for advanced NSCLC patients. Some patients show durable response, while there are cases that show rapid progression after initiation of ICI treatment, which leads to early death. Therefore, we need a clear biomarker that identifies for early death after initiation of ICI treatment. We reported that CRP is a predictive marker for the efficacy of nivolumab for advanced NSCLC. Among pro-inflammatory cytokines, IL 6 and IL-1β are reported as a poor prognostic factor of cancer patients, and TNFα and INF-γ are reported to be one of the predictors of ICI efficacy.The aim of this study is to investigate the relationship between serum pro-inflammatory cytokines levels and the efficacy of ICI treatment and early death after ICI treatment. Methods: We retrospectively reviewed the predictive factors of efficacy and early death (death within 3 months after initiation of treatment) in anti-PD-1 monotherapy in all cohort (N=307). Based on the results in all cohort, we investigated the relationship of proinflammatory cytokines (IL-1β, IL6, IL10, INFγ) level in serum before pre-anti PD-1 therapy by Luminex® system and the clinical outcome of anti-PD-1 treatment in cytokine cohort (N=67). Patients with advanced or postoperative recurrence NSCLC who received 1≤ dose of ICI from December 2015 to September 2018 in our institute were included. Results: Among 307 patients, 45 patients (14.6%) died within 3 months after the initiation of anti-PD-1 therapy in all cohort. The median PFS of ICI treatment was 3.1months (95%CI: 2.5-4.1). EGFR or ALK mutation, poor PS (2≤), PD-L1 negative, high CRP(1.0 mg/dl≤) were identified as predictive factors for shorter PFS using Cox proportional model. Poor PS, high lung immune prognostic index (2≤), low albumin (<3.5mg/dl), and high CRP were identified in multivariate analysis using the log-rank test for early death. In cytokine cohort, high IL6(4ng/dl≤) and high IL-1β(0.5ng/dl) were identified for shorter PFS ([IL-1β]: 3.0 [1.4-4.5] vs 5.9 [1.8-9.6] months, p=0.016, and [IL6]: 1.9 [1.4-2.6] vs. 4.7 [3.0-7.5] months, p=0.008). High IL6 level was identified for the factors of early death after ICI treatment in multivariate analysis (p=0.001). Although IL1β level had no difference in PS and CRP level, IL6 level significantly increased as PS and CRP increased ([PS] 0 to 1, p=0.004, PS1 to 2, p=0.072, and [IL6]: low CRP 19% vs high CRP 86%, p<0.001) . Conclusions:This analysis demonstrated that serum high IL6 level at baseline associated with the early death after initiation anti-PD-1 treatment and shorter PFS in advanced NSCLC. Citation Format: Yuko Oya, Tatsuya Yoshida, Teppei Yamaguchi, Hiroaki Kuroda, Junichi Shimizu, Yoshitsugu Horio, Hirokazu Matsushita, Toyoaki Hida. High serum interleukin 6 level associates with early death after initiation of treatment with PD-1 inhibitor in advanced NSCLC [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 5390.

The New Immunotherapy Combinations in the Treatment of Advanced Non-Small Cell Lung Cancer: Reality and Perspectives.

Background: In the recent years, immunotherapeutics and specifically immune-checkpoints inhibitors have marked a significant shift in the diagnostic and therapeutic algorithm of Non-Small Cell Lung Cancer (NSCLC), allowing us to use immunotherapeutics alone or combined with chemotherapy for a great subset of patients. However, new interesting approaches are being presently investigated, markedly immunotherapy combinations, that is, the use of two or more immunotherapeutics combined.Methods: In particular, the combination of anti-PD-1 nivolumab and anti-CTLA-4 ipilimumab has already provided groundbreaking positive results in the advanced NSCLC and other combinations are currently under investigation.Results: Therefore, this paper aims to provide a comprehensive state-of-the-art review about immunotherapy combination, along with suggestions about future directions. A comprehensive literature search was carried out to identify eligible studies from MEDLINE/PubMed and ClinicalTrials.gov.Conclusion: Nivolumab plus ipilimumab represent the most promising immunotherapy combination for the treatment of advanced NSCLC patients; safety, tolerability and efficacy of new immunotherapeutics (in monotherapy and in immunotherapy combinations) must be further assessed in future studies.

EP1.04-18 Real-World Treatment with Checkpoint Inhibitors: The Swedish Experience

The introduction of checkpoint inhibitors has fundamentally changed the treatment of advanced NSCLC patients. In order to evaluate if the encouraging results from clinical trials translates into the clinical routine and to confirm the value of biomarker testing we evaluated NSCLC patients that were treated with a checkpoint inhibitor in the Uppsala-Gävle health care region between January 2016 and October 2018. Latest patient follow up was done in March 2019. Patient information, including therapy, response rates and survival were obtained from patient records In total, 86 patients, were identified (44 female, median age 71 years; performance status 0=18, 1=45; 2-3=23). 28 patients were treated in the first line setting and 58 patients after previous chemotherapy. Checkpoint inhibitors that were given included pembrolizumab (31), nivolumab (36), atezolizumab (7). Two patients received a combination (durvalumab och tremelimumab). 67 of 86 patients were evaluable for response and of these 23 patients showed progressive disease, 17 stable disease, 22 partial response and 5 complete response. However, most patients that were not evaluable for response either had only 1-2 cycles because of severe side effects or died early independent from treatment. Thus, for all patient treated with at least one course of checkpoint inhibitors response rate were lower (SD:20%; PR:26% and CR:6%). PD-L1 analysis was done for 69/86 patients (80%). The response (PR or CR) was numerically higher in the group with PD-L1 positivity ≥1% or ≥50% than with negative PD-L1 expression (54% vs 47% vs 13%), although not statistically significant (p=0.11). Median overall survival for patients with PD-L1 <1% was 2.3 years, for patients PD-L1 ≥1% 2.7 years and PD-L1≥50% 3.9 years (log rank-test, p=0.95). In conclusion, the response rates to checkpoint inhibitors in the first and second line were comparable to those observed in clinical trials. We confirmed that patients with low PD-L1 expression are unlikely to respond to checkpoint inhibition.

Gefitinib Plus Chemotherapy Versus Cetuximab Plus Chemotherapy in Patients with Advanced Non-small Cell Lung Cancer: &amp;lt;i&amp;gt;A Network Meta-Analysis&amp;lt;/i&amp;gt;

Recent randomized control trials have revealed the efficacy and safety of gefitinib plus chemotherapy and cetuximab plus chemotherapy on the treatment of advanced non-small cell lung cancer, but little is known about the differences between them lacking of direct evidences. Randomized control trials were selected by formal search of electronic databases (PubMed, Embase, and Cochrane Library) and trials registers on the Internet. This systematic review and meta-analysis is reported in accordance with the Preferred Items for Systematic Reviews and Meta-analysis (PRISMA) Statement and was registered at International Prospective Register of Systematic Reviews. 14 trails were identified finally, with 8 studies about gefitinib plus chemotherapy vs chemotherapy alone and 6 studies about cetuximab plus chemotherapy plus vs chemotherapy alone. For overall survival and progression-free survival, the relative HRs of gefitinib plus chemotherapy vs cetuximab plus chemotherapy were 0.96 (0.81-1.13, p=0.583) and 0.69 (0.45-1.05, p=0.080) on first-line treatment and 1.60 (1.01-2.54, p=0.044) and 0.83 (0.61-1.15, p=0.267) on second-line treatment. For objective response rate and one-year survival rate on first-line treatment, the relative RRs of gefitinib plus chemotherapy vs cetuximab plus chemotherapy were 0.89 (0.69-1.15, p=0.395) and 0.84 (0.72-0.98, p=0.026). For adverse events, the risk of relative RR of leukopenia all grades was 0.73 (0.58-0.91, p=0.006), while other events didn’t exhibit significant differences. Subgroup analysis found that comparing to cetuximab plus chemotherapy, gefitinib plus chemotherapy appeared a better improvement in one-year survival rate of USA advanced NSCLC population [RR=0.83 (0.70-0.99, p=0.042)]. It concluded that, on the treatment of advanced NSCLC patients, the efficacy and safety of gefitinib plus chemotherapy are superior to cetuximab plus chemotherapy on first-line treatment, while the latter may be a better choice as well when it occurs to second-line treatment.

New Dancing Couple: PD-L1 and MicroRNA.

Lung cancer (LC) is the most common cause of cancer death in the world. A great challenge in treating NSCLC is the discovery of advanced, molecular tools to diagnose the disease in early stages as well as the development of immunotherapy. MicroRNAs are regulatory molecules (~20 nt in length) with the ability to regulate the expression of genes. The recently described PD-1 and PD-L1 molecules have great importance for potential use in immunotherapy of many cancers. These molecules are associated with immune checkpoints and provide an opportunity for the treatment of advanced NSCLC patients with synthetic monoclonal antibodies. PD-L1 expression is strictly associated with microRNA function in lung cancer cells. The group of microRNAs related to PD-L1 includes, among others, miR-200, miR-197 or miRNA-34. Expression of these molecules may be useful in lung cancer diagnosis, qualification to anti-PD-1 or anti-PD-L1 antibody therapy and could be a potential therapeutic target. However, studies on PD-L1-related microRNAs are necessary to develop advanced targeted molecular therapies.

KEYNOTE-001: 3-year overall survival for patients with advanced NSCLC treated with pembrolizumab.

9011 Background: Pembrolizumab (pembro) is approved as first-line (1L) treatment for advanced NSCLC patients (pts) with PD-L1 tumor proportion score (TPS) ≥50% and as treatment for previously treated advanced NSCLC pts with PD-L1 TPS ≥1%. Here we present 3-y OS results for pts enrolled in KEYNOTE-001 (NCT01295827), the first trial evaluating pembro in advanced NSCLC pts. Methods: 550 pts received pembro 2 or 10 mg/kg Q3W or 10 mg/kg Q2W until intolerable toxicity, progression, or investigator or pt decision to withdraw. PD-L1 expression was assessed by IHC using the 22C3 antibody. Survival was assessed every 2 mo after treatment discontinuation. Results: 550 advanced NSCLC pts enrolled; 101 were first line (1L), and 449 were previously treated. As of the Sept 1, 2016, data cutoff, median follow-up duration was 34.5 mo (range, 25.7-51.5 mo); 8 (7.9%) 1L pts and 28 (6.2%) previously treated pts were still on treatment. 3-y OS was 26.4% (95% CI, 14.3%-40.1%) in 1L pts and 19% (95% CI, 15.0%-23.4%) in previously treated pts. 3-y OS rate and median OS by PD-L1 status are in the Table. Additional description of the pts with long-term survival, including updated safety data as well as 3-y OS by smoking history, histology, EGFRstatus, and prior radiation therapy, will be presented. Conclusions: Pembro provides promising long-term OS benefit for 1L and previously treated advanced NSCLC pts expressing PD-L1. The current data represent the longest efficacy and safety follow-up for pts with advanced NSCLC treated with pembro. Clinical trial information: NCT01295827. [Table: see text]

Contribution of genetic factors to platinum-based chemotherapy sensitivity and prognosis of non-small cell lung cancer.

Although platinum-based chemotherapy remains the standard treatment for advanced NSCLC patients, clinical outcomes are poor and most patients develop high-grade toxicities. Genetic factors, such as single nucleotide polymorphisms (SNPs) involved in platinum pharmacodynamics, metabolism and mechanism of action, may account for inter-individual differences shown in effectiveness and toxicity. Polymorphisms in genes involved in DNA repair and others such as PI3K/PTEN/AKT and TGF-β pathways have been demonstrated to be associated with response, survival and toxicity in advanced NSCLC patients treated with platinum-based chemotherapy. Other cellular processes, like DNA methylation and proliferation have been connected with clinical outcome for platinum-based chemotherapy regimens through folate metabolism and cytokine signaling. The influence of gene polymorphisms in the NER pathway on clinical outcome has been extensively investigated in advanced NSCLC patients treated with platinum-based chemotherapy but contradictory results have been reported. The most recent and thorough meta-analyses have failed to show an association between ERCC1 C118T/C8092A and ERCC5 rs1047768 polymorphisms and response to platinum based chemotherapy. However, other polymorphisms in ERCC2 (Lys751Gln and Asp312Asn) and ERCC5 (rs2094258 and rs2296147) and have been related with overall survival (OS) and progression-free survival (PFS), respectively. The Arg194Trp and Gln399Arg polymorphisms in XRCC1, have also been extensively investigated. Their effects seem to be dependent on ethnicity, and recent meta-analyses have confirmed an association with response in Asian but not in Caucasian patients. The influence on overall response rate (ORR) of the rs861539 polymorphism in XRCC3, part of (DSB) repair pathway, has also been confirmed in a meta-analysis. Finally, SNPs in genes coding proteins of the p53, PI3K, TGF-β, membrane transporters, gluthatione metabolism enzymes and cytokine pathways have been less extensively investigated. Some polymorphisms have been reported to be associated with toxicity or clinical outcome, but data generally come from a limited number of studies and need to be confirmed.

Systemic treatment of non-small cell lung cancer brain metastases.

In the systemic treatment of brain metastases from non-small cell lung cancer (BMF-NSCLC) chemo- and targeted therapy are used. Response rates after platinum-based chemotherapy, range from 23% to 45%. Development of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs): gefitinib or erlotinib, was an improvement in treatment of advanced NSCLC patients. EGFR mutations are present in 10–25% of NSCLC (mostly adenocarcinoma), and up to 55% in never-smoking women of East Asian descent. In the non-selected group of patients with BMF-NSCLC, the overall response rates after gefitinib or erlotinib treatment range from 10% to 38%, and the duration of response ranges from 9 to 13.5 months. In the case of present activating EGFR mutation, the response rate after EGRF-TKIs is greater than 50%, and in selected groups (adenocarcinoma, patients of Asian descent, never-smokers, asymptomatic BMF-NSCLC) even 70%. Gefitinib or erlotinib treatment improves survival of BMF-NSCLC patients with EGFR mutation in comparison to cases without the presence of this mutation. There is no data on the activity of the anti-EML4-ALK agent crizotinib. Bevacizumab, recombinant humanised monoclonal antibody anti-VEGF, in the treatment of advanced non-squamous NSCLC patients is a subject of intense research. Data from a clinical trial enrolling patients with pretreated or occult BMF-NSCLC proved that the addition of bevacizumab to various chemotherapy agents or erlotinib is a safe and efficient treatment, associated with a low incidence of CSN haemorrhages. However, the efficacy and safety of bevacizumab used for therapeutic intent, regarding active brain metastases is unknown.

Considerations on the Management of EGF Receptor-TKIs For Brain Metastases In EGFR -Mutant Lung Carcinoma Patients

SUMMARY Approximately 20–30% of patients with NSCLC are present with brain metastases. The standard management for brain metastases is radiotherapy. Despite the administration of radiation therapy for brain metastases, the prognosis is still poor. The poor prognosis is related to the progression of extracranial lesions. Therefore, systemic therapy is important to improve survival of patients with brain metastases. EGF receptor-tyrosine kinase inhibitor (EGFR-TKI) is a standard treatment for advanced NSCLC patients with sensitive EGFR mutations and is also effective in controlling brain metastasis in such patients. Upfront EGFR-TKI therapy might be one of the treatment choices for EGFR-mutant NSCLC patients with asymptomatic brain metastases. However, it is unclear whether upfront EGFR-TKI or radiation therapy is more preferable. New EGFR-TKIs and combination with existing EGFR-TKIs and other drugs are being investigated for treatment options. Further investigations are required to determine the future direction for management of EGFR-mutant NSCLC patients with brain metastasis.

Abstract 2927: Rapamycin decreases expression of thymidylate synthase and enhances the response to pemetrexed in preclinical studies and a Phase I/II clinical study of subjects with non-small cell lung cancer

Abstract Non-small-cell lung cancer (NSCLC) accounts for 80-85% of lung cancers and almost half of patients with newly diagnosed NSCLC have metastatic disease. Platinum-based chemotherapy regimens given as first-line treatment for advanced NSCLC patients with metastasis are standard but have modest response rates. Pemetrexed is well tolerated and inhibits several folate-dependent enzymes including thymidylate synthase, TS. Increased expression of TS confers resistance to pemetrexed in vitro and is a predictive factor for poor response to pemetrexed. Rapamycin is a mTOR inhibitor and suppresses protein synthesis. Here, we show that rapamycin decreases endogenous expression of TS in NSCLC cells. The combination of rapamycin and pemetrexed synergistically inhibits NSCLC cell proliferation and enhances the inhibition of 4E-binding protein 1 (4E-BP1) activation that is regulated by mTOR. Although pemetrexed as a single agent upregulated expression of TS, pretreatment with rapamycin suppressed pemetrexed-upregulated TS expression. In vivo, the combination of rapamycin and pemetrexed inhibited the growth of NSCLC xenografts, which correlated with decreased mTOR activity and inhibition of pemetrexed-induced upregulated expression of TS. Based on these preclinical data, we have conducted a Phase I/II clinical trial combining rapamycin and pemetrexed in subjects with relapsed NSCLC. This regimen was well tolerated, and resulted in a 22% partial response rate that is above what is expected for response to single agent pemetrexed (9%). In biomarker analyses, pretreatment with rapamycin decreased the expression of TS in peripheral blood mononuclear cells, which correlated with increased progression free survival. Collectively, these studies identify rapamycin and pemetrexed as an effective combination in NSCLC, and suggest that rapamycin enhances the efficacy of pemetrexed by suppressing TS expression. Citation Format: Shigeru Kawabata, Chun-Te Chiang, Regan M. Memmott, Takefumi Komiya, Joell J. Gills, Phillip A. Dennis. Rapamycin decreases expression of thymidylate synthase and enhances the response to pemetrexed in preclinical studies and a Phase I/II clinical study of subjects with non-small cell lung cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2927. doi:10.1158/1538-7445.AM2014-2927

Current Algorithm for Treatment of Advanced NSCLC Patients: How to Include Active Immunotherapy?

Despite the availability of different treatments for advanced NSCLC, all of them have a palliative intention and a cure for the disease is unlikely. Thus, advanced lung cancer remains as an unmet medical need. Chemotherapy has been used as the therapy of choice for advanced NSCLC patients, but it is mainly limited by the patient’s performance status. More recently, targeted therapies have introduced more specific treatment options that show efficacy in specific niche of patients, but precisely due to their target specificity, they usually provoke early resistance. In addition to these limitations, most of the best drugs currently used for treatment of advanced NSCLC show small increases in patient survival with severe associated toxicity. Novel drugs with low toxicity that could be given chronically to control the advanced disease can make a difference. They could allow the management of advanced cancer as a chronic disease that, even when not cured, it can be controlled for long periods of time offering patients a good quality of life. Active-specific immunotherapy is an area of oncology that is rapidly expanding with encouraging results. Cancer vaccines against many potential targets have shown to increase patient survival in clinical trials at all stages NSCLC, when included as first-line, maintenance, or second-line therapy. Safety of cancer vaccines supposes a new hope for cancer therapy, and this unique characteristic makes it possible to be used in sub-sets of patients that cannot receive other approved treatments because of their high toxicity. In this paper, authors propose how active immunotherapy could be included in the current algorithm for treatment of advanced NSCLC patients.

Final result of phase II study of irinotecan (CPT-11) plus oral S-1 for previously treated advanced NSCLC patients.

e18058 Background: Both CPT-11 and S-1, which contains a prodrug of 5-FU, have moderate activity against NSCLC as a single agent and the combination of these agents have been reported to possess marked synergistic effects and tolerability in several gastrointestinal cancers. So the combination of CPT-11 and S-1 will be a promising alternative for the second line treatment of NSCLC patients. We have previously reported the phase I study of this combination and determined the recommended doses of these agents. This study was conducted as a phase II trial to evaluate the efficacy and safety of CPT-11 and S-1 for NSCLC patients who had previously treated. Methods: :This trial was open-label, multicenter study. NSCLC patients who had received one prior chemotherapy with performance status 0-1 were enrolled. Primary endopoint was response rate and secondary endpoints were progression free survival, overall survival, 1-year survival rate and adverse events. CPT-11 (60mg/m2 on days1, 8) and oral S-1 (80mg/m2/day on days1-14) was administered on every 21 days, maximally 6 cycles. Results: By October 2011, 31 patients were enrolled. Nineteen were adenocarcinoma and 12 were non-adenocarcinoma. The median age was 60 y/o (range 35-74) and the median number of treatment cycles was 4 (range 1-6). The objective response rates were PR 7.7%, SD 61.5% and PD 30.8%. Median PFS, median OS and 1-year survival rate were 2.8 month, 12.6 month and 55%, respectively. Grade 3-4 hematologic toxicities comprised neutropenia (15%), anemia (11%) and thrombocytopenia (3%). Other grade 3-4 non-hematologic toxicities comprised pneumonitis (7%), diarrhea (3%), anorexia (3%), liver dysfunction (3%) and mucosal disability (3%). No treatment related death was observed. Conclusions: Combination of CPT-11 and oral S-1 was moderately effective with acceptable toxicities as a second line treatment for advanced NSCLC patients.

RRM1 and BRCA1 mRNA expression levels and clinical outcome of advanced NSCLC patients treated with cisplatin-based chemotherapy

8097 Background: Platinum-based chemotherapy is the standard treatment for advanced NSCLC patients. RRM1 and BRCA1 are important regulators of chemosensitivity of NSCLC. Methods: Stage IIIb/IV NSCLC patients were given cisplatin-based chemotherapy based upon expression levels of RRM1 and BRCA1 mRNA in the tumor. Expression levels of the two genes were determined by real-time PCR and cut-off points were reported in our previous study. The patients with low expression of RRM1 were treated with gemcitabine/cisplatin up to 4 cycles. The others were treated with vinorelbine or paclitaxel plus cisplatin up to 4 cycles. After the chemotherapy, the patients were followed every 6 weeks up to disease progression and then every 3 months up to death. Results: 90 chemonaive, stage IIIB/IV, PS 0–1 NSCLC patients were enrolled. Age 60 (40–78) yrs old, male/female: 73/27%; adenocarcinoma/squamous/adeno-squamous/undefined NSCLC: 49/33/11/7%;,stage IIIb/IV: 13/87%. Overall response rate was 41.1%, stable disease 42.2%, progressive disease 16.7%. Disease was not progressive in 33 patients. Median TTP was 5 months. Response rate and TTP were better in those with low RRM1 expression ( Table ). Toxicity of the chemotherapy was acceptable. Overall survival will be reported in the conference. Conclusions: RRM1 and BRCA1 mRNA expression levels in non-small cell lung cancer are associated with clinical outcome to cisplatin-based chemotherapy. Prospective studies are ongoing to evaluate the role of the two genes in tailoring chemotherapy in our center. [Table: see text] No significant financial relationships to disclose.

Acceptable safety of bevacizumab therapy in patients with brain metastases due to non-small cell lung cancer

8043 Background: Bevacizumab (Bv) + carboplatin/paclitaxel received FDA approval in 10/06 for improving survival in first-line treatment of advanced NSCLC patients (pts) without brain metastases (m...