Combination In Non-small Cell Lung Cancer Research Articles

Efficacy and safety of the combination of paclitaxel, cisplatin and bevacizumab for the treatment of non-small cell lung cancer

Purpose: To investigate the efficacy and safety of the combined use of paclitaxel, cisplatin, and bevacizumab for the treatment of non-small cell lung cancer (NSCLC). Methods: 98 NSCLC patients who received therapy at Hainan Hospital of Traditional Chinese Medicine, Changsha, China from January 2018 to December 2022 were retrospectively analyzed. The 45 patients who received paclitaxel and cisplatin injections were enrolled in a control group while 53 patients who received additional chemotherapy with bevacizumab injection were enrolled in a study group. Levels of vascular endothelial growth factor (VEGF), and basic fibroblast growth factor (bFGF) were compared before and after treatment. Furthermore, the efficacy and incidence of adverse reactions were evaluated and compared between the two groups. Results: There was no significant inter-group difference in VEGF and bFGF levels (p > 0.05) before treatment. There was a significant reduction in VEGF and bFGF levels in the study group compared to control group (p < 0.05). The study group showed a significantly higher total remission rate compared to control group (p < 0.05). Furthermore, there was no significant difference in the incidence of adverse reactions between the two groups (p > 0.05). Also, age, tumor, node, metastasis (TNM) stage, metastasis, and smoking history are risk factors that influence patient prognosis. Conclusion: Combination of paclitaxel, cisplatin and bevacizumab demonstrates significant efficacy in the treatment of NSCLC. The combination lowers VEGF and bFGF levels without worsening adverse reactions. Future large population studies would be required to obtain a more detailed and comprehensive outcome on this combination in NSCLC.

Durvalumab and taxane family combination therapy enhances the antitumoral effects for NSCLC: An in vitro study.

Immunotherapy has lately become the most preferred cancer treatment method, and for non-small cell lung cancer (NSCLC) first-line treatment, there are many immunotherapy options. This study aimed to assess the effectiveness and toxicity of paclitaxel (PTX), docetaxel (DTX) chemotherapy, immune checkpoint inhibitor treatment (durvalumab; DVL), and their combination in NSCLC. A-549 cells were treated with DVL in combination with PTX and DTX (a quarter of the IC50 ) to investigate their anticancer effects on these cells. The MTT assay, wound healing tests, and double-staining with Annexin V/PI were used to assess the cell viability, apoptosis, and migration. The results showed that a combination of 0.35 mg/mL DVL with 6.5 μg/mL PTX and 1.75 μg/mL DTX produced a synergistic effect with CI values of 0.88, 0.37, and 0.81, respectively. Moreover, the PTX + DTX + DVL combination led to a significantly increased apoptotic rate up to 88.70 ± 3.39% in the A549 cell line compared to monotherapy (p < .001). In addition, we found that the combination therapy with these agents increased the expression level of Bax, Cas-3, p53, and Bax/Bcl-2 ratio in all experimental groups. In conclusion, the results suggest that combining anti-PD-L1 antibody therapy with chemotherapy may provide a promising approach to enhance treatment outcomes and be a potentially efficacious strategy for treating NSCLC patients. Further research and clinical investigations are needed to elucidate the underlying molecular mechanisms and validate the therapeutic potential of these compounds in vivo.

Abstract 3878: Targeting Hippo-YAP, BRD4 and RAS-MAPK interplay in lung cancer to forestall drug resistance

Abstract Introduction: Identifying parallel survival pathways or compensatory mechanisms that limit the response to targeted therapy is critical to discover effective combinatorial strategies for the treatment of lung cancer and to prevent emergence of drug resistance Results: Using combination drug screening in a panel of cell line models of non-small cell lung cancer (NSCLC), we identified the tumor suppressor STK11 (aka LKB1) as a molecular biomarker of sensitivity to BET and RAS-MAPK pathway inhibitors combination in NSCLC. We found a small molecule inhibitor of BET (bromodomain and extra terminal) family proteins (BRD4, 3, 2), PLX51107, suppressed BRAF and KRAS mutant NSCLC cell proliferation and in combination with RAS (KRAS G12C), RAF or MEK inhibitor led to pronounced loss in cell viability with potent MYC downregulation and synergistic apoptosis induction in vitro and potent tumor regression or stasis in vivo in several KRAS mutant CDX and PDX mouse models of NSCLC. However, BRAF and KRAS mutant NSCLC cells with co-occurring mutations in STK11 were resistant to BET and RAS, RAF or MEK co-inhibition. To unravel the underlying mechanism of resistance to BET and RAS-MAPK inhibitors upon STK11 loss we modeled STK11 deficiency in BRAF and KRAS mutant NSCLC cells and tumors. We found that STK11 loss creates an unprecedented dependence on YAP/TEAD TFs. STK11 silencing in BRAF and KRAS mutant NSCLC cells resulted in nuclear transfer/activation of the HIPPO pathway effector, YAP, upregulation of the YAP target BIRC5 (aka Survivin) and rescued the synthetic lethality due to BET and RAS, RAF or MEK co-inhibition. Phenocopying STK11 loss, constitutively active YAP (YAP5SA), but not transcriptionally inactive YAP (YAPS94A), mitigated the deleterious effects of BET and RAS, RAF or MEK co-suppression in BRAF and KRAS mutant NSCLC cells with potent upregulation of the pro-survival factor BIRC5. Conversely, we found that co-silencing YAP or TEADs with BETs re-sensitized BRAF and KRAS mutant NSCLC cells with co-occurring mutations in STK11 to BET and RAS-MAPK inhibitors combination and caused synthetic lethality. Conclusion: This study uncovered a functional interaction between BET proteins, STK11, HIPPO-YAP and RAS-MAPK signaling pathways in lung cancer. These results will help identify combinatorial strategies for treating aberrant RAS-MAPK pathway driven lung cancer more effectively and forestall drug resistance. Citation Format: Nilanjana Chatterjee, Victor Olivas, Wei Wu, Ben Powell, Trever Bivona. Targeting Hippo-YAP, BRD4 and RAS-MAPK interplay in lung cancer to forestall drug resistance. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3878.

Activity of Birinapant, a SMAC Mimetic Compound, Alone or in Combination in NSCLCs With Different Mutations.

Liver kinase B1 (LKB1/STK11) is the second tumor suppressor gene most frequently mutated in non-small-cell lung cancer (NSCLC) and its activity is impaired in about half KRAS-mutated NSCLCs. Nowadays, no effective therapies are available for patients having these mutations. To highlight new vulnerabilities of this subgroup of tumors exploitable to design specific therapies we screened an US FDA-approved drug library using an isogenic system of wild-type (WT) or deleted LKB1. Among eight hit compounds, Birinapant, an inhibitor of the Inhibitor of Apoptosis Proteins (IAPs), was the most active compound in LKB1-deleted clone only compared to its LKB1 WT counterpart. We validated the Birinapant cells response and its mechanism of action to be dependent on LKB1 deletion. Indeed, we demonstrated the ability of this compound to induce apoptosis, through activation of caspases in the LKB1-deleted clone only. Expanding our results, we found that the presence of KRAS mutations could mediate Birinapant resistance in a panel of NSCLC cell lines. The combination of Birinapant with Ralimetinib, inhibitor of p38α, restores the sensitivity of LKB1- and KRAS-mutated cell lines to the IAP inhibitor Birinapant. Our study shows how the use of Birinapant could be a viable therapeutic option for patients with LKB1-mutated NSCLCs. In addition, combination of Birinapant and a KRAS pathway inhibitor, as Ralimetinib, could be useful for patients with LKB1 and KRAS-mutated NSCLC.

Abstract 557: Novel targeted combination therapies active in KRAS mutant non-small cell lung cancer (NSCLC) identified using patient-derived xenografts (PDX)

Abstract PDXs recapitulate histologic features, gene expression patterns, and genomic alterations in human primary tumors, and thus have emerged as robust preclinical models for drug development, molecular characterization of cancers, identification of biomarkers, and strategic development of precision therapy. We tested multiple combinations of small molecule targeted drugs selected on the basis of known NSCLC vulnerabilities for efficacy in NSCLC PDXs with known genotypes. We determined in vivo treatment responses to single agent and combination therapies for pathway targeted therapeutic agents, including the MEK inhibitor trametinib, the MDM2 inhibitor KRT-232, the BCL2/BCL-XL inhibitor navitoclax, and their combinations in 8-23 molecularly annotated NSCLC PDX models. Mice (n=3-5/group) were enrolled into treatment individually when tumors reached 200 mm3 in size, and were treated 5 days/week for 3 weeks. Tumor growth was monitored 2-3 times/week. We used the following criteria to determine treatment responses: 1) Tumor Regression (or partial response): tumor regression ≥ -30% based on tumor volume changes calculated by AUC0-21day or at day 21 after treatment start when compared with baseline (beginning of treatment at day 0); 2) Tumor Growth Inhibition (or stable disease): Tumor growth was significantly suppressed when compared with control (P &amp;lt; 0.05), but no tumor regression was observed, or tumor regression was less than -30% based on tumor volume changes calculated by AUC0-21day or at day 21 after treatment start when compared with baseline; 3) Resistance: Tumor volume changes calculated by AUC0-21day was not significantly different from control group (P&amp;gt;0.05). Our results showed that KRT-232 alone resulted in 15.8% (3/19) tumor regression and 26.3% (5/19) tumor growth inhibition, all in TP53 wild type PDXs. Trametinib alone induced 10% (2/20) tumor regression and 50% (10/20) growth inhibition, respectively. 80% (8/10) of KRAS mutant PDXs responded to trametinib treatment with tumor regression (1/10) or growth inhibition (7/10). Combination therapies of trametinib plus KRT-232 and trametinib plus navitoclax led to improved in vivo anticancer activity over single agent activity in a subset PDX models with KRAS mutations. Tumor regression was observed in 26% (6/23) and 50% (5/10) of trametinib plus KRT-232 and trametinib plus navitoclax treatment groups, respectively. Navitoclax alone did not induce tumor regression in 8 PDX models tested, and navitoclax plus KRT-232 did not lead to significant improvement in activity over single agents in 11 PDXs. Our results show that combination therapies of trametinib plus KRT-232 or navitoclax result in improved efficacy in a subgroup of NSCLC PDX models with KRAS mutations. Clinical trials with these targeted drug combinations in NSCLC are warranted. Citation Format: Xiaoshan Zhang, Ran Zhang, Huiqin Chen, Li Wang, Chenghui Ren, Shuhong Wu, Min Jin Ha, Jeffrey Morris, Yuanxin Xi, Jing Wang, Don L. Gibbons, John V. Heymach, Funda Meric-Bernstam, John Minna, Stephen G. Swisher, Jack A. Roth, Bingliang Fang. Novel targeted combination therapies active in KRAS mutant non-small cell lung cancer (NSCLC) identified using patient-derived xenografts (PDX) [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 557.

5'-nucleotidase cN-II emerges as a new predictive biomarker of response to gemcitabine/platinum combination chemotherapy in non-small cell lung cancer.

A number of pharmacogenetic studies have been carried out in non-small-cell lung cancer (NSCLC) to identify and characterize genes involved in chemotherapy activity. However, the results obtained so far are controversial and no reliable biomarker is currently used to predict clinical benefit from platinum-based chemotherapy, which represents the cornerstone of treatment of advanced NSCLC. This study investigated the expression levels of ERCC1 and of six genes (RRM1, RRM2, hENT1, dCK, cN-II and CDA) involved in gemcitabine metabolism in locally/advanced NSCLC patients treated with gemcitabine/platinum combination. Gene expression was assessed by quantitative-PCR in laser-microdissected specimens and correlated with tumor response. Frequency distribution of responses above and below the median expression level of biomarkers was compared using a two-sided Fisher’s test. 5′-nucleotidase (cN-II) was the only gene differently expressed (p = 0.016) in the responders (complete/partial-response) compared to non-responders (stable/progressive disease). In the multivariate analysis, overexpression of this catabolic enzyme of gemcitabine remained a significant negative predictive factor. Patients with low cN-II had a modest trend toward increased survival, while both survival and progression-free survival were significantly longer in a more homogenous validation cohort of 40 advanced NSCLC (8.0 vs. 5.1 months, p = 0.026). Moreover, in vitro studies showed that silencing or pharmacological inhibition of cN-II increased the cytotoxicity of gemcitabine. This is the first study demonstrating the role of cN-II as a predictor of response to gemcitabine/platinum combinations in NSCLC. Its validation in prospective studies may improve clinical outcome of selected patients.

Nivolumab (nivo) + nab-paclitaxel (nab-P) + carboplatin (C) in patients (pts) with non-small cell lung cancer (NSCLC): Interim results from a multicenter phase I study.

9095 Background: Despite success of single-agent immune checkpoint inhibitors, an unmet therapeutic need remains in pts with NSCLC. Chemotherapy and immunotherapy may have synergistic antitumor activity, but safety and efficacy need to be established. Here, we present interim results for pts with NSCLC (Arm C) from the phase I safety trial of nivo + nab-P in pancreatic cancer (± gemcitabine), NSCLC (+ C), and metastatic breast cancer. Methods: Part 1 evaluated potential dose-limiting toxicities (DLTs) before Part 2 expansion. Chemotherapy-naive pts with histologically/cytologically confirmed stage IIIB/IV NSCLC received 4 cycles of nab-P 100 mg/m2d 1, 8, 15 + C AUC 6 d 1 + nivo 5 mg/kg d 15 of each 21-d cycle; in cycles 5+, nivo was continued as maintenance monotherapy. Primary endpoints: number of pts with DLTs (Part 1) and percentage of pts with grade 3/4 treatment-emergent adverse events (TEAEs) or treatment discontinuation due to TEAEs (Parts 1 and 2). DLT-evaluable pts included those who received ≥ 2 complete nivo cycles and remained on study for 14 d after the last nivo dose in cycle 2, received ≥ 1 nivo dose and discontinued due to DLT before completing 2 nivo cycles, or experienced equivocal DLT after ≥ 1 nivo dose. Secondary endpoints included safety, PFS, OS, DCR, ORR, and DOR. Results: All pts (n = 22) received nab-P/C; results for nivo-treated pts (n = 20) are presented. Of the nivo-treated pts, the median age was 66 y (55% ≥ 65 y), 75% were female, 80% were white, and 70% had ECOG PS 1. More pts had adenocarcinoma (50%) than squamous cell carcinoma (35%; 10% other, 5% data pending). No DLTs reported (5 DLT-evaluable pts). Most common grade 3/4 TEAEs were neutropenia (45%) and anemia (35%). No grade 3/4 immune-related colitis or pneumonitis reported. Best ORR (RECIST v1.1) was 50% (1 CR [unconfirmed, 5%] and 9 PRs [45%]; 6 pts had SD [30%]; 4 pts had PD [20%]). Best ORR by histology: squamous, 71%; nonsquamous, 54%. Median PFS was 10.5 months (squamous, 10.5 months; nonsquamous, not evaluable). Conclusions: Results demonstrated safety of the nivo + nab-P/C combination in NSCLC with no unexpected safety signals. Preliminary efficacy results are promising. (NCT02309177) Clinical trial information: NCT02309177.

A phase 1B study of SNX-5422 plus carboplatin (C) and paclitaxel (P) in patients with advanced non-small-cell lung cancer (NSCLC).

e20622 Background: SNX-5422 is an orally bioavailable pro-drug of SNX-2112, a highly potent and selective heat shock protein (Hsp) 90 inhibitor with synergy with platinum and paclitaxel. In this study, SNX-5422 + C/P followed by SNX-5422 maintenance therapy was examined in patients (pts) with NSCLC. Preliminary study results from the first 12 pts established the maximum tolerated dose (MTD) for SNX-5422 as 100 mg/m2 for the combination, with one G3 dose limiting toxicity (DLT) of diarrhea. The updated efficacy and safety results following enrollment completion (N = 20) are presented. Methods: Eligible pts had NSCLC (EGFR wild-type or non-sensitizing mutation) and ≤1 prior line of chemotherapy. Pts received C (AUC 5) and P (175 mg/m2) every 3 weeks for up to 6 cycles and SNX-5422 every other day (starting at 50 mg/m2) for 21 of 28 days, with a standard 3+3 dose escalation design during the combination, followed by SNX-5422 (100 mg/m2 every other day) monotherapy for maintenance until disease progression. Results: Twenty pts with NSCLC (pathology assessment: 18 adenocarcinoma, 2 squamous cell carcinoma) were enrolled (mean age, 59 yrs), with 19 evaluable for efficacy. Best response was partial response in 37% (7/19) of pts, stable disease in 58% (11/19) of pts, and progressive disease in 5% (1/19) of pts. Twelve of the 19 pts (63%) continued maintenance SNX-5422 monotherapy, and 7 of the 12 (58%) received therapy for ≥8 cycles. Four pts had G3 DLTs with combined therapy (considered possibly related to ≥1 agent): diarrhea (1 pt discontinued), increased alanine aminotransferase/aspartate aminotransferase (ALT/AST) (1), nausea, vomiting, and diarrhea (1), and peripheral sensory neuropathy (1). The most common adverse events considered possibly related to the combination were diarrhea (n = 14), nausea (n = 10), fatigue (n = 8), alopecia (n = 5), and vomiting (n = 5), and the majority of these events were G1/2. Conclusions: SNX-5422 added to C/P was well-tolerated at doses up to 100 mg/m2, and preliminary efficacy of this combination in NSCLC warrants further study. Clinical trial information: NCT01892046.

Vinflunine for the treatment of non-small cell lung cancer

ABSTRACTIntroduction: Vinflunine belongs to the class of vinca alkaloids and acts by disrupting the microtubule dynamics during cell cycle; this agent is currently available for previously treated advanced transitional cell carcinoma in Europe. The aim of this invited review is to evaluate the potential role of vinflunine for the treatment of non-small cell lung cancer (NSCLC).Areas covered: The potential role of vinflunine in NSCLC is discussed on the basis of the available data, including full papers and meeting abstracts. Relevant preclinical studies describing the pharmacological properties of vinflunine are also included. The review also summarizes clinical studies, including phase I trials involving NSCLC among other tumors as well as phase II/III trials specifically addressing this malignancy. Additionally, the safety profile and the current regulatory status of vinflunine is discussed.Expert opinion: Vinflunine is active as single agent and as part of platinum-based combinations in NSCLC. It results non-inferior to docetaxel in a randomized phase III trial including previously treated NSCLC patients; additionally, its safety profile is generally considered manageable. Ultimately, further studies are needed to confirm the role of vinflunine in NSCLC, in consideration of the evolving evidence regarding targeted therapies and immune check-point inhibitors.

Abstract B14: Erlotinib-cisplatin combination inhibits growth and angiogenesis via c-MYC and HIF-1a in EGFR mutated lung cancer

Abstract Introduction: Combination treatment for non-small cell lung cancer (NSCLC) is becoming more popular due to the anticipation that it may be more effective than single drug treatment. In addition, there are efforts to genetically screen patients for specific mutations in light of attempting to administer specific anticancer agents that are most effective. In this study, we evaluate the anticancer and anti-angiogenic effects of low dose erlotinib-cisplatin combination in NSCLC in vitro and in vivo. Method: Human lung adenocarcinoma cell lines (A549, NCI-H292, H1650, PC9, H3255 and HCC827) were utilized. Each cell line had four treatment groups: control, erlotinib, cisplatin, and erlotinib -cisplatin combination. Alamar Blue Assay was utilized to evaluate for in vitro cell death following two day treatments. PC9 cells were used for in vivo experiments. Erlotinib and/or cisplatin treatments were injected directly into the tumor and tumor measurements were made every 2 days for a total of 14 days. Western blot analysis was performed to measure the level of VEGF, CD31, c-MYC, and HIF-1a for both in vitro and in vivo samples. Hematoxylin and eosin (H&amp;E) staining and 3,3'-Diaminobenzidine (DAB) staining for CD31 were done on tumor samples. In vivo angiogenesis assay was tested though the use of the matrigel plug assay. Microvessel density quantification was quantified using ImageJ, and the percentage area of CD31 was calculated by imaging four different 20x high power fields through hotspot method. Results: In NSCLC cells harboring epidermal growth factor receptor (EGFR) mutations, combination erlotinib-cisplatin treatment led to synergistic cell death, but there minimal efficacy in NSCLC cells with wild-type EGFR. In xenograft models, combination treatment also demonstrated greater inhibition of tumor growth compared to individual treatment. The anti-tumor effect observed was secondary to the targeting of angiogenesis, evidenced by decreased VEGF levels, and decreased levels of CD31 and microvessel density. Combination treatment targets angiogenesis through down-regulation of the c-MYC/HIF-1a pathway. In fact, cell lines with EGFR exon 19 deletions expressed high basal levels of c-MYC and HIF-1a and correlate with robust responses to combination treatment. Conclusion: These results suggest that low dose erlotinib-cisplatin combination exhibits its anti-tumor activity by targeting angiogenesis through the modulation of the c-MYC/HIF-1a/VEGF pathway in NSCLC with EGFR exon 19 deletions. These findings may have significant clinical implications in patients with tumors harboring EGFR exon 19 deletions as they may be particularly sensitive to this regimen. Citation Format: Jasmine G. Lee, Reen Wu. Erlotinib-cisplatin combination inhibits growth and angiogenesis via c-MYC and HIF-1a in EGFR mutated lung cancer. [abstract]. In: Proceedings of the AACR Special Conference: Tumor Angiogenesis and Vascular Normalization: Bench to Bedside to Biomarkers; Mar 5-8, 2015; Orlando, FL. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl):Abstract nr B14.

Erlotinib-Cisplatin Combination Inhibits Growth and Angiogenesis through c-MYC and HIF-1α in EGFR-Mutated Lung Cancer In Vitro and In Vivo

Combination treatment for non–small cell lung cancer (NSCLC) is becoming more popular due to the anticipation that it may be more effective than single drug treatment. In addition, there are efforts to genetically screen patients for specific mutations in light of attempting to administer specific anticancer agents that are most effective. In this study, we evaluate the anticancer and anti-angiogenic effects of low dose erlotinib-cisplatin combination in NSCLC in vitro and in vivo. In NSCLC cells harboring epidermal growth factor receptor (EGFR) mutations, combination erlotinib-cisplatin treatment led to synergistic cell death, but there was minimal efficacy in NSCLC cells with wild-type EGFR. In xenograft models, combination treatment also demonstrated greater inhibition of tumor growth compared to individual treatment. The anti-tumor effect observed was secondary to the targeting of angiogenesis, evidenced by decreased vascular endothelial growth factor (VEGF) levels and decreased levels of CD31 and microvessel density. Combination treatment targets angiogenesis through down-regulation of the c-MYC/hypoxia inducible factor 1-alpha (HIF-1α) pathway. In fact, cell lines with EGFR exon 19 deletions expressed high basal levels of c-MYC and HIF-1α and correlate with robust responses to combination treatment. These results suggest that low dose erlotinib-cisplatin combination exhibits its anti-tumor activity by targeting angiogenesis through the modulation of the c-MYC/HIF-1α/VEGF pathway in NSCLC with EGFR exon 19 deletions. These findings may have significant clinical implications in patients with tumors harboring EGFR exon 19 deletions as they may be particularly sensitive to this regimen.

Phase I/II trial of combination nab-paclitaxel and pemetrexed in advanced solid tumor patients (pts) with emphasis on non-small cell lung cancer (NSCLC).

e19147 Background: Despite advances in targeted therapies, there is an ongoing need to develop new and effective cytotoxic drug combinations in NSCLC. Preclinical evaluation has demonstrated additive cytotoxicity of pemetrexed and taxanes. We evaluated the safety and efficacy of combining nab-paclitaxel (nP) and pemetrexed (P) in solid tumors with a focus on NSCLC for the phase II expansion. Methods: A 3+3 dose-escalation design was used to determine the maximum tolerated dose (MTD) and the recommended phase II dose (RP2D). Three dose levels were tested: P 500 mg/m2 day 1 plus nP on day 1 at doses of 180, 220, and 260 mg/m2 every 21 days. Dose limiting toxicity (DLT) in cycle 1 was defined as: grade 4 platelets or grade 3 platelets with bleeding, neutropenia with fever or documented infection, or other grade ≥ 3 non-heme toxicity. Phase II eligibility included advanced NSCLC, ≤ 2 line prior therapy, PS 0-1, adequate organ function. Primary endpoint for further study was response rate (RR) ≥ 25%. Results: Planned dose escalation during the Phase I portion was completed without reaching the MTD. The RP2D was P 500 mg/m2 and nP 260 mg/m2. The phase II portion accrued 37 pts before early closure due to increasing use of first-line pemetrexed/platinum doublet therapy in non-squamous NSCLC. Phase II patient characteristics: median 63 (45-77); M:F 23:14; median cycles 3. In 31 assessable patients: 5 PR, 12 SD and 14 PD. Efficacy: RR =14%; disease control rate (DCR) = 46%; median survival time (MST) = 8.7 months. Pts in the DCR group had a MST of 15.4 vs 4 months in the PD group (p=0.02). Conclusions: P 500 mg/m2 day 1 with nP 260 mg/m2 was feasible and well tolerated. The phase II component demonstrated activity in second-line therapy of advanced NSCLC. Practice patterns have evolved; so further trials of this regimen are not planned. Clinical trial information: NCT00470548.

Molecular Mechanisms and Modulation of Key Pathways Underlying the Synergistic Interaction of Sorafenib with Erlotinib in Non-Small-Cell-Lung Cancer (NSCLC) Cells

Combination of drugs with different targets is a logical approach to overcome multilevel cross-stimulation among key pathways in NSCLC progression such as EGFR, K-Ras and VEGFR. The sorafenib-erlotinib combination showed clinical activity and acceptable safety. Therefore, we evaluated mechanisms underlying sorafenib-erlotinib interaction in seven NSCLC cell lines selected for their heterogeneous pattern of EGFR and Raf-kinase-inhibitor protein (RKIP) expression, and EGFR/K-Ras mutations. Pharmacologic interaction was studied using MTT/SRB assays and the combination index (CI) method, while effects on EGFR, Erk1/2 and Akt phosphorylation, cell cycle and apoptosis were studied with western-blot, ELISA, and flow cytometry. Intracellular drug concentrations were measured with LC-MS/MS, whereas kinase activity profiles were generated on tyrosine kinase peptide substrate arrays. Synergism was detected in all cell lines, with CIs < 0.6 in K-Ras mutated A549, SW1573 and H460, as well as in H1975 (EGFR-T790M) cells. Sorafenib slowed cell cycle progression and induced apoptosis, which was significantly increased in the combination. Moreover, sorafenib reduced Akt/ERK phosphorylation in erlotinib-resistant cells, associated with significant RKIP up-regulation. No direct drug interaction was detected by LC-MS/MS measurement, while lysates from A549 and H1975 cells exposed to erlotinib+sorafenib showed a significant inhibition in the phosphorylation of 16 overlapping peptides, including sites from RAF, VEGFR2, PDGFR, CDK2 and SRC, suggesting new markers to identify NSCLC patients who are likely to respond to this treatment. In conclusion, several mechanisms, including apoptosis-induction, modulation of expression/phosphorylation of RKIP and crucial kinases contribute to erlotinib-sorafenib synergistic interaction and should be evaluated in future trials for the rational development of this combination in NSCLC.

Activity and tolerability of afatinib (BIBW 2992) and cetuximab in NSCLC patients with acquired resistance to erlotinib or gefitinib.

7525^ Background: Despite initial responses to reversible epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors, (erlotinib or gefitinib), all non-small cell lung cancer (NSCLC) patients with EGFR-sensitizing mutations experience disease progression. This “acquired resistance” (AR) is associated with a second site exon 20 EGFR T790M mutation (M) in >50% of cases. No therapy, including the anti-EGFR antibody cetuximab plus erlotinib, has proven effective in treating AR (Janjigian YY. Clin Cancer Res; Epub Jan 2011). Preclinical data suggest afatinib, a potent ErbB family blocker, is active in T790M M cell lines such as H1975. Combined EGFR targeting with afatinib and cetuximab has induced near complete responses in T790M transgenic murine models. This study assesses safety and preliminary efficacy of this combination in NSCLC. Methods: NSCLC patients with clinically defined AR (Jackman D. J Clin Oncol 2010;28:357) received oral afatinib 40 mg daily with escalating dose cohorts of biweekly cetuximab at 250 and 500 mg/m2. Patients receiving the recommended Phase II dose (RP2D) were evaluated for objective response. Acquisition of tumor tissue after emergence of AR was mandated. Results: Of 26 treated patients, 22 received the predefined maximum dose (RP2D: afatinib 40 mg + cetuximab 500 mg/m2). Median time on erlotinib or gefitinib at study entry was 2.4 years. No dose-limiting toxicity was observed. Common adverse events were grade 1/2 rash (35/46%) and diarrhea (50/19%), respectively, and three patients (11.5%) had grade 3 rash. Disease control was observed in all patients enrolled at RP2D (tumor size reduction up to 76%; treatment duration up to 5+ months so far). Confirmed partial responses (PRs) were seen in 8/22 evaluable patients (36%, 95% confidence interval [CI]: 0.17–0.59), including 4/13 (29%) confirmed PRs in T790M+NSCLC. Enrollment has now begun in an 80-patient expansion cohort. Conclusions: Combined EGFR targeting with afatinib and cetuximab is tolerable at RP2D. Owing to encouraging clinical activity in AR to prior erlotinib or gefitinib, the study has been expanded. Elucidating mechanisms underlying regression in T790M+ and T790M– patients is critical.

Pemetrexed Plus Bevacizumab for Second-Line Therapy of Non–Small-Cell Lung Cancer: The Importance of Patient Selection

TO THE EDITOR: Pemetrexed is an antifolate drug that inhibits multiple enzymes involved in purine and pyrimidine synthesis, but thymidylate syntase is its primary target. Dihydrofolate reductase and glycinamide ribonucleotide formyl transferase are its secondary targets. The differential expression of thymidylate syntase between adenocarcinoma and squamous cell carcinoma could explain the differential efficacy according to histology in non–small-cell lung cancer (NSCLC). 1 The results of two published phase III trials with pemetrexed versus docetaxel 2 and cisplatin plus pemetrexed versus cisplatin plus gemcitabine 3 were consistent with those of the phase III study comparing pemetrexed with placebo. 4 Bevacizumab is a humanized monoclonal antivascular endothelial growth factor antibody with demonstrated significant clinical benefit in first-line treatment of nonsquamous NSCLC. This was observed in the phase III trials with the combination of carboplatin plus paclitaxel and bevacizumab and with cisplatin plus gemcitabine and bevacizumab over the same combinations without this antibody. 5-6 On the basis of these studies, tumor histology should be carefully assessed when selecting treatment options for patients with advanced NSCLC. Both pemetrexed and bevacizumab have demonstrated significant clinical activity for nonsquamous NSCLC. In the recent published North Central Cancer Treatment Group and Southwest Oncology Group study N0426, Adjei et al 7 evaluated the combination of pemetrexed and bevacizumab as second-line therapy for NSCLC. Then they evaluated the impact of three single nucleotide polymorphisms (SNPs) in genes that code proteins linked to pemetrexed activity: SLC19A1 codes a protein responsible for the transport,FPGS codes a protein linked to activation, andGGH codes a protein important for inactivation. The authors reported a promising progression-free survival of 4 months but no correlation of these polymorphisms with efficacy and toxicity. They concluded that the small sample size and the bevacizumab were confounding variables. The article was unclear about the histologic types of the patients’ samples, and this is a main issue when evaluating the clinical importance of any treatment combination in NSCLC. We should evaluate

The Clinical Applications of Combined HBV Approach to Chemotherapy for Non-small Cell Lung Cancer while Adoption of Antivirus Therapy.

Lung cancer has become the most serious malignant tumor threating the human beings' health and life, and chemotherapy postponing or suspending contributes to one of the prognostic causes. In this research, we try to explore the importance of combined HBV approach to chemotherapy for non-small cell lung cancer while adoption of antivirus therapy. Select 60 cases of patients suffering from combined HBV IIIA non-small cell lung cancer, who were divided into two groups, the experimental group and control group. For the experimental group, a NP-approach chemotherapy was adopted along with addition of Lamivudine (NP+Lam group), while for the control group, only NP-approach was applied (NP group), in order to compare whether there would be any statistical difference between the two groups in terms of damage to the functions of liver and immune system as well as reactivation of HBV. The blood serum of the patients from both of the two groups rises, with the NP group being prominently higher than the NP+Lam group on an average (P<0.05). Upon completion of the chemotherapy, the percentage of CD3(+)/CD4(+) and CD4(+)/ CD8(+) decreases. As the percentage of CD8(+) increases, the differences in these items turn out to be marked (P<0.05). The reactivation of HBV and postponing or suspending of the chemotherapy are also find prominently different (P<0.05). It is necessary to use antiviral therapy while the patents with combined non-small cell lung cancer receive therapy.

A Phase II Study of Irinotecan and Carboplatin in Advanced Non-small Cell Lung Cancer with Pharmacogenomic Analysis: Final Report

We conducted a phase II study of carboplatin and irinotecan in patients with advanced non-small cell lung cancer (NSCLC). In addition, we studied the correlation between certain genotypes of enzymes involved in irinotecan metabolism with efficacy and toxicity. Patients with stage IIIB, IV, or recurrent NSCLC received a combination of irinotecan and carboplatin every 3 weeks at a dose of 200 mg/m2 and area under the curve of 5. Pharmacogenomic analysis was performed on several genes of interest (ABCB1, CYP3A4*1B, ERCC2, GSTP1, UGT1A1*28, and XRCC1). Forty-two patients enrolled between December 2001 and January 2004. Six patients achieved partial responses (14%), and 19 (45%) had stable disease. The median progression-free survival was 6.9 months. The median overall survival was 11.7 months, with 1-year overall survival of 42%. The most common toxicities were hematologic; grade 3 or 4 neutropenia was experienced by 26 patients (62%) during treatment, and 15 patients (36%) experienced grade 3 or 4 thrombocytopenia. The homozygous UGT1A1*28 (7/7) genotype was associated with grade 4 neutropenia in three of four patients (75%), but only eight out of 30 (27%) with 6/6 or 6/7 genotypes experienced grade 4 neutropenia (p = 0.09). None of the 14 patients with the GSTP1 I105V A/A genotype had a partial response, as opposed to five out of 19 (26%) of those with the G/A or G/G genotypes (p = 0.057). The combination of carboplatin and irinotecan is an active combination in NSCLC, with response rates comparable with other platinum-containing doublets. Further studies with irinotecan should incorporate prospective pharmacogenomic analysis to identify markers for response and toxicity.

Optimizing chemotherapy and targeted agent combinations in NSCLC

Chemotherapy extends life and provides symptom palliation for patients with advanced non-small cell lung cancer (NSCLC). Numerous trials have been conducted that evaluate a variety of doublet regimens, but the majority of trials have found equal efficacy among the treatment arms. Indeed, a plateau appears to have been reached with respect to survival associated with traditional cytotoxic drug regimens. It was initially hoped that the addition of novel targeted agents to conventional chemotherapy would produce significant survival benefits for patients with advanced NSCLC; however, most trials have failed to show such a benefit. There is no survival benefit associated with adding erlotinib or gefitinib to a chemotherapy regimen, although there is a significant improvement in survival associated with erlotinib monotherapy in the second- and third-line advanced disease setting. In contrast, the results of E4599 clearly demonstrate that the addition of bevacizumab to paclitaxel-carboplatin chemotherapy extends survival in a select group of patients with non-squamous cell NSCLC. E4599 also represents a rational approach to drug development that could be modeled in other trials, namely, the use of a large, well designed, randomized trial prior to beginning a traditional phase II approach. This strategy can lead to the identification of subgroups most likely to benefit, as well as those that might experience increased toxicity, such as patients with squamous cell carcinoma treated with bevacizumab. Another approach to optimizing targeted therapy involves selecting a chemotherapy regimen with the greatest potential for synergy based on preclinical modeling. Because docetaxel has been shown to prolong survival in second-line treatment, a number of novel agents have been combined with docetaxel in order to improve efficacy. Alternatively, investigators have sought to combine novel agents with either carboplatin-paclitaxel or cisplatin-gemcitabine in first-line treatment. A number of trials are underway that combine these agents with inhibitors of the epidermal growth factor receptor (EGFR), vascular endothelial growth factor (VEGF), and the proteasome, as well as COX2 inhibitors, and novel immunomodulators.

Bortezomib-Based Combinations in the Treatment of Non–Small-Cell Lung Cancer

Lung cancer is the most common cause of cancer-related death among men and women in the United States. Current trials are focusing on the integration of novel therapeutic agents into current non-small-cell lung cancer (NSCLC) treatment paradigms. Bortezomib, a small-molecule proteasome inhibitor, has single-agent activity in NSCLC and in combination with agents commonly used in NSCLC. This article will review the rationale and preclinical data supporting bortezomib combinations and the clinical trials with bortezomib alone and in combination in NSCLC to date.

Phase II trial of oral vinorelbine in combination with cisplatin followed by consolidation therapy with oral vinorelbine in advanced NSCLC

Among the cytotoxic agents commonly combined with cisplatin in the treatment of advanced NSCLC, vinorelbine has led to significant outcome improvements. Adding more than four cycles of the combination regimen increase toxicities. The availability of an oral form of vinorelbine appeared as a particularly convenient way to provide a consolidation treatment to patients who have achieved an objective response or stable disease. This multi-centre phase II open-label, non-comparative study was designed to evaluate the treatment with four cycles of the combination chemotherapy with oral vinorelbine at the dose of 60 mg/m2 on day 1 and day 8 for the first cycle and then 80 mg/m2 plus cisplatin 80 mg/m2 on day 1 every 3 weeks followed for patients with objective response or stable disease by consolidation therapy with oral vinorelbine at 80 mg/m2 weekly on patients with unresectable localised or metastatic non-small-cell lung cancer (NSCLC). The primary endpoint was tumor response. The secondary objectives were progression free-survival, overall survival and toxicity assessment. Visual analogue scales (VAS) filled by the patients were also used to evaluate subjective changes under treatment, reflecting patients' clinical benefit. Fifty-six patients enrolled into the study from April 2001 to April 2002 received the combination regimen. Twenty-five patients (43.9%) also received the subsequent consolidation treatment. Partial tumor responses were obtained in 13 patients (26.5%, 95% CI 15.0-41.1) of 49 evaluable patients. Stable disease was observed in 22 (44.9%) of patients. The median duration of response was 6 months (95% CI 4.3-8.2). The median progression free-survival was 4.2 months (95% CI 2.8-6). The median overall survival time was 10 months (95% CI 7.4-14) and the 1 year survival was 42.6%. The main toxicities recorded were haematological. Grade 3 and 4 neutropenia were observed in 16 patients (29.1%). Nausea, vomiting and fatigue were the major non-haematological toxicities reported. Among the symptoms recorded by the patients on VAS scales (appetite, fatigue, pain, cough, dyspnea, haemoptysis), except anorexia, all symptoms were improved during the combination therapy and in the consolidation phase. This study confirms that the efficacy of the cisplatin/oral vinorelbine combination in NSCLC is comparable to cisplatin/I.V. vinorelbine. This study also suggests that consolidation therapy with vinorelbine alone may probably prolong the efficacy of the combination regimen. The convenience offered to patients by an oral form of vinorelbine is a definite asset for consolidation therapy.