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PURPOSE We present 5-year results from CheckMate 227 Part 1, in which nivolumab plus ipilimumab improved overall survival (OS) versus chemotherapy in patients with metastatic non–small-cell lung cancer, regardless of tumor programmed death ligand 1 (PD-L1) status. METHODS Adults with stage IV/recurrent non–small-cell lung cancer without EGFR mutations or ALK alterations and with tumor PD-L1 ≥ 1% or < 1% (n = 1739) were randomly assigned. Patients with tumor PD-L1 ≥ 1% were randomly assigned to first-line nivolumab plus ipilimumab, nivolumab alone, or chemotherapy. Patients with tumor PD-L1 < 1% were randomly assigned to nivolumab plus ipilimumab, nivolumab plus chemotherapy, or chemotherapy. End points included exploratory 5-year results for efficacy, safety, and quality of life. RESULTS At a minimum follow-up of 61.3 months, 5-year OS rates were 24% versus 14% for nivolumab plus ipilimumab versus chemotherapy (PD-L1 ≥ 1%) and 19% versus 7% (PD-L1 < 1%). The median duration of response was 24.5 versus 6.7 months (PD-L1 ≥ 1%) and 19.4 versus 4.8 months (PD-L1 < 1%). Among patients surviving 5 years, 66% (PD-L1 ≥ 1%) and 64% (PD-L1 < 1%) were off nivolumab plus ipilimumab without initiating subsequent systemic anticancer treatment by the 5-year time point. Survival benefit continued after nivolumab plus ipilimumab discontinuation because of treatment-related adverse events, with a 5-year OS rate of 39% (combined PD-L1 ≥ 1% and < 1% populations). Quality of life in 5-year survivors treated with nivolumab plus ipilimumab was similar to that in the general US population through the 5-year follow-up. No new safety signals were observed. CONCLUSION With all patients off immunotherapy treatment for ≥ 3 years, nivolumab plus ipilimumab increased 5-year survivorship versus chemotherapy, including long-term, durable clinical benefit regardless of tumor PD-L1 expression. These data support nivolumab plus ipilimumab as an effective first-line treatment for patients with metastatic non–small-cell lung cancer. [Media: see text]

Tobacco cessation is a critical but challenging intervention for cancer patients. Our National Cancer Institute-designated Comprehensive Cancer Center instituted a tobacco cessation program in 2019. This manuscript reports on the first 2 years of our experience.Patients were referred to the program by their care team, and a certified tobacco treatment specialist contacted patients remotely and provided behavioral therapy and coordinated pharmacotherapy. We retrospectively captured data from patients with a cancer diagnosis referred to the tobacco cessation program. Univariate and multivariable logistic regression analyses with the backward elimination approach were performed to determine factors associated with patient acceptance of referral to the tobacco cessation program. Tobacco cessation rates after referral to the program were also captured.Between July 2019 and August 2021, 194 patients were referred to the tobacco cessation program. Of the 194 patients referred, 93 agreed to enroll in the tobacco cessation program (47.9%), of which 84 requested pharmacotherapy (90.3%). Twenty-four were able to cease tobacco use (25.8%). Only 7 patients out of the 101 patients (6.9%) who declined cessation services were successful (p 0.001). On univariate logistic regression, race (p = 0.027) and marital status (p = 0.020) were associated with referral acceptance. On multivariable analysis, single patients (odds ratio [OR] = 0.33) and Caucasian patients (OR = 0.43) were less likely to accept a referral.Access to tobacco cessation services is a critical component of comprehensive cancer care. Our experience highlights the need to understand patient-specific factors associated with engagement with a tobacco cessation program during cancer treatment. The use of pharmacotherapy is also a critical component of successful tobacco cessation.

Higher estimated radiation doses to immune cells (EDIC) have correlated with worse overall survival (OS) in patients with locally-advanced non-small cell lung cancer (NSCLC) prior to the PACIFIC trial, which established consolidative durvalumab as standard-of-care. Here, we examine the prognostic impact of EDIC in the durvalumab era.This single-institution, multi-center study included patients with unresectable stage II/III NSCLC treated with chemoradiation followed by durvalumab. Associations between EDIC [analyzed continuously and categorically (≤6 Gy vs 6 Gy)] and OS, progression-free survival (PFS), and locoregional control (LRC) were evaluated by Kaplan-Meier and Cox proportional methods.100 patients were included with median follow-up of 23.7 months. The EDIC 6 Gy group had a significantly greater percentage of stage IIIB/IIIC disease (76.0 % vs 32.6 %; p 0.001) and larger tumor volumes (170 cc vs 42 cc; p 0.001). There were no differences in early durvalumab discontinuation from toxicity (24.1 % vs 15.2 %; p = 0.27). Median OS was shorter among the EDIC 6 Gy group (29.6 months vs not reached; p 0.001). On multivariate analysis, EDIC 6 Gy correlated with worse OS (HR: 4.15, 95 %CI: 1.52-11.33; p = 0.006), PFS (HR: 3.79; 95 %CI: 1.80-8.0; p 0.001), and LRC (HR: 2.66, 95 %CI: 1.15-6.18; p = 0.023). Analyzed as a continuous variable, higher EDIC was associated with worse OS (HR: 1.34; 95 %CI: 1.16-1.57; p 0.001), PFS (HR: 1.52; 95 %CI: 1.29-1.79; p 0.001), and LRC (HR: 1.34, 95 %CI: 1.13-1.60; p = 0.007).In the immunotherapy era, EDIC is an independent predictor of OS and disease control in locally advanced NSCLC, warranting investigation into techniques to reduce dose to the immune compartment.

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.In the longest follow-up, to our knowledge, for a KRASG12C inhibitor, we assessed the long-term efficacy, safety, and biomarkers of sotorasib in patients with KRAS G12C-mutated advanced non-small-cell lung cancer (NSCLC) from the CodeBreaK 100 clinical trial (ClinicalTrials.gov identifier: NCT03600883). This multicenter, single-group, open-label phase I/phase II trial enrolled 174 patients with KRAS G12C-mutated, locally advanced or metastatic NSCLC after progression on prior therapies. Patients (N = 174) received sotorasib 960 mg once daily with the primary end points for phase I of safety and tolerability and for phase II of objective response rate (ORR). Sotorasib produced an ORR of 41%, median duration of response of 12.3 months, progression-free survival (PFS) of 6.3 months, overall survival (OS) of 12.5 months, and 2-year OS rate of 33%. Long-term clinical benefit (PFS ≥ 12 months) was observed in 40 (23%) patients across PD-L1 expression levels, in a proportion of patients with somatic STK11 and/or KEAP1 alterations, and was associated with lower baseline circulating tumor DNA levels. Sotorasib was well tolerated, with few late-onset treatment-related toxicities, none of which led to treatment discontinuation. These results demonstrate the long-term benefit of sotorasib, including in subgroups with poor prognosis. ispartof: J Clin Oncol vol:41 issue:18 pages:3311-3317 ispartof: location:United States status: published

The emergence of resistance to EGF receptor (EGFR) inhibitor therapy is a major clinical problem for patients with non–small cell lung cancer (NSCLC). The mechanisms underlying tumor resistance to inhibitors of the kinase activity of EGFR are not fully understood. Here, we found that inhibition of EGFR by erlotinib induces STAT3 phosphorylation at Tyr705 in association with increased Bcl2/Bcl-XL at both mRNA and protein levels in various human lung cancer cells. PTPMeg2 is a physiologic STAT3 phosphatase that can directly dephosphorylate STAT3 at the Tyr705 site. Intriguingly, treatment of cells with erlotinib results in downregulation of PTPMeg2 without activation of STAT3 kinases [i.e., Janus-activated kinase (JAK2) or c-Src], suggesting that erlotinib-enhanced phosphorylation of STAT3 may occur, at least in part, from suppression of PTPMeg2 expression. Because elevated levels of phosphorylated STAT3 (pSTAT3), Bcl2, and Bcl-XL were observed in erlotinib-resistant lung cancer (HCC827/ER) cells as compared with erlotinib-sensitive parental HCC827 cells, we postulate that the erlotinib-activated STAT3/Bcl2/Bcl-XL survival pathway may contribute to acquired resistance to erlotinib. Both blockage of Tyr705 phosphorylation of STAT3 by niclosamide and depletion of STAT3 by RNA interference in HCC827/ER cells reverse erlotinib resistance. Niclosamide in combination with erlotinib potently represses erlotinib-resistant lung cancer xenografts in association with increased apoptosis in tumor tissues, suggesting that niclosamide can restore sensitivity to erlotinib. These findings uncover a novel mechanism of erlotinib resistance and provide a novel approach to overcome resistance by blocking the STAT3/Bcl2/Bcl-XL survival signaling pathway in human lung cancer. Mol Cancer Ther; 12(10); 2200–12. ©2013 AACR.

Supplementary Methods, Supplementary References, Supplementary Table Legends, and Supplementary Figure Legends.

Supplementary Tables S1 - S3. Supplementary Table S1. Summary of EGFR alterations in NSCLC identified by FoundationOne. Supplementary Table S2. Summary of genomic coordinates for the kinase fusions identified in this study. Supplementary Table S3. Results of MTT curve fitting from Prism.

PDF file - 47K, Differentially methylated genes with beta values (3KT vs carcinogen exposed).

PDF file, 171K, Inhibition of EGFR by erlotinib (Erlo) results in STAT3 phosphorylation at Tyr 705 and increased Bcl2/Bcl-XL in human lung cancer H1650 and H1975 cells.

Osimertinib decreases PD-L1 mRNA levels (A-C) and exerts differential effects on reducing PD-L1 induced by EGF and INFg (D and E), which might increase PD-L1 via different mechanisms (F), in EGFRm NSCLC cells.

Supplementary Figures S1 - S10. Supplementary Figure S1. Additional information for Patient 1. Supplementary Figure S2. Additional information for Patient 2. Supplementary Figure S3. Additional information for Patient 3. Supplementary Figure S4. Additional clinical information for Patient 4. Supplementary Figure S5. Characterization of EGFR-RAD51 in NR6 cells. Supplementary Figure S6. Relative stability of EGFR-WT, -L858R, and -RAD51. Supplementary Figure S7. Structural model of EGFR-RAD51 filaments. Supplementary Figure S8. On-target inhibition of EGFR-RAD51 by EGFR TKI. Supplementary Figure S9. Cetuximab inhibits ligand-induced activation of downstream signaling pathways in cells expressing EGFR-RAD51. Supplementary Figure S10. cDNA sequence of EGFR-RAD51.

PDF file, 46K, Structures of erlotinib and niclosamide.

PDF file - 65K, Pathway analysis of differentially methylated genes.

DNA methylation is an early event in bronchial carcinogenesis and increased DNA methyltransferase (DNMT)1 protein expression is a crucial step in the oncogenic transformation of epithelia. Here, we investigate the role of class I histone deacetylases (HDAC) 1 to 3 in the stabilization of DNMT1 protein and as a potential therapeutic target for lung cancer chemoprevention. Long-term exposure of immortalized bronchial epithelial cells (HBEC-3KT) to low doses of tobacco-related carcinogens led to oncogenic transformation, increased HDAC expression, cell-cycle independent increased DNMT1 stability, and DNA hypermethylation. Overexpression of HDACs was associated with increased DNMT1 stability and knockdown of HDACs reduced DNMT1 protein levels and induced DNMT1 acetylation. This suggests a causal relationship among increased class I HDACs levels, upregulation of DNMT1 protein, and subsequent promoter hypermethylation. Targeting of class I HDACs with valproic acid (VPA) was associated with reduced HDAC expression and a profound reduction of DNMT1 protein level. Treatment of transformed bronchial epithelial cells with VPA resulted in reduced colony formation, demethylation of the aberrantly methylated SFRP2 promoter, and derepression of SFRP2 transcription. These data suggest that inhibition of HDAC activity may reverse or prevent carcinogen-induced transformation. Finally, immunohistochemistry on human lung cancer specimens revealed a significant increase in DNMT1, HDAC1, HDAC2, and HDAC3 expression, supporting our hypotheses that class I HDACs are mediators of DNMT1 stability. In summary, our study provides evidence for an important role of class I HDACs in controlling the stability of DNMT1 and suggests that HDAC inhibition could be an attractive approach for lung cancer chemoprevention. Cancer Prev Res; 7(3); 351–61. ©2014 AACR.

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Expression of programmed death-ligand 1 (PD-L1) on cancer cells is a critical mechanism contributing to immunosuppression and immune escape. PD-L1 expression may also affect therapeutic outcomes of epidermal growth factor receptor (EGFR)-targeted therapy (e.g., with osimertinib/AZD9291) against EGFR-mutant non–small cell lung cancers (NSCLC) and can even be altered during the treatment albeit with largely undefined mechanisms. This study primarily focuses on elucidating the mechanism by which osimertinib induces PD-L1 degradation in addition to validating osimertinib's effect on decreasing PD-L1 expression in EGFR-mutant NSCLC cells and tumors. Osimertinib and other EGFR inhibitors effectively decreased PD-L1 levels primarily in EGFR-mutant NSCLCs and xenografted tumors. Osimertinib not only decreased PD-L1 mRNA expression, but also prompted proteasomal degradation of PD-L1 protein, indicating both transcriptional and posttranslational mechanisms accounting for osimertinib-induced reduction of PD-L1. Knockdown of β-TrCP or inhibition of GSK3 failed to prevent PD-L1 reduction induced by osimertinib. Rather, knockdown of membrane-associated RING-CH 8 (MARCH8) that encodes a membrane-bound E3 ubiquitin ligase rescued osimertinib-induced PD-L1 reduction. Furthermore, manipulation of MARCH8 expression accordingly altered PD-L1 degradation rate. Critically, MARCH8 interacted with PD-L1 through its N-terminal region and also ubiquitinated PD-L1 in cells. Collectively, these results strongly suggest that MARCH8 is a previously undiscovered E3 ubiquitin ligase responsible for PD-L1 degradation including osimertinib-induced PD-L1 degradation, establishing a novel connection between MARCH8 and PD-L1 regulation.Implications:This study has demonstrated a previously undiscovered function of MARCH8 in mediating PD-L1 degradation induced by EGFR inhibitors in EGFR-mutant NSCLC cells, establishing a novel connection between MARCH8 and PD-L1 regulation.

PDF file, 78K, Treatment of mice with human lung cancer HCC827/ER xenografts using a combination of erlotinib and niclosamide results in a long term tumor-free survival.

PDF file, 152K, Toxicity analysis for treatments with erlotinib and niclosamide in mice bearing HCC827/ER xenografts.

PDF file - 1302K, S1: Primary transcript qPCR indicates HDAC1 and 2 are regulated transcriptionally, HDAC3 is not. S2: Analysis of golden gate methylation array identifies 42/807 genes hypermethylated after long term carcinogen exposure. S3: Cycloheximide 2ug/ml final was added to cultures of 3kt or T31 cells for the indicated times (hours). Cycloheximide blocks the VPA induced degradation of DNMT1. S4: HEK293 cells transiently transfected with pDest51-V5tagged HDAC1, 2 demonstrates protective role of HDACs on DNMT1. % indicates percent fold change of DNMT1 expression over parental cell. S5: 3kt cells stably transfected with HDAC3 demonstrates protective role on DNMT1. % indicates percent fold change of DNMT1 expression over parental cell. S6: Overexpression of HDAC1 or HDAC3 do not increase cellular proliferation compared to empty vector control. S7: 6 tumor samples and matched resected histologically normal lungs were stained for PCNA. PCNA staining intensity is quantified by weighted index. S8: AKT phosphorylation (S473) was assessed with and without VPA exposure in several different passages of carcinogen exposure. VPA had no effect on AKT phosphorylation. S9: T31 wells were grown in triplicates in logarithmic phase and counted manually. VPA's effects on proliferation were assessed at 0.1 mM and 0.5 mM. No discernable effect of particularly the low dose of VPA on growth was observed. S10: carcinogen-transformed T31 cells were passaged for 28 days in the presence of VPA (0.5mM). Bisulfite sequencing of the RASSF1 locus was performed on cells derived from day 0 and day 28.

PDF file, 161K, Toxicity analysis for treatments with erlotinib and niclosamide in mice bearing HCC827 xenografts.

Table S2 shows the categorization of local testing methods based on assay limit of detection compared to the cobas® EGFR Mutation Test v2

A rationale exists for pharmacologic manipulation of the serine (S)184 phosphorylation site of the proapoptotic Bcl2 family member Bax as an anticancer strategy. Here, we report the refinement of the Bax agonist SMBA1 to generate CYD-2-11, which has characteristics of a suitable clinical lead compound. CYD-2-11 targeted the structural pocket proximal to S184 in the C-terminal region of Bax, directly activating its proapoptotic activity by inducing a conformational change enabling formation of Bax homooligomers in mitochondrial membranes. In murine models of small-cell and non–small cell lung cancers, including patient-derived xenograft and the genetically engineered mutant KRAS-driven lung cancer models, CYD-2-11 suppressed malignant growth without evident significant toxicity to normal tissues. In lung cancer patients treated with mTOR inhibitor RAD001, we observed enhanced S184 Bax phosphorylation in lung cancer cells and tissues that inactivates the propaoptotic function of Bax, contributing to rapalog resistance. Combined treatment of CYD-2-11 and RAD001 in murine lung cancer models displayed strong synergistic activity and overcame rapalog resistance in vitro and in vivo. Taken together, our findings provide preclinical evidence for a pharmacologic combination of Bax activation and mTOR inhibition as a rational strategy to improve lung cancer treatment. Cancer Res; 77(11); 3001–12. ©2017 AACR.

Supplementary Figures. Supplemental Figure S1: Representative sections showing changes in expression between baseline biopsy and post-treatment surgical specimens. Supplemental Figure S2: Correlogram showing the correlation between changes in protein expression immunoscore, metabolic activity on PET and tumor size by CT scan.

Mcl-1 is a unique antiapoptotic Bcl2 family protein that functions as a gatekeeper in manipulating apoptosis and survival in cancer cells. Akt is an oncogenic kinase that regulates multiple cellular functions and its activity is significantly elevated in human cancers. Here we discovered a cross-talk between Mcl-1 and Akt in promoting lung cancer cell growth. Depletion of endogenous Mcl-1 from human lung cancer cells using CRISPR/Cas9 or Mcl-1 shRNA significantly decreased Akt activity, leading to suppression of lung cancer cell growth in vitro and in xenografts. Mechanistically, Mcl-1 directly interacted via its PEST domain with Akt at the pleckstrin homology (PH) domain. It is known that the interactions between the PH domain and kinase domain (KD) are important for maintaining Akt in an inactive state. The binding of Mcl-1/PH domain disrupted intramolecular PH/KD interactions to activate Akt. Intriguingly, Mcl-1 expression correlated with Akt activity in tumor tissues from patients with non–small cell lung cancer. Using the Mcl-1–binding PH domain of Akt as a docking site, we identified a novel small molecule, PH-687, that directly targets the PH domain and disrupts Mcl-1/Akt binding, leading to suppression of Akt activity and growth inhibition of lung cancer in vitro and in vivo. By targeting the Mcl-1/Akt interaction, this mechanism-driven agent provides a highly attractive strategy for the treatment of lung cancer.Significance:These findings indicate that targeting Mcl-1/Akt interaction by employing small molecules such as PH-687 represents a potentially new and effective strategy for cancer treatment.

Purpose:On the basis of synergistic effects between green tea polyphenon E (PPE) and EGFR–tyrosine kinase inhibitor in preclinical studies, we conducted a phase Ib study of the PPE and erlotinib combination in patients with advanced premalignant lesions (APL) of the oral cavity and larynx.Patients and Methods:Patients were treated with a fixed dose of PPE (200 mg three times a day) and dose escalation of erlotinib (50, 75, 100 mg daily) for 6 months with tissue biopsy at baseline and 6 months. Primary endpoints were safety and toxicity; secondary endpoints were evaluation of pathologic response, cancer-free survival (CFS), overall survival (OS), and biomarker modulation.Results:Among 21 enrolled patients, 19 began treatment and 17 completed 6 months of treatment with PPE and erlotinib. Main characteristics of treated patients: 15 severe dysplasia or carcinoma in situ and 17 oral cavity. Only skin rash was associated with dose-limiting toxicity and MTD. Recommended doses for phase II studies are PPE 600 mg daily plus erlotinib 100 mg daily for 6 months. Pathologic responses in 17 evaluable patients: pathologic complete response (47%) and pathologic partial response (18%). The 5-year CFS and OS were 66.3% and 93%, respectively. Among tested biomarkers, only phosphorylated ERK was correlated with response to treatment.Conclusions:Treatment with PPE and erlotinib combination was well tolerated in patients with APLs of the head and neck, and showed a high rate of pathologic response with excellent CFS. This combination deserves further investigation for the chemoprevention and/or prevention of second primary tumors in early-stage head and neck cancer.

Supplemental Table 7: Cases with two or more oncogenic driver alterations. Supplemental Table 8. Comparison of LCMC I and LCMC II.

Supplementary Figure 1. Knockout of Mcl-1 from H1299 by CRISPR/Cas9 system results in decreased cell proliferation and increased caspase 3/7 activity. Supplementary Figure 2. Expression of constitutive active form of Akt in H1299 Mcl-1 knockout cells restores cell growth. Supplementary Figure 3. Depletion of Mcl-1 by shRNA retards the growth of H460 lung xenografts. Supplementary Figure 4. Expression of WT Mcl-1 but not the PEST deletion mutant Mcl-1 in H1299 Mcl-1 knockout cells restores Akt/PDK1 and Akt/mTORC2 interactions. Supplementary Figure 5. Treatment of H1299 cells with PH-687 results in increased intramolecular PH/KD interactions in Akt and decreased interaction of Akt with PDK1 or mTORC2. Supplementary Figure 6. Mcl-1/Akt signaling pathway is essential for PH-687 inhibition of cancer cell growth. Supplementary Figure 7. Knockout of Mcl-1 or treatment of cells with PH-687 inhibits growth factor (s)-stimulated Akt activation. Supplementary Figure 8. In vivo toxicity analysis. Supplementary Methods