c-MET (MET) receptor activation is associated with poor prognosis and epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) resistance in non-small-cell lung cancer (NSCLC). This ...global, randomized phase II trial examined erlotinib plus tivantinib (ARQ 197; ArQule, Woburn, MA), a novel MET inhibitor.
Previously treated patients with EGFR TKI-naive advanced NSCLC were randomly assigned to receive oral erlotinib (150 mg daily) plus oral tivantinib (360 mg twice daily) or erlotinib plus placebo (EP). The primary end point was progression-free survival (PFS). At the time of progression, cross-over from EP to erlotinib plus tivantinib (ET) was permitted. Archival tumor tissue specimens were required.
One hundred sixty-seven patients were randomly assigned to ET (n = 84) and to EP (n = 83). Median PFS was 3.8 months for ET and 2.3 months for EP (hazard ratio HR, 0.81; 95% CI, 0.57 to 1.16; P = .24). Exploratory analysis revealed that the small cohort with KRAS mutations achieved a PFS HR of 0.18 (95% CI, 0.05 to 0.70; interaction P = .006). Objective responses were seen in 10% of patients on ET, 7% of patients on EP, and in two patients who crossed over from EP to ET, including one with EGFR mutation and MET gene copy number greater than 5. There were no significant differences in adverse events between study arms.
The combination of the MET inhibitor tivantinib and erlotinib is well-tolerated. Although the study did not meet its primary end point, evidence of activity was demonstrated, especially among patients with KRAS mutations. Additional study of tivantinib and erlotinib in patients with NSCLC is planned.
Efficacy of MEK inhibitors in KRAS+ NSCLC may differ based on specific KRAS mutations and comutations. Our hypothesis was that docetaxel and trametinib would improve activity in KRAS+ NSCLC and ...specifically in KRAS G12C NSCLC.
S1507 is a single-arm phase II study assessing the response rate (RR) with docetaxel plus trametinib in recurrent KRAS+ NSCLC and secondarily in the G12C subset. The accrual goal was 45 eligible patients, with at least 25 with G12C mutation. The design was two-stage design to rule out a 17% RR, within the overall population at the one-sided 3% level and within the G12C subset at the 5% level.
Between July 18, 2016, and March 15, 2018, 60 patients were enrolled with 53 eligible and 18 eligible in the G12C cohort. The RR was 34% 95% confidence interval (CI), 22-48 overall and 28% (95% CI, 10-53) in G12C. Median PFS and OS were 4.1 and 3.3 months and 10.9 and 8.8 months, overall and in the subset, respectively. Common toxicities were fatigue, diarrhea, nausea, rash, anemia, mucositis, and neutropenia. Among 26 patients with known status for TP53 (10+ve) and STK11 (5+ve), OS (HR, 2.85; 95% CI, 1.16-7.01), and RR (0% vs. 56%, P = 0.004) were worse in patients with TP53 mutated versus wild-type cancers.
RRs were significantly improved in the overall population. Contrary to preclinical studies, the combination showed no improvement in efficacy in G12C patients. Comutations may influence therapeutic efficacy of KRAS directed therapies and are worthy of further evaluation. See related commentary by Cantor and Aggarwal, p. 3563.
Disulfiram and metals inactivate key oncoproteins resulting in anti-neoplastic activity. The goal of this study was to determine the maximum tolerated dose of copper when administered with disulfiram ...in patients with advanced solid tumors and liver involvement.
Disulfiram 250 mg was administered daily in 28-day cycles. Four doses of copper gluconate were tested (2, 4, 6, and 8 mg of elemental copper) in a standard 3 + 3 dose escalation design. Patients were evaluated for dose limiting toxicities and response. Protein S-glutathionylation was evaluated as a pharmacodynamic marker.
Twenty-one patients were enrolled and 16 patients were evaluable for dose limiting toxicities. Among the 21 patients, there was a median of 4 lines of prior chemotherapy. Five Grade 3 toxicities were observed (anorexia, elevated aspartate aminotransferase or AST, elevated alkaline phosphatase, fever, and fatigue). Response data was available for 15 patients. Four patients had stable disease with the longest duration of disease control being 116 days. The median duration of treatment for evaluable patients was 55 days (range 28-124). Reasons for discontinuation included functional decline, disease progression, and disease-associated death. Increased S-glutathionylation of serum proteins was observed with treatment.
Disulfiram 250 mg daily with copper gluconate (8 mg of elemental copper) was well-tolerated in patients with solid tumors involving the liver and was not associated with dose limiting toxicities. While temporary disease stabilization was noted in some patients, no objective responses were observed. Treatment was associated with an increase in S-glutathionylation suggesting that this combination could exert a suppressive effect on cellular growth and protein function.
NCT00742911 , first posted 28/08/2008.
After sequential treatment with first- and third-generation EGFR tyrosine kinase inhibitors (TKIs), EGFR-mutant non-small cell lung cancers frequently harbor multiple resistance mutations in exon 20 ...of EGFR including T790M, mediating resistance to first-generation TKIs, and at codons 792, 796, or 797 mediating resistance to third-generation TKIs. However, whether these resistance mutations are in cis or trans has therapeutic implications for patients. We analyzed a cohort of 29 patients with NSCLC harboring EGFR mutations at codons 792, 796, or 797 to establish the configuration of these mutations. We performed hybrid capture-based, next-generation sequencing on formalin-fixed paraffin-embedded biopsy tissue or liquid biopsy. 27 samples had both a T790M mutation and a mutation at codons 792, 796, or 797. In all of these cases, the mutations were found in the cis configuration; the trans configuration was not observed. Two patients' samples harbored a mutation at codon 797 but no T790M mutation. In these two cases, longitudinal analysis showed earlier biopsies harbored EGFR T790M, which was undetectable following osimertinib treatment. Treatment of one these patients with both first- and third-generation EGFR TKIs resulted in a mixed response. Here we describe multiple configurations of EGFR T790M and third-generation TKI resistance mutations at codons 792, 796, and 797. These mutations are most commonly found in cis, which confers resistance to all current EGFR TKIs. We also describe two patients that exhibited T790M loss with acquisition of a mutation at codon 797. In addition, one of these patients, with an EGFR C797S in a lung biopsy was subsequently found to have EGFR C797N in a later biopsy of pleural fluid, highlighting the dynamic multiclonal nature of advanced NSCLC.
Signaling pathway stimulation by activating mutations of oncogenes occurs in most melanomas and can provide excellent targets for therapy, but the short-term therapeutic success is limited by ...intrinsic and acquired resistance. The mitogen-activated protein kinase and phosphoinositide 3-kinase/AKT/mTOR pathways are activated in most cutaneous melanomas. The purpose of this trial was to prospectively evaluate 2 molecularly targeted drug combinations in patients with untreated metastatic melanoma.
This randomized phase II study enrolled patients between May 2008 and November 2009 with nonocular melanoma, no prior systemic chemotherapy, and no history of brain metastasis. Arm A received oral sorafenib 200 mg twice daily plus i.v. temsirolimus 25 mg weekly; and arm B received oral sorafenib 400 mg every morning, 200 mg every night daily plus oral tipifarnib 100 mg twice daily, 3 weeks of every 4. The primary objectives were to evaluate progression-free survival (PFS), objective response rate, and toxicity for the 2 regimens.
On arm A (63 evaluable patients), the median PFS was 2.1 months and median overall survival (OS) was 7 months. Three patients achieved partial response (PR). Thirty-nine evaluable patients were accrued to arm B, which closed after first-stage accrual; the median PFS was 1.8 months and OS was 7 months, with 1 patient achieving PR.
The combinations of molecularly targeted agents tested did not show sufficient activity to justify further use. Newer agents and improved patient selection by characterization of the molecular targets in individual tumors show great promise and should be incorporated into future studies, along with appropriate laboratory correlates.
Purpose Concurrent chemoradiotherapy is standard treatment for patients with stage III non-small-cell lung cancer. Elderly patients may experience increased rates of adverse events (AEs) or less ...benefit from concurrent chemoradiotherapy. Patients and Methods Individual patient data were collected from 16 phase II or III trials conducted by US National Cancer Institute-supported cooperative groups of concurrent chemoradiotherapy alone or with consolidation or induction chemotherapy for stage III non-small-cell lung cancer from 1990 to 2012. Overall survival (OS), progression-free survival, and AEs were compared between patients age ≥ 70 (elderly) and those younger than 70 years (younger). Unadjusted and adjusted hazard ratios (HRs) for survival time and CIs were estimated by single-predictor and multivariable frailty Cox models. Unadjusted and adjusted odds ratio (ORs) for AEs and CIs were obtained from single-predictor and multivariable generalized linear mixed-effect models. Results A total of 2,768 patients were classified as younger and 832 as elderly. In unadjusted and multivariable models, elderly patients had worse OS (HR, 1.20; 95% CI, 1.09 to 1.31 and HR, 1.17; 95% CI, 1.07 to 1.29, respectively). In unadjusted and multivariable models, elderly and younger patients had similar progression-free survival (HR, 1.01; 95% CI, 0.93 to 1.10 and HR, 1.00; 95% CI, 0.91 to 1.09, respectively). Elderly patients had a higher rate of grade ≥ 3 AEs in unadjusted and multivariable models (OR, 1.35; 95% CI, 1.07 to 1.70 and OR, 1.38; 95% CI, 1.10 to 1.74, respectively). Grade 5 AEs were significantly higher in elderly compared with younger patients (9% v 4%; P < .01). Fewer elderly compared with younger patients completed treatment (47% v 57%; P < .01), and more discontinued treatment because of AEs (20% v 13%; P < .01), died during treatment (7.8% v 2.9%; P < .01), and refused further treatment (5.8% v 3.9%; P = .02). Conclusion Elderly patients in concurrent chemoradiotherapy trials experienced worse OS, more toxicity, and had a higher rate of death during treatment than younger patients.
Identification of unsuspected nodal metastasis may occur at the time of operation for a stage I non-small cell lung cancer. Guidelines for this scenario are unclear. Our goal was to assess the ...cost-effectiveness of aborting the operation in an attempt to first provide neoadjuvant systemic therapy compared with upfront resection.
A computer simulation Markov model with a lifetime horizon was constructed to compare the costs and clinical outcomes, as measured by quality-adjusted life-years (QALYs), of upfront resection at the time of identification of unsuspected N2 mediastinal disease
aborting initial resection and continuing with neoadjuvant therapy prior to resection. Input parameters for the model were derived from published literature with costs measured from the healthcare perspective. The incremental cost-effectiveness ratio (ICER) was evaluated with a willingness-to-pay (WTP) threshold of $150,000/QALY. Both deterministic (one-, two-, and three-way) and probabilistic sensitivity analysis (PSA) were performed to assess the impact of variation in input parameter values on model results.
Aborting initial resection in favor of neoadjuvant therapy resulted in both higher costs ($40,415
$29,873) and more QALYs (3.95
2.84) relative to upfront resection, yielding an ICER of $9,526/QALY. While variation in overall survival had a significant impact on the ICER, perioperative variables did not. As the annual mortality of best-case therapy in the abort group increased from a base-case estimate of 11% to 15%, the ICER exceeded the WTP threshold of $150,000/QALY. Subsequent one- and two-way sensitivity analyses did not find substantially alter the overall results. PSA resulted in aborting resection to be cost-effective in 99.7% of samples, with 13% of samples dominating upfront resection.
Treatment of stage IIIa lung cancer requires the input of a multidisciplinary team who must consider cost, quality of life, and overall survival. As new treatments are developed, further analyses should be performed to determine optimal therapy.
Primary carcinoid tumors of the lung are rare tumors which comprise approximately 0.5% to 5% of all lung malignancies in adults and roughly 20% to 30% of all carcinoid tumors. The purpose of this ...retrospective, descriptive study was to describe the incidence, characteristics, and outcomes of patients treated for primary pulmonary carcinoid tumor at a single institution.
All patients with a diagnosis of primary pulmonary carcinoid tumor treated from 1989 to 2009 were reviewed. Data collected included demographics, pathology, tobacco use, clinical presentation, tumor location, tumor spread, treatment, and survival.
There were 59 cases of pulmonary carcinoid tumors: 47 typical (80%) and 12 atypical (20%). All but 4 patients underwent surgery, including 54 (92%) lung-sparing resections and 1 pneumonectomy. Five of 55 patients received concurrent adjuvant chemoradiation therapy; 4 patients with atypical and 1 with typical histology. Three additional patients with atypical carcinoid were treated only with adjuvant radiotherapy, palliative radiotherapy, or palliative chemotherapy, respectively. The Kaplan-Meier 5- and 10-year overall survivals were both 80% within the entire population. In the 88% of patients who achieved complete remission, disease-free survival was 98%. A review of a large series from the literature is also presented.
Surgical resection was primary and adequate therapy for most typical carcinoid tumors with high overall survival and disease-free survival. Adjuvant chemotherapy or radiotherapy might be considered for patients with atypical carcinoid tumors who present with adverse pathologic findings.
Although early detection of lung cancer through screening is associated with better prognosis, most lung cancers are diagnosed among unscreened individuals. We therefore sought to characterize ...pathways to lung cancer diagnosis among unscreened individuals.
Participants were individuals with lung cancer who did not undergo asymptomatic lung cancer screening (n = 13) and healthcare providers who may be involved in the pathway to lung cancer diagnosis (n = 13). We conducted semi-structured interviews to identify themes in lung cancer patients' narratives of their cancer diagnoses and providers' personal and/or professional experiences of various pathways to lung cancer diagnoses, to identify delays in diagnosis. We audio-recorded, transcribed, and coded interviews in two stages. First, we conducted deductive coding using three time-period intervals from the Models of Pathways to Treatment framework: appraisal, help-seeking, and diagnostic (i.e., excluding pre-treatment). Second, we conducted inductive coding to identify themes within each time-period interval, and classified these themes as either barriers or facilitators to diagnosis. Coding and thematic summarization were completed independently by two separate analysts who discussed for consensus.
Eight of the patient participants had formerly smoked, and five had never smoked. We identified eight barrier/facilitator themes within the three time-period intervals. Within the appraisal interval, the barrier theme was (1) minimization or misattribution of symptoms, and the facilitator theme was (2) acknowledgment of symptoms. Within the help-seeking interval, the barrier theme was (3) hesitancy to seek care, and the facilitator theme was (4) routine care. Within the diagnosis interval, barrier themes were (5) health system challenges, and (6) social determinants of health; and facilitator themes were (7) severe symptoms and known risk factors, and (8) self-advocacy. Many themes were interrelated, including minimization or misattribution of symptoms and hesitancy to seek care, which may collectively contribute to care and imaging delays.
Interventions to reduce hesitancy to seek care may facilitate timely lung cancer diagnoses. More prompt referral to imaging-especially computed tomography (CT)-among symptomatic patients, along with patient self-advocacy for imaging, may reduce delays in diagnosis.
Objective: The VeriStrat
1
(VS) test is intended to help guide treatment decisions for patients with advanced non-small-cell lung cancer (NSCLC) without an EGFR-sensitizing mutation, classifying ...patients into two categories. Patients classified as VSGood have a favorable prognosis and significant clinical response to EGFR tyrosine kinase inhibitors (TKIs). Patients classified as VSPoor have a less favorable prognosis and exhibit no significant response to EGFR-TKIs. The objective of this paper is to assess the real-world impact of VS test results on physicians' treatment recommendations including referrals for best supportive care (BSC).
Methods: Between 1 January 2012 and 1 November 2016, physician respondents were asked to complete standardized questionnaires before and after receiving VS results in patients meeting criteria for the intended use of the VS test. This study evaluated three endpoints: whether physicians followed VS test results in making treatment recommendations, the extent to which tests results changed these treatment recommendations, and the patterns of care subsequent to VS testing.
Results: Of the tests ordered by 989 physicians, 2494 VS tests had completed treatment recommendation questionnaires both prior to and after testing. Prior to VS testing, physicians were considering treatment with EGFR-TKIs for 2250 patients (90%). The VS test classified 1950 patients as VSGood and 544 patients as VSPoor. For patients classified as VSPoor, physicians recommended BSC for 25% of patients and standard systemic treatments such as chemotherapies for 65% of patients. Consistent with previous publications, physicians recommended EGFR-TKI therapy for only 10% of VSPoor patients but for 89% of VSGood patients. Overall, physician's treatment recommendations were consistent with test results in 98% of cases. Availability of test results decreased ineffective treatment recommendations by 89% for VSPoor patients.
Conclusions: Among physicians ordering VS, the test significantly influenced treatment recommendations for patients with NSCLC, reducing ineffective and expensive treatment at the end of life.
PDF
