Dacomitinib as a retreatment for advanced non-small cell lung cancer patient with an uncommon EGFR mutation.

In non-small cell lung cancer (NSCLC), uncommon epidermal growth factor receptor (EGFR) mutations are mutations other than Ex19 deletion and Ex21 L858R, which are common mutations highly sensitive to EGFR-tyrosine kinase inhibitors. Afatinib, a second-generation EGFR-tyrosine kinase inhibitor, has been shown to be effective in patients with uncommon mutations. Dacomitinib, another second-generation EGFR-tyrosine kinase inhibitor, has not previously been shown to be effective in patients with uncommon mutations. Here, we report the efficacy of dacomitinib for uncommon EGFR mutations in a 71-year-old woman diagnosed with metastatic lung adenocarcinoma with uncommon EGFR mutation (Ex18 G719A). Afatinib was administered as the first-line treatment, and a remarkable antitumor effect was observed. However, the tumor grew after 14 months. Pemetrexed plus carboplatin followed by pemetrexed, docetaxel, atezolizumab and S-1 were performed in sequence. Although approximately four years had passed since the start of treatment, her physical condition was good. The patient started dacomitinib as the sixth-line treatment. Lesions were markedly reduced and treatment with dacomitinib was continued for 7.8 months. Dacomitinib is a possible treatment option for NSCLC with uncommon mutations.

VEGFR2 blockade augments the effects of tyrosine kinase inhibitors by inhibiting angiogenesis and oncogenic signaling in oncogene-driven non-small-cell lung cancers.

Molecular agents targeting the epidermal growth factor receptor (EGFR)-, anaplastic lymphoma kinase (ALK)- or c-ros oncogene 1 (ROS1) alterations have revolutionized the treatment of oncogene-driven non-small-cell lung cancer (NSCLC). However, the emergence of acquired resistance remains a significant challenge, limiting the wider clinical success of these molecular targeted therapies. In this study, we investigated the efficacy of various molecular targeted agents, including erlotinib, alectinib, and crizotinib, combined with anti-vascular endothelial growth factor receptor (VEGFR) 2 therapy. The combination of VEGFR2 blockade with molecular targeted agents enhanced the anti-tumor effects of these agents in xenograft mouse models of EGFR-, ALK-, or ROS1-altered NSCLC. The numbers of CD31-positive blood vessels were significantly lower in the tumors of mice treated with an anti-VEGFR2 antibody combined with molecular targeted agents compared with in those of mice treated with molecular targeted agents alone, implying the antiangiogenic effects of VEGFR2 blockade. Additionally, the combination therapies exerted more potent antiproliferative effects in vitro in EGFR-, ALK-, or ROS1-altered NSCLC cells, implying that VEGFR2 inhibition also has direct anti-tumor effects on cancer cells. Furthermore, VEGFR2 expression was induced following exposure to molecular targeted agents, implying the importance of VEGFR2 signaling in NSCLC patients undergoing molecular targeted therapy. In conclusion, VEGFR2 inhibition enhanced the anti-tumor effects of molecular targeted agents in various oncogene-driven NSCLC models, not only by inhibiting tumor angiogenesis but also by exerting direct antiproliferative effects on cancer cells. Hence, combination therapy with anti-VEGFR2 antibodies and molecular targeted agents could serve as a promising treatment strategy for oncogene-driven NSCLC.

Beneficial effect of erlotinib and trastuzumab emtansine combination in lung tumors harboring EGFR mutations.

Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) is the standard therapy for non-small cell lung cancer (NSCLC) harboring EGFR mutations, but the resistance is inevitable. The drug-tolerant persister cancer cells are thought to be involved in the resistance. We recently reported that HER2 expression had a negative impact on time-to-treatment-failure in patients with EGFR mutant NSCLC. In this study, we hypothesized that HER2 might be a potential target for alternative combination therapy in NSCLC harboring EGFR mutations. In vitro study showed that the level of HER2 expression had no correlation with the sensitivity to EGFR-TKI, erlotinib but showed some correlation with HER2-inhibitor, ado-trastuzumab emtansine (T-DM1) in multiple EGFR-mutant lung cancer cell lines. In addition, HER2 expression was increased in persister cancer cells in 11-18 cell line harboring EGFR L858R or HCC827 cell line harboring EGFR exon 19 deletion after the exposure to erlotinib in vitro and in vivo. The combination of erlotinib and T-DM1 showed a superior inhibitory effect on cell proliferation compared with those of the erlotinib or T-DM1 alone in either 11-18 or HCC827 cells in vitro. The combination therapy also induced a significantly greater inhibitory effect on tumor growth in xenograft model in mice transplanted with either 11-18 or HCC827 cells compared with erlotinib alone or T-DM1 alone. No body weight loss was observed in these mice. These results suggested that the combination therapy with EGFR-TKI and T-DM1 might be a potentially promising strategy for treating lung cancer harboring EGFR mutations.

Utility of immune checkpoint inhibitors in non-small-cell lung cancer patients with poor performance status.

Most clinical trials of non-small-cell lung cancer (NSCLC) exclude patients with poor ECOG performance status (PS). Thus, the efficacy of immune checkpoint inhibitors (ICIs) in patients with poor PS remains unclear. Herein, we used data from a retrospective cohort to assess the potential clinical benefits of ICIs in NSCLC patients with poor PS. Data from NSCLC patients who received ICI monotherapy at 9 institutions between December 2015 and May 2018 were retrospectively analyzed. After excluding 4 patients who lacked PS data, a total of 527 ICI-treated patients, including 79 patients with PS 2 or higher, were used for our analyses. The progression-free survival (PFS) and overall survival (OS) of patients with PS 2 or higher were significantly shorter compared with those of PS 0-1 patients (median PFS, 4.1 vs 2.0 months; P < .001 and median OS, 17.4 vs 4.0 months; P < .001). Among NSCLC patients with programmed cell death protein-ligand 1 (PD-L1) expression of 50% or higher who were treated with pembrolizumab as first-line therapy, the median PFS times of patients with PS 2 and 0-1 were 7.3 and 8.1 months, respectively. There was no significant difference in PFS between patients with PS 2 and 0-1 (P = .321). Although poor PS was significantly associated with worse outcomes in NSCLC patients treated with ICIs, pembrolizumab as a first-line treatment in NSCLC patients expressing high levels of PD-L1 could provide a clinical benefit, even in patients with PS 2.

Rapidly Progressive Acute Kidney Injury Associated with Nivolumab Treatment.

A 63-year-old man with pulmonary adenocarcinoma was treated with nivolumab. High fever developed within several hours after the first administration of nivolumab; subsequently, serum creatinine levels kept increasing daily. We diagnosed acute kidney injury (AKI) as an immune-related adverse event; the patient was initially treated with 50 mg prednisolone, and the dose was then tapered. Renal biopsy pathologically revealed tubulointerstitial inflammation with strong infiltration of only T cells that were CD3+, CD4+, and CD8+. The infiltration of CD163+ M2 macrophage was also observed. AKI within 1 week after the administration of nivolumab seems to be rare; therefore, the present case provides important findings useful in daily clinical practice.

Deterioration of high-resolution computed tomography findings predicts disease progression after initial decline in forced vital capacity in idiopathic pulmonary fibrosis patients treated with pirfenidone.

BACKGROUND: Pirfenidone suppresses the decline of forced vital capacity (FVC) in patients with idiopathic pulmonary fibrosis (IPF). However, IPF progresses in some patients despite treatment. We analyzed patients with meaningful FVC declines during pirfenidone treatment and explored the factors predictive of disease progression after FVC decline. METHODS: This study was a retrospective, multicenter, observational study conducted by the Okayama Respiratory Disease Study Group. We defined initial decline in %FVC as 5% or greater per 6-month period during pirfenidone treatment. IPF patients who were treated with pirfenidone and experienced an initial decline from December 2008 to September 2017 were enrolled. RESULTS: We analyzed 21 patients with IPF. After the initial decline, 4 (19.0%) patients showed improvement in disease, 11 (52.4%) showed stable disease, and 6 (28.6%) showed progressive disease. There was no significant correlation between %FVC reduction on initial decline and subsequent %FVC change (p = 0.475). Deterioration of high-resolution computed tomography (HRCT) findings on initial decline was observed significantly more often in the progressive versus improved/stable disease groups (100% vs 20.0%, p = 0.009). CONCLUSIONS: We revealed that deterioration of HRCT findings may predict disease progression after the initial decline in %FVC in IPF patients treated with pirfenidone.

Pilot evaluation of a HER2 testing in non-small-cell lung cancer.

AIMS: HER2-positivity pattern in the specimens of immunohistochemistry (IHC) and fluorescence in situ hybridisation (FISH) has been hardly reported in non-small-cell lung cancer (NSCLC). METHODS: We evaluated the characteristics of HER2-positivity pattern in formalin-fixed paraffin-embedded samples using IHC and FISH in 15 patients enrolled in a larger prospective cohort study to survey a HER2-positive NSCLC. RESULTS: As for the immunostaining pattern, most specimens (79%) demonstrated incomplete or mixed-typed membranous immunoreactivity with heterogeneity, resembling that observed in gastric cancer rather than breast cancer. Concordance between IHC-positivity and FISH-positivity was 87.5% according to the criteria for breast cancer scoring system. On application of the gastric cancer scoring system to the examined tumours, the IHC score increased in the seven (43.8%) specimens, and the concordance between IHC positivity and FISH positivity rose to 93.8%. CONCLUSIONS: In our pilot series, the pattern of IHC reactivity closely resembled that observed in gastric cancer rather than breast cancer. TRIAL REGISTRATION NUMBER: 000017003.

EGFR-TKI acquired resistance in lung cancers harboring EGFR mutations in immunocompetent C57BL/6J mice.

OBJECTIVES: Lung cancers harboring epidermal growth factor receptor (EGFR) mutations inevitably develop resistance to EGFR tyrosine-kinase inhibitors (EGFR-TKIs). Therefore, we sought to establish clinically relevant lung-cancer mouse models to achieve deep remission of cancers. MATERIALS AND METHODS: We previously established two transgenic lung-cancer mouse models harboring human EGFR exon 21 L858R substitution (hLR) and mouse Egfr exon 19 deletion (mDEL) in the C57BL/6 J background. Lung tumors from these two transgenic mouse strains were transplanted subcutaneously into BALB/c-nunu mice or C57BL/6 J mice. RESULTS: The transplanted tumors developed the ability to grow on the subcutaneous tissue, peritoneum, or lung of C57BL/6 J mice. While hLR tumors could grow only in C57BL/6 J mice carrying the transgene, mDEL tumors could grow in wild-type C57BL/6 J mice. The tumors maintained EGFR-dependency, and, thus, the EGFR-TKI gefitinib inhibited tumor growth; however, similar to human lung cancers, hLR and mDEL tumors acquired resistance in 60 and 200 days, respectively, following gefitinib administration. Secondary EGFR T790 M mutation in hLR tumors and secondary Egfr T792I mutation in mDEL tumors developed; however, no MET activation was detected. Accordingly, the third-generation EGFR-TKI osimertinib effectively inhibited gefitinib-resistant tumors in vivo. Furthermore, gefitinib-resistant tumors developed resistance to osimertinib in 100 days. CONCLUSION: These syngeneic lung-cancer mouse models harboring EGFR mutations are suitable for studying the drug-resistance mechanisms and the role of the tumor microenvironment. Further investigation with these mouse models is warranted for developing next-generation treatment strategies for lung cancer.

Rapid Acquisition of Alectinib Resistance in ALK-Positive Lung Cancer With High Tumor Mutation Burden.

INTRODUCTION: The highly selective ALK receptor tyrosine kinase (ALK) inhibitor alectinib is standard therapy for ALK-positive lung cancers; however, some tumors quickly develop resistance. Here, we investigated the mechanism associated with rapid acquisition of resistance using clinical samples. METHODS: Autopsied samples were obtained from lung, liver, and renal tumors from a 51-year-old male patient with advanced ALK-positive lung cancer who had acquired resistance to alectinib in only 3 months. We established an alectinib-resistant cell line (ABC-14) from pleural effusion and an alectinib/crizotinib-resistant cell line (ABC-17) and patient-derived xenograft (PDX) model from liver tumors. Additionally, we performed next-generation sequencing, direct DNA sequencing, and quantitative real-time reverse transcription polymerase chain reaction. RESULTS: ABC-14 cells harbored no ALK mutations and were sensitive to crizotinib while also exhibiting MNNG HOS transforming gene (MET) gene amplification and amphiregulin overexpression. Additionally, combined treatment with crizotinib/erlotinib inhibited cell growth. ABC-17 and PDX tumors harbored ALK G1202R, and PDX tumors metastasized to multiple organs in vivo, whereas the third-generation ALK-inhibitor, lorlatinib, diminished tumor growth in vitro and in vivo. Next-generation sequencing indicated high tumor mutation burden and heterogeneous tumor evolution. The autopsied lung tumors harbored ALK G1202R (c. 3604 G>A) and the right renal metastasis harbored ALK G1202R (c. 3604 G>C); the mutation thus comprised different codon changes. CONCLUSIONS: High tumor mutation burden and heterogeneous tumor evolution might be responsible for rapid acquisition of alectinib resistance. Timely lorlatinib administration or combined therapy with an ALK inhibitor and other receptor tyrosine-kinase inhibitors might constitute a potent strategy.

Bilateral Testicular Metastases from Lung Adenocarcinoma Showing an Objective Response to Nivolumab: A Case Report and Review of the Literature.

A 69-year-old man who had undergone chemoradiotherapy for advanced pulmonary adenocarcinoma had bilateral testicular and adrenal gland masses on a routine follow-up examination. We performed left orchiectomy, and the histopathological examination confirmed metastatic pulmonary adenocarcinoma involving the extracted testis. He was treated for disease progression with nivolumab after unsuccessful cytotoxic chemotherapy, which resulted in regression of recurrent adrenal and right testicular tumors. We reviewed the existing literature on metastatic testicular tumors and found that testicular metastasis from lung cancer is rare and poses a chemotherapeutic challenge. Based on our experience, immune checkpoint inhibitors seem to have good efficacy for treating testicular metastasis.

Transoesophageal ultrasound-guided bronchoscopic aspiration of a superior mediastinal tumour using the BF-UC290F instrument.

A 46-year-old male with a superior mediastinal mass presented with a one-month history of hoarseness and chest pain and was referred to our hospital. Although endobronchial, ultrasound-guided, transbronchial needle aspiration (EBUS-TBNA) was initially performed, we could not obtain an adequate specimen because of his severe cough and an inadequate EBUS view. During the same endoscopic session, we performed endoscopic, ultrasound-guided, bronchoscopic fine-needle aspiration (EUS-B-FNA) via a transoesophageal approach using the BF-UC290F (Olympus, Tokyo, Japan), a third-generation EBUS-TBNA endoscope. The BF-UC290F enabled smooth access through the oesophagus and a clear EBUS view of the mass, attributable, respectively, to the compact distal tip and the powerful angulation. Rapid on-site cytology revealed that an adequate specimen had been obtained, and we terminated the procedure without inducing a severe cough. Histologically, the mass was a squamous cell carcinoma. EUS-B-FNA employing the BF-UC290F was useful to diagnose the superior mediastinal mass.

Pembrolizumab-induced Autoimmune Hemolytic Anemia and Hemophagocytic Lymphohistiocytosis in Non-small Cell Lung Cancer.

We herein report a 78-year old man with squamous cell carcinoma of the lungs treated with pembrolizumab. At 10 days after the administration of pembrolizumab, he showed progressive anemia and increased levels of bilirubin. Because the findings of a direct coombs test and cold hemagglutinin were positive, we diagnosed the patient with autoimmune hemolytic anemia and treated him with prednisolone. Subsequently, he was admitted to our hospital owing to fatigue, a high fever, and jaundice. His clinical findings met the diagnostic criteria of hemophagocytic lymphohistiocytosis, and he was rescued with a high dose of glucocorticoids. Marked tumor regression was obtained and has been maintained since then.

Comparing the Clinical Performance of the New 19-G ViziShot FLEX and 21- or 22-G ViziShot 2 Endobronchial Ultrasound-guided Transbronchial Needle Aspiration Needles.

Objective Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) is a minimally invasive procedure for pulmonary and mediastinal diseases. This study compared the performance of a novel 19-G needle with a 21- or 22-G needle. Patients and Methods Eleven patients at Okayama Medical Center were enrolled retrospectively between April and December 2017. Enlarged lymph nodes and a pulmonary nodule were sampled with both 19-G and 21- or 22-G needles in nine patients. Two patients underwent biopsies for suspected lymphoma with only the 19-G needle. We examined their medical records on the diagnosis, size of the lymph nodes and pulmonary nodule, and complications. Results The median longest diameter of the 13 lymph nodes (8 #7, 4 #4R, and 1 #11) and 1 pulmonary nodule (right segment 6) in the 11 patients was 31.6 mm (range, 10.4-45.0 mm). Definitive diagnoses were made using the 19-G needle in nine patients. EBUS-TBNA with a 19-G needle resulted in successful diagnoses of one case of retinal hemangioblastoma, one case of tuberculous lymphadenitis, and one case of lung adenocarcinoma, as well as the evaluation of the programmed death-ligand 1 (PD-L1) expression following initial negative findings after a 21- or 22-G biopsy. A small pulmonary nodule (lung squamous cell carcinoma) with negative findings after a 19-G biopsy was diagnosed with a 22-G biopsy. Two suspected lymphoma patients were diagnosed with a 19-G needle: one had lymphoma and the other sarcoidosis. Three patients were diagnosed with sarcoidosis using both the 19-G and 21- or 22-G needles. Conclusion EBUS-TBNA with a 19-G needle was useful for diagnosing retinal hemangioblastoma and tuberculous lymphadenitis as well as for PD-L1 testing after 21- and 22-G biopsies were unsuccessful.

MET or NRAS amplification is an acquired resistance mechanism to the third-generation EGFR inhibitor naquotinib.

As a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), osimeritnib is the standard treatment for patients with non-small cell lung cancer harboring the EGFR T790M mutation; however, acquired resistance inevitably develops. Therefore, a next-generation treatment strategy is warranted in the osimertinib era. We investigated the mechanism of resistance to a novel EGFR-TKI, naquotinib, with the goal of developing a novel treatment strategy. We established multiple naquotinib-resistant cell lines or osimertinib-resistant cells, two of which were derived from EGFR-TKI-naïve cells; the others were derived from gefitinib- or afatinib-resistant cells harboring EGFR T790M. We comprehensively analyzed the RNA kinome sequence, but no universal gene alterations were detected in naquotinib-resistant cells. Neuroblastoma RAS viral oncogene homolog (NRAS) amplification was detected in naquotinib-resistant cells derived from gefitinib-resistant cells. The combination therapy of MEK inhibitors and naquotinib exhibited a highly beneficial effect in resistant cells with NRAS amplification, but the combination of MEK inhibitors and osimertinib had limited effects on naquotinib-resistant cells. Moreover, the combination of MEK inhibitors and naquotinib inhibited the growth of osimertinib-resistant cells, while the combination of MEK inhibitors and osimertinib had little effect on osimertinib-resistant cells. Clinical assessment of this novel combination (MEK inhibitors and naquotinib) is worth considering in osimertinib-resistant lung tumors.

Success of Crizotinib Combined with Whole-Brain Radiotherapy for Brain Metastases in a Patient with Anaplastic Lymphoma Kinase Rearrangement-Positive Non-Small-Cell Lung Cancer.

Although crizotinib shows marked antitumor activity in anaplastic lymphoma kinase (ALK) rearrangement-positive non-small-cell lung cancer (NSCLC) patients, all treated patients ultimately develop resistance to this drug. Isolated central nervous system failure without progression at extracranial sites is a common progression pattern in ALK rearrangement-positive NSCLC patients treated with crizotinib. Here, we report the success of crizotinib combined with whole-brain radiotherapy in an ALK rearrangement-positive NSCLC patient who developed leptomeningeal carcinomatosis and progression of multiple brain metastases. Additionally, we focused on the mechanism involved by examining the plasma and cerebrospinal fluid concentrations of crizotinib in the present case.

Triplet therapy with afatinib, cetuximab, and bevacizumab induces deep remission in lung cancer cells harboring EGFR T790M in vivo.

Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) have changed the treatment strategy for EGFR-mutant lung cancers; however, resistance usually occurs due to a secondary mutation, T790M, in EGFR. Combination therapy using afatinib and cetuximab has had good results in lung tumors harboring EGFRT790M mutations in clinical trials. The effect of bevacizumab, an antivascular endothelial growth factor (VEGF) antibody, combined with EGFR-TKIs has also been investigated. We hypothesized that the dose of afatinib and cetuximab could be reduced by combination with bevacizumab and that the triplet therapy may result in better tumor inhibition with tolerable toxicity. Using a xenograft mouse model with H1975-harboring EGFRL858R+T790M and RPC-9-harboring EGFR19DEL+T790M , we tested the efficacy of the triplet therapy with a modified dose of afatinib, cetuximab, and bevacizumab, and compared this therapy to single and double therapies. Triplet therapy with afatinib, cetuximab, and bevacizumab induced pathological complete remission in xenograft tumors with H1975 and RPC-9 cells versus tumors treated with single or double therapies. We saw no body weight loss in the mice. The triple therapy induced a significant reduction in CD31-positive vascular endothelial cells and increased cleaved caspase-3-positive cells in the tumors. This suggests that one mechanism underlying the deep remission could be suppression of neovascularization and induction of apoptosis by intensive inhibition of driver oncoproteins and VEGF. These results highlight the potential of afatinib, cetuximab, and bevacizumab to induce deep remission in tumors harboring EGFRT790M mutations. Therefore, clinical trials of this combination therapy are warranted.

Trastuzumab Emtansine in HER2+ Recurrent Metastatic Non-Small-Cell Lung Cancer: Study Protocol.

The treatment outcome has been unsatisfactory for patients with non-small-cell lung cancer (NSCLC) refractory to standard first-line chemotherapy. Trastuzumab emtansine (T-DM1), an anti-HER2 antibody conjugated with a vinca alkaloid, has been approved for clinical use in HER2+ breast cancer in many countries. Approximately 5% of NSCLC tumors possess HER2 alterations, and T-DM1 has shown excellent antitumor effects against HER2+ lung cancer cell lines in preclinical models. Therefore, we hypothesized that T-DM1 could significantly inhibit the growth of HER2+ lung cancers. We have launched a nonrandomized phase II trial of T-DM1 monotherapy for patients with HER2+ lung cancers. The major eligibility criteria are as follows: age ≥ 20 years, pathologically diagnosed NSCLC with documented HER2 positivity (immunohistochemistry 3+, both immunohistochemistry 2+ and fluorescence in situ hybridization positive, or exon 20 insertion mutation), and previous chemotherapy. Thirty patients will receive T-DM1 3.6 mg/kg every 3 weeks. The primary endpoint is the overall response rate. This trial will provide information on whether T-DM1 monotherapy is effective against HER2+ lung cancer.

Short-term low-volume hydration in cisplatin-based chemotherapy for patients with lung cancer: the second prospective feasibility study in the Okayama Lung Cancer Study Group Trial 1201.

OBJECTIVE: We previously reported the feasibility of short-term low-volume hydration in patients with advanced lung cancer who received cisplatin-based chemotherapy (Jpn J Clin Oncol 2013). We sought to determine the clinical usefulness of a more convenient hydration method, evaluating the safety and efficacy of shorter-term and lower-volume hydration. METHOD: Chemonaïve patients with advanced lung cancer who were ≤ 75 years and reserved an adequate renal function for cisplatin use (≥ 60 mg/m(2)) were eligible. An intravenously administered hydration of 1700 ml in ~3.5 h with 1500 ml of orally administered hydration was investigated. The primary endpoint was the proportion of patients without grade 2 or worse renal toxicity in the first cycle. RESULTS: A total of 45 patients were registered, all of whom were evaluable for renal toxicity. The median baseline creatinine score was 0.70 mg/dl, and the median cisplatin dose on day 1 was 75 mg/m(2). In the first cycle, one patient (2 %) developed grade 2 creatinine toxicity, and thus, the proportion of patients with less than grade 2 was 98 % (the lower limit of 95 % confidence interval; 93 %), which met the primary endpoint. Five patients (11 %) had grade 1 or greater nephrotoxicity, three of whom successfully recovered. The objective response rate was 24 % and median progression-free survival 5.8 months. CONCLUSION: This prospective study demonstrated the safety and efficacy of shorter-term lower-volume hydration.

Magnitude of the benefit of progression-free survival as a potential surrogate marker in phase 3 trials assessing targeted agents in molecularly selected patients with advanced non-small cell lung cancer: systematic review.

BACKGROUND: In evaluation of the clinical benefit of a new targeted agent in a phase 3 trial enrolling molecularly selected patients with advanced non-small cell lung cancer (NSCLC), overall survival (OS) as an endpoint seems to be of limited use because of a high level of treatment crossover for ethical reasons. A more efficient and useful indicator for assessing efficacy is needed. METHODS AND FINDINGS: We identified 18 phase 3 trials in the literature investigating EGFR-tyrosine kinase inhibitor (TKIs) or ALK-TKIs, now approved for use to treat NSCLC, compared with standard cytotoxic chemotherapy (eight trials were performed in molecularly selected patients and ten using an "all-comer" design). Receiver operating characteristic analysis was used to identify the best threshold by which to divide the groups. Although trials enrolling molecularly selected patients and all-comer trials had similar OS-hazard ratios (OS-HRs) (0.99 vs. 1.04), the former exhibited greater progression-free survival-hazard ratios (PFS-HR) (mean, 0.40 vs. 1.01; P<0.01). A PFS-HR of 0.60 successfully distinguished between the two types of trials (sensitivity 100%, specificity 100%). The odds ratio for overall response was higher in trials with molecularly selected patients than in all-comer trials (mean: 6.10 vs. 1.64; P<0.01). An odds ratio of 3.40 for response afforded a sensitivity of 88% and a specificity of 90%. CONCLUSION: The notably enhanced PFS benefit was quite specific to trials with molecularly selected patients. A PFS-HR cutoff of ∼0.6 may help detect clinical benefit of molecular targeted agents in which OS is of limited use, although desired threshold might differ in an individual trial.

Pulmonary tumor thrombotic microangiopathy diagnosed antemortem and treated with combination chemotherapy.

A 29-year-old man developed a persistent dry cough. Chest high-resolution computed tomography (HRCT) revealed centrilobular ultrafine granular shadows scattered in all lung fields. A lung biopsy with video-assisted thoracoscopic surgery revealed findings compatible with pulmonary tumor thrombotic microangiopathy (PTTM). However, the primary tumor was not identified. Combination chemotherapy with S-1 and cisplatin decreased his cough and improved the chest HRCT findings. The illness, however, gradually became difficult to control. He eventually developed pulmonary hypertension and died. Typically, an antemortem diagnosis of PTTM cannot be made. In this case, the diagnosis of PTTM and combination chemotherapy improved the chest HRCT findings, respiratory symptoms, and prognosis.