P. Fidias

Genotypic and Histological Evolution of Lung Cancers Acquiring Resistance to EGFR Inhibitors

Lung cancers undergo dynamic genetic and histological changes upon developing resistance to EGFR inhibitors. The Shifting Sands of Lung Cancer Lung cancer is the leading cause of death globally and has proven very difficult to treat. The development almost a decade ago of tyrosine kinase inhibitors that specifically block the epidermal growth factor receptor (EGFR), which is switched on in many lung cancers, provided hope that targeted therapies would finally combat this deadly disease. However, only a certain subpopulation of lung cancer patients carrying specific activating mutations in EGFR responded clinically to EGFR inhibitors, and even among these patients, resistance to the inhibitor emerged within 12 months. To better understand how lung cancers develop drug resistance, Sequist and colleagues undertook a comprehensive genetic and histological analysis of 37 patients with non–small cell lung cancer (NSCLC), and they made some surprising discoveries. In an effort to understand the exact mechanism underscoring the acquisition of drug resistance in NSCLC patients treated with EGFR inhibitors, the investigators analyzed tumor biopsies from patients at the time they acquired resistance. All of the lung cancer patients retained their original activating EGFR mutations, but some patients had acquired another mutation in EGFR (T790M), which interferes with binding of the drug to the receptor, rendering the tumors resistant. Meanwhile, another group of patients became resistant because they developed amplification of a gene encoding the MET tyrosine kinase receptor, which, like EGFR, drives cell growth. Yet other patients acquired drug resistance mechanisms that had not been reported before including amplification of the EGFR gene itself and mutations in the PIK3CA gene (which encodes a subunit of the signaling molecule phosphatidylinositol 3-kinase). In addition, the authors observed that a few lung cancers transitioned from an epithelial cell morphology to a mesenchymal cell–like appearance, which is associated with a more aggressive type of tumor. In five patients, the authors discovered another type of transition that was even more surprising: the conversion of NSCLCs into small cell lung cancers (SCLCs), which are easier to treat. Indeed, these five patients responded well to the typical chemotherapy regimen used to treat SCLCs. To study the evolution of lung tumors in patients over the course of their disease, the investigators took serial biopsies from three lung cancer patients over 2 years. They found that when the patients acquired drug resistance and were then taken off the EGFR inhibitor, they lost the resistance mutations and their tumors once again became sensitive to treatment by either the same or a different EGFR inhibitor. The detailed genetic and histological analysis by Sequist and colleagues provides new insights into the shifting sands of drug resistance evolution in lung cancers and suggests that serial biopsies may be essential in the quest to reverse or even prevent the development of drug resistance. Lung cancers harboring mutations in the epidermal growth factor receptor (EGFR) respond to EGFR tyrosine kinase inhibitors, but drug resistance invariably emerges. To elucidate mechanisms of acquired drug resistance, we performed systematic genetic and histological analyses of tumor biopsies from 37 patients with drug-resistant non–small cell lung cancers (NSCLCs) carrying EGFR mutations. All drug-resistant tumors retained their original activating EGFR mutations, and some acquired known mechanisms of resistance including the EGFR T790M mutation or MET gene amplification. Some resistant cancers showed unexpected genetic changes including EGFR amplification and mutations in the PIK3CA gene, whereas others underwent a pronounced epithelial-to-mesenchymal transition. Surprisingly, five resistant tumors (14%) transformed from NSCLC into small cell lung cancer (SCLC) and were sensitive to standard SCLC treatments. In three patients, serial biopsies revealed that genetic mechanisms of resistance were lost in the absence of the continued selective pressure of EGFR inhibitor treatment, and such cancers were sensitive to a second round of treatment with EGFR inhibitors. Collectively, these results deepen our understanding of resistance to EGFR inhibitors and underscore the importance of repeatedly assessing cancers throughout the course of the disease.

Randomized, multinational, phase III study of docetaxel plus platinum combinations versus vinorelbine plus cisplatin for advanced non-small-cell lung cancer: The TAX 326 Study Group

PURPOSE To investigate whether docetaxel plus platinum regimens improve survival and affect quality of life (QoL) in advanced non-small-cell lung cancer (NSCLC) compared with vinorelbine plus cisplatin as first-line chemotherapy. PATIENTS AND METHODS Patients (n = 1,218) with stage IIIB to IV NSCLC were randomly assigned to receive docetaxel 75 mg/m2 and cisplatin 75 mg/m2 every 3 weeks (DC); docetaxel 75 mg/m2 and carboplatin area under the curve of 6 mg/mL * min every 3 weeks (DCb); or vinorelbine 25 mg/m2/wk and cisplatin 100 mg/m2 every 4 weeks (VC). RESULTS Patients treated with DC had a median survival of 11.3 v 10.1 months for VC-treated patients (P =.044; hazard ratio, 1.183 [97.2% confidence interval, 0.989 to 1.416]). The 2-year survival rate was 21% for DC-treated patients and 14% for VC-treated patients. Overall response rate was 31.6% for DC-treated patients v 24.5% for VC-treated patients (P =.029). Median survival (9.4 v 9.9 months [for VC]; P =.657; hazard ratio, 1.048 [97.2 confidence interval, 0.877 to 1.253]) and response (23.9%) with DCb were similar to those results for VC. Neutropenia, thrombocytopenia, infection, and febrile neutropenia were similar with all three regimens. Grade 3 to 4 anemia, nausea, and vomiting were more common (P <.01) with VC than with DC or DCb. Patients treated with either docetaxel regimen had consistently improved QoL compared with VC-treated patients, who experienced deterioration in QoL. CONCLUSION DC resulted in a more favorable overall response and survival rate than VC. Both DC and DCb were better tolerated and provided patients with consistently improved QoL compared with VC. These findings demonstrate that a docetaxel plus platinum combination is an effective treatment option with a favorable therapeutic index for first-line treatment of advanced or metastatic NSCLC.

Activity and safety of crizotinib in patients with ALK-positive non-small-cell lung cancer: updated results from a phase 1 study

BACKGROUND ALK fusion genes occur in a subset of non-small-cell lung cancers (NSCLCs). We assessed the tolerability and activity of crizotinib in patients with NSCLC who were prospectively identified to have an ALK fusion within the first-in-man phase 1 crizotinib study. METHODS In this phase 1 study, patients with ALK-positive stage III or IV NSCLC received oral crizotinib 250 mg twice daily in 28-day cycles. Endpoints included tumour responses, duration of response, time to tumour response, progression-free survival (PFS), overall survival at 6 and 12 months, and determination of the safety and tolerability and characterisation of the plasma pharmacokinetic profile of crizotinib after oral administration. Responses were analysed in evaluable patients and PFS and safety were analysed in all patients. This study is registered with ClinicalTrials.gov, number NCT00585195. FINDINGS Between Aug 27, 2008, and June 1, 2011, 149 ALK-positive patients were enrolled, 143 of whom were included in the response-evaluable population. 87 of 143 patients had an objective response (60·8%, 95% CI 52·3-68·9), including three complete responses and 84 partial responses. Median time to first documented objective response was 7·9 weeks (range 2·1-39·6) and median duration of response was 49·1 weeks (95% CI 39·3-75·4). The response rate seemed to be largely independent of age, sex, performance status, or line of treatment. Median PFS was 9·7 months (95% CI 7·7-12·8). Median overall survival data are not yet mature, but estimated overall survival at 6 and 12 months was 87·9% (95% CI 81·3-92·3) and 74·8% (66·4-81·5), respectively. 39 patients continued to receive crizotinib for more than 2 weeks after progression because of perceived ongoing clinical benefit from the drug (12 for at least 6 months from the time of their initial investigator-defined disease progression). Overall, 144 (97%) of 149 patients experienced treatment-related adverse events, which were mostly grade 1 or 2. The most common adverse events were visual effects, nausea, diarrhoea, constipation, vomiting, and peripheral oedema. The most common treatment-related grade 3 or 4 adverse events were neutropenia (n=9), raised alanine aminotransferase (n=6), hypophosphataemia (n=6), and lymphopenia (n=6). INTERPRETATION Crizotinib is well tolerated with rapid, durable responses in patients with ALK-positive NSCLC. There seems to be potential for ongoing benefit after initial disease progression in this population, but a more formal definition of ongoing benefit in this context is needed.

Phase I clinical trial of bortezomib in combination with gemcitabine in patients with advanced solid tumors

Bortezomib is the first proteasome inhibitor to show preliminary evidence of activity against solid tumors. Findings from preclinical studies prompted a Phase I trial to determine the maximum tolerated dose (MTD) and dose‐limiting toxicities (DLTs) of bortezomib in combination with gemcitabine in patients with recurring/refractory advanced solid tumors. The effect of gemcitabine on proteasome inhibition by bortezomib in whole blood was also investigated.

DNA Repair Biomarkers Predict Response to Neoadjuvant Chemoradiotherapy in Esophageal Cancer

PURPOSE The addition of neoadjuvant chemoradiotherapy prior to surgical resection for esophageal cancer has improved clinical outcomes in some trials. Pathologic complete response (pCR) following neoadjuvant therapy is associated with better clinical outcome in these patients, but only 22% to 40% of patients achieve pCR. Because both chemotherapy and radiotherapy act by inducing DNA damage, we analyzed proteins selected from multiple DNA repair pathways, using quantitative immunohistochemistry coupled with a digital pathology platform, as possible biomarkers of treatment response and clinical outcome. METHODS AND MATERIALS We identified 79 patients diagnosed with esophageal cancer between October 1994 and September 2002, with biopsy tissue available, who underwent neoadjuvant chemoradiotherapy prior to surgery at the Massachusetts General Hospital and used their archived, formalin-fixed, paraffin-embedded biopsy samples to create tissue microarrays (TMA). TMA sections were stained using antibodies against proteins in various DNA repair pathways including XPF, FANCD2, PAR, MLH1, PARP1, and phosphorylated MAPKAP kinase 2 (pMK2). Stained TMA slides were evaluated using machine-based image analysis, and scoring incorporated both the intensity and the quantity of positive tumor nuclei. Biomarker scores and clinical data were assessed for correlations with clinical outcome. RESULTS Higher scores for MLH1 (p = 0.018) and lower scores for FANCD2 (p = 0.037) were associated with pathologic response to neoadjuvant chemoradiation on multivariable analysis. Staining of MLH1, PARP1, XPF, and PAR was associated with recurrence-free survival, and staining of PARP1 and FANCD2 was associated with overall survival on multivariable analysis. CONCLUSIONS DNA repair proteins analyzed by immunohistochemistry may be useful as predictive markers for response to neoadjuvant chemoradiotherapy in patients with esophageal cancer. These results are hypothesis generating and need confirmation in an independent data set.

Preoperative Cetuximab, Irinotecan, Cisplatin, and Radiation Therapy for Patients With Locally Advanced Esophageal Cancer

PURPOSE To determine the efficacy and toxicity of weekly neoadjuvant cetuximab combined with irinotecan, cisplatin, and radiation therapy in patients with locally advanced esophageal or gastroesophageal junction cancer. METHODS AND MATERIALS Patients with stage IIA-IVA esophageal or gastroesophageal junction cancer were enrolled in a Simons two-stage phase II study. Patients received weekly cetuximab on weeks 0-8 and irinotecan and cisplatin on weeks 1, 2, 4, and 5, with concurrent radiotherapy (50.4 Gy on weeks 1-6), followed by surgical resection. RESULTS In the first stage, 17 patients were enrolled, 16 of whom had adenocarcinoma. Because of a low pathologic complete response (pCR) rate in this cohort, the trial was discontinued for patients with adenocarcinoma but squamous cell carcinoma patients continued to be enrolled; two additional patients were enrolled before the study was closed as a result of poor accrual. Of the 19 patients enrolled, 18 patients proceeded to surgery, and 16 patients underwent an R0 resection. Three patients (16%) had a pCR. The median progression-free survival interval was 10 months, and the median overall survival duration was 31 months. Severe neutropenia occurred in 47% of patients, and severe diarrhea occurred in 47% of patients. One patient died preoperatively from sepsis, and one patient died prior to hospital discharge following surgical resection. CONCLUSIONS This schedule of cetuximab in combination with irinotecan, cisplatin, and radiation therapy was toxic and did not achieve a sufficient pCR rate in patients with localized esophageal adenocarcinoma to undergo further evaluation.

Neo-adjuvant radiation, cisplatin, 5-FU +/− paclitaxel in locally advanced esophageal cancer

4042 Background: A phase I-II study of neo-adjuvant cisplatin, 5-FU, paclitaxel and radiation (PFT-R) performed at our institution yielded encouraging pathologic complete response (pCR) rates, but with significant toxicity. This retrospective study was designed to examine the results of our experience with PFT-R compared to our experience with cisplatin, 5-FU and RT (PF-R) in patients with locally advanced esophageal cancer. METHODS We searched the MGH cancer registry for all patients with esophageal cancer treated with radiation (RT) and chemotherapy between 1994-2002. Records of patients treated with curative, neo-adjuvant therapy were examined for chemotherapeutic regimen. The outcomes of patients treated with PF-R or PFT-R were assessed for response to therapy, toxicity, and survival. Most patients received two cycles of either cisplatin 25 mg/m2, 5-FU 1000 mg/m2 or cisplatin 20 mg/m2, 5-FU 800 mg/m2 and taxol 100 mg/m2 with a median RT dose of 54 Gy. RESULTS 177 patients were treated with a curative neo-adjuvant approach. 166 (94%) were treated with PF-R (N=82) or PFT-R (N=84). 16 patients (PF=8, PFT=8) treated with neo-adjuvant intent did not have surgical resection of their tumor. The pCR rate for all patients was 37 %. There was no difference between PF-R (40%) and PFT-R (33%). There was no difference in median survival between PF-R and PFT-R with an overall median survival of 24 months. After a median follow-up of 54 months for surviving patients overall survival at 3 years was 40 % with no significant difference PF-R (39 %) and PFT-R (42 %). There were 12 treatment related deaths (7%), 6 in each treatment group. There were no differences in the incidence of ≥ Grade 3 toxicities PF-R (79%), PFT-R (80%). CONCLUSIONS The addition of paclitaxel to neo-adjuvant PF-R as delivered in this regimen failed to improve pCR rates or overall survival. Our results do not support the use of this regimen of concurrent neoadjuvant PFT-R in patients with esophageal cancer. No significant financial relationships to disclose.

Case records of the Massachusetts General Hospital. Case 17-2014. A 64-year-old man with chest pain and a pleural effusion.

Dr. Richard L. Kradin: A 64-year-old man was admitted to this hospital because of recurrent pleuritic chest pain and a pleural effusion. The patient had been in his usual health until 3.5 weeks before this admission, when left-sided chest pain developed suddenly; it was not associated with exertion, was worse with inspiration, and was associated with dyspnea. He came to the emergency department of this hospital. He rated the pain at 4 on a scale of 0 to 10 (with 10 indicating the most severe pain) and reported that it was unlike any pain he had had before. He had not had a fever or chills. On examination, there were decreased breath sounds on the left side. There was swelling of the right calf, with 3+ pitting edema, which the patient described as chronic. The white-cell count and levels of d-dimer and troponin I were normal. Dr. Subba Digumarthy: A frontal chest radiograph obtained at that time (Fig. 1A) shows a left basilar opacity obscuring the left hemidiaphragm and blunting of the left costophrenic angle. These features are indicative of a left pleural effusion and atelectasis or consolidation in the left lower lobe. Computed tomography (CT) of the chest, performed according to the pulmonary-embolism protocol, reveals a small loculated left pleural effusion, with thickened and enhancing pleura (Fig. 1B). There is patchy consolidation in the left lower lobe (Fig. 1C). These findings could represent pneumonia, possibly due to aspiration, and associated empyema. There are scattered small indeterminate lung nodules, measuring up to 4 mm in diameter. There are no pulmonary emboli. An abdominal CT scan that was obtained 1 year earlier shows no left pleural effusion or thickening (Fig. 1D). Dr. Kradin: Metronidazole and levofloxacin were administered, and the patient was admitted to the hospital (3.5 weeks before the current admission). Fluoroscopic studies revealed normal oropharyngeal swallowing with moderate intraesophageal retrograde flow, a finding possibly consistent with postprandial aspiration. A pneumococcal vaccine was administered, and previous influenza vaccinations were documented. Sputum cultures grew very few colonies of yeast and normal respiratory flora. Aspiration of the loculated effusion that was seen on the CT scan was not Case 17-2014: A 64-Year-Old Man with Chest Pain and a Pleural Effusion

Phase II trial of carboplatin, abraxane, and bevacizumab in NSCLC.

e18016 Background: The addition of bevacizumab to carboplatin and paclitaxel has been shown to improve survival. Abraxane (nab-paclitaxel) may yield higher response rates than paclitaxel in NSCLC. This Phase II study was designed to investigate the combination of carboplatin (C), nab-paclitaxel (N-P), and bevacizumab (B) in first-line treatment of advanced NSCLC. Pharmacodynamic blood and imaging studies were performed to better understand the mechanism of action of bevacizumab both alone and in combination with chemotherapy and to assess biomarkers of response. METHODS Pts with previously untreated, non-squamous, advanced NSCLC were enrolled in an open-label Phase II trial. All patients were given a single induction dose of B 15 mg/kg on day -14. On day 1 combination therapy started with C AUC 6 d1, N-P 100 mg/m2 d 1, 8, 15, and B 15 mg/kg d1, on a 21 day cycle. Correlative imaging and biomarker studies were performed with FDG-PET, perfusion CT, and blood for circulating cellular and molecular biomarkers, on days -14 and -2 (prior to and 12 days after induction B), and every two cycles during treatment. Planned enrollment was 36. Changes in biomarkers from day -14 to day -2 were tested using the exact paired Wilcoxon test, and correlations with best percent difference in RECIST measurements of response were tested using the Kendalls tau test. RESULTS Twenty-five pts have been enrolled thus far. Four pts came off study prior to first restaging; one for painful bony disease requiring radiation and three for toxicity (perforated diverticulitis, LFT abnormalities, and nausea/vomiting). One pt is currently in cycle 1; another pt dropped out before receiving any study drug. Of 19 pts evaluable for response to date, best response was 8 PR, 9 SD, and 2 PD. Induction B treatment was associated with statistically significant increases in levels of VEGF, PIGF, and SDF1a, and decrease in sVEGFR-1 levels. Blood flow and permeability decreased from baseline to day -2. CONCLUSIONS Disease control rate (PR + SD) with combination therapy with C, N-P, and B was 74% (17/23). Pharmacodynamic blood and imaging biomarker studies in bevacizumab-treated NSCLC patients are feasible.