Clinical and Genomic Features of Response and Toxicity to Sotorasib in a Real-World Cohort of Patients With Advanced KRAS G12C-Mutant Non-Small Cell Lung Cancer.

PURPOSE: With the recent approval of the KRAS G12C inhibitor sotorasib for patients with advanced KRAS G12C-mutant non-small cell lung cancer (NSCLC), there is a new need to identify factors associated with activity and toxicity among patients treated in routine practice. MATERIALS AND METHODS: We conducted a multicenter retrospective study of patients treated with sotorasib outside of clinical trials to identify factors associated with real-world progression free survival (rwPFS), overall survival (OS), and toxicity. RESULTS: Among 105 patients with advanced KRAS G12C-mutant NSCLC treated with sotorasib, treatment led to a 5.3-month median rwPFS, 12.6-month median OS, and 28% real-world response rate. KEAP1 comutations were associated with shorter rwPFS and OS (rwPFS hazard ratio [HR], 3.19; P = .004; OS HR, 4.10; P = .003); no significant differences in rwPFS or OS were observed across TP53 (rwPFS HR, 1.10; P = .731; OS HR, 1.19; P = .631) or STK11 (rwPFS HR, 1.66; P = .098; OS HR, 1.73; P = .168) comutation status. Notably, almost all patients who developed grade 3 or higher treatment-related adverse events (G3+ TRAEs) had previously been treated with anti-PD-(L)1 therapy. Among these patients, anti-PD-(L)1 therapy exposure within 12 weeks of sotorasib was strongly associated with G3+ TRAEs (P < .001) and TRAE-related sotorasib discontinuation (P = .014). Twenty-eight percent of patients with recent anti-PD-(L)1 therapy exposure experienced G3+ TRAEs, most commonly hepatotoxicity. CONCLUSION: Among patients treated with sotorasib in routine practice, KEAP1 comutations were associated with resistance and recent anti-PD-(L)1 therapy exposure was associated with toxicity. These observations may help guide use of sotorasib in the clinic and may help inform the next generation of KRAS G12C-targeted clinical trials.

Brief Report: Combination of Osimertinib and Dacomitinib to Mitigate Primary and Acquired Resistance in EGFR-Mutant Lung Adenocarcinomas.

PURPOSE: Primary and acquired resistance to osimertinib remain significant challenges for patients with EGFR-mutant lung cancers. Acquired EGFR alterations such as EGFR T790M or C797S mediate resistance to EGFR tyrosine kinase inhibitors (TKI) and combination therapy with dual EGFR TKIs may prevent or reverse on-target resistance. PATIENTS AND METHODS: We conducted two prospective, phase I/II trials assessing combination osimertinib and dacomitinib to address on-target resistance in the primary and acquired resistance settings. In the initial therapy study, patients received dacomitinib and osimertinib in combination as initial therapy. In the acquired resistance trial, dacomitinib with or without osimertinib was administered to patients with EGFR-mutant lung cancers with disease progression on osimertinib alone and evidence of an acquired EGFR second-site mutation. RESULTS: Cutaneous toxicities occurred in 93% (any grade) of patients and diarrhea in 72% (any grade) with the combination. As initial therapy, the overall response to the combination was 73% [95% confidence interval (CI), 50%-88%]. No acquired secondary alterations in EGFR were observed in any patients at progression. In the acquired resistance setting, the overall response was 14% (95% CI, 1%-58%). CONCLUSIONS: We observed no acquired secondary EGFR alterations with dual inhibition of EGFR as up-front treatment, but this regimen was associated with greater toxicity. The combination was not effective in reversing acquired resistance after development of a second-site acquired EGFR alteration. Our study highlights the need to develop better strategies to address on-target resistance in patients with EGFR-mutant lung cancers.

A Phase 1 Safety Study of Avelumab Plus Stereotactic Body Radiation Therapy in Malignant Pleural Mesothelioma.

Introduction: Single-agent monoclonal antibody therapy against programmed death-ligand 1 (PD-L1) has modest effects in malignant pleural mesothelioma. Radiation therapy can enhance the antitumor effects of immunotherapy. Nevertheless, the safety of combining anti-PD-L1 therapy with stereotactic body radiation therapy (SBRT) is unknown. We present the results of a phase 1 trial to evaluate the safety of the anti-PD-L1 antibody avelumab plus SBRT in patients with malignant pleural mesothelioma. Methods: This was a single-arm, investigator-initiated trial in patients who progressed on prior chemotherapy. Avelumab was delivered every other week, and SBRT was delivered to one lesion in three to five fractions (minimum of 30 Gy) followed by continuation of avelumab up to 24 months or until disease progression. The primary end point of the study was safety on the basis of grade 3+ nonhematologic adverse events (AEs) within 3 months of SBRT. Results: Thirteen assessable patients received a median of seven cycles (range: 2-26 cycles) of avelumab. There were 27 grade 1, 17 grade 2, four grade 3, and no grade 4 or 5 avelumab-related AEs. The most common were infusion-related allergic reactions (n = 6), anorexia or weight loss (n = 6), fatigue (n = 6), thyroid disorders (n = 5), diarrhea (n = 3), and myalgia or arthralgias (n = 3). There were 10 grade 1, four grade 2, one grade 3, and no grade 4 or 5 SBRT-related AEs. The most common were diarrhea (n = 3), chest pain/myalgia (n = 2), fatigue (n = 2), cough (n = 2), dyspnea (n = 2), and nausea/vomiting (n = 2). Conclusions: Combination avelumab plus SBRT seems tolerable on the basis of the prespecified toxicity end points of the first stage of this Simon two-stage design phase 1 study.

Overall survival with circulating tumor DNA-guided therapy in advanced non-small-cell lung cancer.

Circulating tumor DNA (ctDNA) sequencing guides therapy decisions but has been studied mostly in small cohorts without sufficient follow-up to determine its influence on overall survival. We prospectively followed an international cohort of 1,127 patients with non-small-cell lung cancer and ctDNA-guided therapy. ctDNA detection was associated with shorter survival (hazard ratio (HR), 2.05; 95% confidence interval (CI), 1.74-2.42; P < 0.001) independently of clinicopathologic features and metabolic tumor volume. Among the 722 (64%) patients with detectable ctDNA, 255 (23%) matched to targeted therapy by ctDNA sequencing had longer survival than those not treated with targeted therapy (HR, 0.63; 95% CI, 0.52-0.76; P < 0.001). Genomic alterations in ctDNA not detected by time-matched tissue sequencing were found in 25% of the patients. These ctDNA-only alterations disproportionately featured subclonal drivers of resistance, including RICTOR and PIK3CA alterations, and were associated with short survival. Minimally invasive ctDNA profiling can identify heterogeneous drivers not captured in tissue sequencing and expand community access to life-prolonging therapy.

Erlotinib and Trametinib in Patients With EGFR-Mutant Lung Adenocarcinoma and Acquired Resistance to a Prior Tyrosine Kinase Inhibitor.

Inhibition of the MEK/ERK pathway is critical for Bcl-2-like protein 11 (BIM)-mediated epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI)-induced apoptosis, and dysregulation of this pathway may be a mechanism of acquired resistance. Therefore, MEK inhibition with trametinib and an EGFR TKI may resensitize tumors with acquired resistance. Limited targeted therapies are available after progression on EGFR TKIs, and it is in this setting that we completed a phase I/II study of erlotinib and trametinib. METHODS: Patients with metastatic EGFR-mutant lung adenocarcinoma and acquired resistance to an EGFR TKI received combination erlotinib 75 mg and trametinib 1.5 mg daily until progression or unacceptable side effects. The primary objective was objective response rate determined using RECIST version 1.1. RESULTS: Twenty-three patients were accrued; patients had received a median of two lines of prior TKI therapy (61% prior osimertinib), and 48% had acquired EGFR T790M. We confirmed one partial response (1/23, 4%, 95% CI, 0 to 22). The median progression-free survival was 1.8 months, and the median overall survival was 21 months. Diarrhea (87%), acneiform rash (87%), and fatigue (52%) were the most common treatment-related adverse events. Two patients who had tumor shrinkage both harbored a BRAF fusion. CONCLUSION: Addition of trametinib to erlotinib in the acquired resistance setting in an unselected population is not efficacious. Future studies should focus on targeted therapies in molecularly selected populations. Acquired BRAF fusions in patients with EGFR-sensitizing mutations may be a molecular subset where EGFR and MEK combination therapy could be studied further.

Pilot Study of Dacomitinib for Patients With Metastatic EGFR-Mutant Lung Cancers With Disease Progression After Initial Treatment With Osimertinib.

Patients with EGFR-mutant lung cancer have no approved targeted therapies after disease progression on first-line osimertinib, a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI). Preclinical studies suggest that tumors with both EGFR-sensitizing alteration and acquired second-site EGFR resistance alterations after treatment with osimertinib retain sensitivity to second-generation EGFR TKIs. We hypothesized that dacomitinib, a pan-human epidermal growth factor receptor TKI, may be effective in this setting. METHODS: In this phase II study, patients who had progressed on first-line osimertinib were treated with dacomitinib 45 mg orally daily until disease progression or intolerability. The primary end point was objective response rate. RESULTS: We enrolled 12 patients. Two partial responses were documented (17% objective response rate; 95% CI, 5 to 45). The median progression-free survival was 1.8 months (95% CI, 1.6 to not reached). One patient with an original sensitizing EGFR G719A mutation and one patient without molecular testing available had partial responses, whereas 0 of the 3 patients with second-site acquired EGFR resistance mutations (two C797S and one G724S) met the response criteria. The patient with EGFR G719A has an ongoing response at 17 months, which exceeds prior time on osimertinib (11 months). CONCLUSION: In the first trial evaluating a second-generation EGFR TKI after first-line third-generation osimertinib, we found that dacomitinib after disease progression on osimertinib has limited benefit.

A Phase II Trial of Albumin-Bound Paclitaxel and Gemcitabine in Patients with Newly Diagnosed Stage IV Squamous Cell Lung Cancers.

PURPOSE: Gemcitabine and albumin-bound paclitaxel (ABP) exhibit synergistic antitumor efficacy, with ABP serving to increase the intratumoral gemcitabine concentration. Both drugs are active in squamous cell lung cancers (SQCLC) and are conventional partners for carboplatin. We hypothesized that combining gemcitabine and ABP would enhance the antitumor activity in patients with advanced SQCLCs. PATIENTS AND METHODS: This was a Simon two-stage, open-label, single-arm, multicenter phase II study that enrolled patients between August 1, 2015 and June 1, 2018. We enrolled 37 patients with chemotherapy-naïve, PD-L1 low/unknown advanced stage IV SQCLC. Patients were administered weekly intravenous gemcitabine (1,000 mg/m2) plus ABP (100 mg/m2) in a 3-week on, 1-week off schedule during stage I and a 2-week on, 1-week off schedule in stage II. The primary endpoint was best objective response rate (ORR). Next-generation sequencing by MSK-IMPACT was used to calculate tumor mutation burden and genome doubling and assess somatic variants for correlations with efficacy. RESULTS: Thirty-two patients were evaluable for response assessment. The study satisfied its primary endpoint, with confirmed partial responses in 18 of 32 patients and a complete response in 1 patient [ORR 59%; 95% confidence interval (CI), 42%-74%]. Median progression-free survival (PFS), a secondary endpoint, was 7.5 (95% CI, 6.7-10.5) months. There were no unexpected toxicities. CONCLUSIONS: Gemcitabine plus ABP was a safe, tolerable, and effective first-line therapy for patients with chemotherapy-naïve SQCLCs, with an ORR and median PFS substantially higher than carboplatin doublet regimens and efficacy comparable with carboplatin plus taxane plus pembrolizumab.

Skeletonization of Left Internal Mammary Artery in Coronary Artery Bypass Grafting.

OBJECTIVE: To compare mean per-operative flow capacity between skeletonized and pedicled left internal mammary artery (LIMA) in patients undergoing coronary artery bypass grafting (CABG) surgery. STUDY DESIGN: Randomized control trial. PLACE AND DURATION OF STUDY: Department of Cardiac Surgery, Armed Forces Institute of Cardiology and National Institute of Heart Diseases (AFIC-NIHD), Rawalpindi, Pakistan from February to August, 2013. METHODOLOGY: Patients undergoing CABG for coronary artery disease, under 80 years, excluded by the exclusion criteria; and fulfilling the inclusion criteria were randomly assigned to two groups of 70 each. One group underwent skeletonized and the other underwent pedicled technique of LIMAharvesting. Free flow was checked just before anastamosis of each LIMAto the LAD, manually in blood flow in ml per minute during cardiopulmonary bypass by allowing it to bleed into a 100 ml container over 20 seconds. Aspecialized proforma was used to record the age, gender, weight, disease, type of IMA used, and free flow of the IMA. Data was analyzed using SPSS 18. RESULTS: The mean age of the patients was 57.16 years in 40 patients, ranging from 36 to 75 years. Disease pattern analysis showed 5%, 10.7% and 84.3% single, double and triple vessel coronary artery disease, respectively. There was significantly higher free flow in the skeletonized group than the pedicled group (p=0.04). CONCLUSION: Skeletonized IMAhad superior flow to pedicled IMAin addition to its traditional proven advantages, which justifies its further use as a conduit for myocardial revascularization.

Large Cell Neuroendocrine Carcinoma of the Lung: Clinico-Pathologic Features, Treatment, and Outcomes.

BACKGROUND: Large cell neuroendocrine carcinoma (LCNEC) accounts for approximately 3% of lung cancers. Pathologic classification and optimal therapies are debated. We report the clinicopathologic features, treatment and survival of a series of patients with stage IV LCNEC. MATERIALS AND METHODS: Cases of pathologically-confirmed stage IV LCNEC evaluated at Memorial Sloan Kettering Cancer Center from 2006 to 2013 were identified. We collected demographic, treatment, and survival data. Available radiology was evaluated by Response Evaluation Criteria In Solid Tumors (RECIST) 1.1 criteria. RESULTS: Forty-nine patients with stage IV LCNEC were identified. The median age was 64 years, 63% of patients were male, and 88% were smokers. Twenty-three patients (n = 23/49; 47%) had brain metastases, 17 at diagnosis and 6 during the disease course. Seventeen LCNEC patients (35%) had molecular testing, of which 24% had KRAS mutations (n = 4/17). Treatment data for first-line metastatic disease was available on 37 patients: 70% (n = 26) received platinum/etoposide and 30% (n = 11) received other regimens. RECIST was completed on 23 patients with available imaging; objective response rate was 37% (95% confidence interval, 16%-62%) with platinum/etoposide, while those treated with other first-line regimens did not achieve a response. Median overall survival was 10.2 months (95% confidence interval, 8.6-16.4 months) for the entire cohort. CONCLUSION: Patients with stage IV LCNEC have a high incidence of brain metastases. KRAS mutations are common. Patients with stage IV LCNEC do not respond as well to platinum/etoposide compared with historic data for extensive stage small-cell lung cancer; however, the prognosis is similar. Prospective studies are needed to define optimum therapy for stage IV LCNEC.

Topical application of tranexamic acid reduces postoperative bleeding in open-heart surgery: myth or fact?

OBJECTIVE: To determine the efficacy of topical application of Tranexamic acid in controlling postoperative bleeding in open-heart surgery. STUDY DESIGN: Double blind randomized control trial. PLACE AND DURATION OF STUDY: Departments of Cardiac Surgery and Intensive Care of Armed Forces Institute of Cardiology and National Institute of Heart Diseases (AFIC-NIHD), Rawalpindi, Pakistan, from May to October 2011. METHODOLOGY: A total of 100 consecutive adult patients fulfilling the inclusion criteria undergoing elective on-pump cardiac surgeries were randomly divided in groups 'A' and 'B'. A study solution that contained 2.5 g of Tranexamic acid in 250 ml normal saline in group-A and equal amount of normal saline (placebo) in group-B was poured in the pericardial cavity over the mediastinal tissues before sternal closure. Postoperative bleeding was measured in both groups for 24 hours in the cardiac surgical ICU. Efficacy of Topical Tranexamic Acid / Placebo was measured in terms of mean postoperative bleeding in ml. Kindly again include these lines which seem to have been omitted in the final proof. RESULTS: There was significant difference in the mean postoperative bleeding within 24 hours among the two groups 340.1 ± 112.4 ml in Tranexamic acid group vs. 665 ± 187.28 ml in placebo group (p < 0.001). CONCLUSION: Patients who did not have topical Tranexamic acid before chest closure had a significantly higher postoperative bleeding. Topical Tranexamic acid application is an effective and economical way for controlling non-surgical bleeding in patients undergoing cardiac surgery with cardiopulmonary bypass.

A Case of Malignant Metastatic Pheochromocytoma After Eight Years of Primary Diagnosis.

We report a case of a 66-year-old female who presented to the hospital with abdominal discomfort for 3 months. Work-up revealed a 2.4 cm mass in the right adrenal gland. A laparoscopic resection of the adrenal mass was performed and the histopathology was consistent with a pheochromocytoma. Patient was under active surveillance for 8 years, until she developed local recurrence in the right adrenal bed. A right adrenal bed resection and right nephrectomy were performed. Although the tumor margins were positive, none of the sampled lymph nodes (0/6) were positive for metastasis. Patient refused any adjuvant therapy, and was discharged on surveillance from the hospital. A year later, patient was found to have metastatic disease involving her spine, iliac bones, bilateral hips and right dome of the diaphragm. Patient was offered a metaiodobenzylguanidine scan, and positive subsequent treatment with radioactive iodine was discussed with her. However, she denied any further intervention and was made hospice.

Induced remote ischemic pre-conditioning on ischemia-reperfusion injury in patients undergoing coronary artery bypass.

OBJECTIVE: To determine the role of remote ischemic pre-conditioning (rIPC) on myocardium, against ischemia reperfusion injury in patients undergoing coronary artery bypass graft (CABG) surgery by measuring CKMB levels. STUDY DESIGN: A randomized controlled trial. PLACE AND DURATION OF STUDY: The Surgical Department of Armed Forces Institute of Cardiology/National Institute of Heart Diseases, Rawalpindi, from January to June 2008. METHODOLOGY: One hundred patients with double and triple vessels coronary artery disease were randomized in two groups of 50 each. rIPC protocol consisted of 3 x 5 minutes of forearm ischemia, induced by a blood pressure cuff inflated to 200 mmHg, with an intervening 5 minutes of reperfusion, during which the cuff was deflated. Patients in the control group were not subjected to limb ischemia. The protocol of induced ischemia was completed before placing patients on extracorporeal bypass circuit. At the end of surgery serum CKMB levels were measured and compared at 8, 16, 24 and 48 hours from both the groups. Written informed consent was taken from patients. Study was approved by the hospital ethical committee. RESULTS: Remote ischemic pre-conditioning significantly reduced CKMB levels at 8, 16, 24 and 48 hours after surgery with p-values of 0.026, 0.021, 0.052 and 0.003 respectively. There was mean reduction of 3 iu/l in CKMB levels, in patients who underwent rIPC protocol prior to CABG surgery, compared to control group. CONCLUSION: This study showed a significant reduction of enzyme marker CKMB in patients subjected to rIPC prior to CABG surgery. This suggests lesser degree of myocardial damage compared to control group in CABG patients.

Coronary endarterectomy for severe diffuse coronary artery disease.

OBJECTIVE: To determine the outcome of Coronary Endarterectomy (CE) in patients undergoing Coronary Artery Bypass Graft (CABG) surgery for diffuse Coronary Artery Disease (CAD), in terms of postoperative mortality and morbidity, relief from angina and survival at one year. STUDY DESIGN: A case series. PLACE AND DURATION OF STUDY: Department of Cardiac Surgery, Armed Forces Institute of Cardiology and National Institute of Heart Diseases, Rawalpindi, from January 2003 to November 2005. METHODOLOGY: Included in the study were all patients with such diffuse CAD that conventional bypass grafting was not possible. Those with the diseased coronary artery supplying an akinetic myocardium and a fixed perfusion defect on perfusion scan, or with poor left ventricular function (ejection fraction<30%) in association with severe chronic hepatic disease and deranged liver function tests, permanent severe immune deficiency state, or poor results at lung function tests were excluded. Cardiopulmonary Bypass (CPB) was used in all patients. All patients were followed up for a mean time of one year, for assessment of postoperative mortality and morbidity, relief from angina and survival. RESULTS: Fifty five patients (3.2%) underwent CE of at least one major coronary artery for severe diffuse atheromatous disease. The mean age was 53.9+/-9.5 years. Twenty six (47.3%) had previous Myocardial Infarction (MI), 16 (29.1%) had unstable angina, 12 (21.8%) had poor Left Ventricular (LV) function, 5 (9.1%) underwent emergency CABG surgery for impending infarction, 39 (70.9%) had angina Canadian Cardiovascular Society (CCS) class II/III, 11 (20%) had critical left main stem disease and 12 (21.8%) required Intra-Aortic Balloon Pump (IABP) for hemodynamic support. There were 2 (3.6%) early deaths and 2 (3.6%) cases of non-fatal infarctions. Three (5.4%) patients had low Cardiac Output (CO) after operation. At one year follow-up, there were no late deaths and 43 patients (91.5% of those reporting for follow-up) did not have angina. CONCLUSION: CE acted as an adjunct to CABG surgery with acceptable operative risks and satisfactory results at one year in terms of mortality and angina relief.

Placing epicardial pacing wires in isolated coronary artery bypass graft surgery--a procedure routinely done but rarely beneficial.

BACKGROUND: After Coronary Artery Bypass Graft (CABG) surgery, temporary epicardial pacing wires are placed on heart to meet unforeseen complications like bradyarrhythmias or asystoles. This step needs additional time, resources and has potential to cause complication. Even having less complications, is this additional step in elective CABG surgery necessary? Some important predictive factors in patients who require this pacing wire placement have to be isolated. The objective of the study was to avoid this step if not required especially in elective CABG surgery. METHODS: This prospective observational study involved 1047 consecutive patients undergoing CABG at our institution from May 2006 to April 2008. Patient who did not receive pacing wire (230), Preoperative pacemaker (2), CABG with valvular surgery (10), CABG with Ischemic VSD or MR surgery (3), off-pump CABG (21), or incomplete follow-up (11) were excluded from the study. Patients who received pacing wire (770) were divided in two groups. Group A, consisted of patients who did not require pacing postoperatively 748 (97.1%), and Group B, who required pacing postoperatively 22 (2.9%). Both groups were compared in demographic, preoperative, per-operative and postoperative variables. The incidence of pacing during the postoperative period was recorded. Predictors for postoperative pacing were determined using medical records and the AFIC/NIHD cardiac surgery database. RESULTS: In the postoperative period, 22 of 770 patients (2.9%) required pacing. Analysis identified age (p = 0.02), preoperative arrhythmia, especially Bundle Branch Block (p = 0.000), pacing utilized at separation from bypass (p = 0.000) and use of antiarrhythmics on leaving the operating room (p = 0.015) as predictors of the need for postoperative pacing. Diabetes, considered one of the major factor requiring pacing was not significant in our study (p = 0.379). Preoperative arrhythmias, pacing utilized to separate from bypass and use of antiarrhythmics on leaving the operating room were found to be three most significant risk factors. If the patients with any of these three risk factors are excluded, only 1.11% (8/716) of them would have required pacing. CONCLUSIONS: Procedure of routine use of temporary epicardial pacing after elective CABG surgery has negligible role, rather has additional cost and potential of rare complications. Diabetes is not a risk factor for post operative pacing.

Persistent pain in anal cancer survivors.

INTRODUCTION: Anorectal cancers are highly curable malignancies. Combined modality treatment with chemotherapy and radiation has dramatically improved both disease-free and overall survival. Little is known about symptomatic complications of treatment. METHODS: Case report based on chart review. RESULTS: Two patients presented with painful anal lesions that were diagnosed as squamous cell carcinoma of the anus. Despite successful treatment with chemotherapy and radiation, their pain syndromes worsened after treatment with development of a lumbosacral plexopathy that required regular followup, imaging, and pain medications. CONCLUSION: Pain syndromes may worsen after successful treatment given with curative intent, and may be a form of treatment toxicity. IMPLICATIONS FOR CANCER SURVIVORS: Treatment related lumbosacral plexopathy may be an unrecognized consequence of the successful treatment of anal carcinoma. These symptoms can be controlled with analgesics.