Immunotherapy in lung cancer Massarelli, Erminia; Papadimitrakopoulou, Vassiliki; Welsh, James ...
Translational lung cancer research,
02/2014, Volume:
3, Issue:
1
Journal Article
Survival rates for metastatic lung cancer including non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC) are poor with 5-year survival of less than 5%. The use of molecular targeted ...therapies has improved median overall survival (OS) in a limited group of NSCLC patients whose tumors harbor specific genetic alterations. However for a large group of NSCLC and SCLC molecular alterations are not available to lead to direct targeted therapies. Recent favorable results of newer trials of therapeutic vaccines and checkpoint inhibitors have proven against the common belief that lung cancer is nonimmunogenic. In particular, the checkpoint inhibitors targeting cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) and the programmed death-1 (PD-1) pathway have shown durable clinical responses with manageable toxicity. Several phase II and III clinical trials testing the association of different schedule of chemotherapy and immunotherapy or immunotherapy alone are ongoing in lung cancer and important results are expected in the near future. However, more studies are needed to understand the optimal combination of immunotherapeutic agents with chemotherapy and radiation therapy for the treatment of NSCLC and SCLC.
Trimodality therapy may prolong survival for patients with resectable malignant pleural mesothelioma. However, many patients are unable to complete therapy. We sought to identify risk factors for ...failing to complete adjuvant intensity-modulated radiation therapy after cytoreduction for malignant pleural mesothelioma.
We performed a single-institution review of those who received an extrapleural pneumonectomy or pleurectomy/decortication for malignant pleural mesothelioma from 2004 to 2017. Multivariable logistic regression was used to assess preoperative or intraoperative risk factors associated with failing to complete adjuvant intensity-modulated radiation therapy.
A total of 160 patients were identified, among whom 94 (59%) received an extrapleural pneumonectomy and 66 (41%) received a pleurectomy/decortication. Adjuvant intensity-modulated radiation therapy was completed among 105 patients (66%). Reasons for failing to complete adjuvant intensity-modulated radiation therapy included mortality (19), dose constraints (21), postoperative morbidity or delayed recovery (11), and refused or unknown status (4). On multivariable analysis, American Society of Anesthesiologists 3+ classification (P = .002) and smoking history (P = .022) were associated with failure to complete adjuvant intensity-modulated radiation therapy, whereas forced expiratory volume in 1 second 70% or less of predicted and pStage 4 (T4) were significant on univariable analysis only. Other factors, including extrapleural pneumonectomy or pleurectomy/decortication, margin status, age, and histology, were not associated with receiving adjuvant intensity-modulated radiation therapy.
Many patients are unable to complete adjuvant intensity-modulated radiation therapy after cytoreduction. Failure to complete adjuvant intensity-modulated radiation therapy was associated with worse preoperative comorbidity, but not the type of surgery or margin status.
Background
Malignant pleural mesothelioma (MPM) is associated with poor prognosis despite advances in multimodal therapeutic strategies. While patients with resectable disease may benefit from added ...survival with oncologic resection, patient selection for mesothelioma operations often relies on both objective and subjective evaluation metrics. We sought to evaluate factors associated with improved overall survival (OS) in patients with mesothelioma who underwent macroscopic complete resection (MCR).
Methods
Patients with MPM who received neoadjuvant therapy and underwent MCR were identified in a prospectively maintained departmental database. Clinicopathologic, blood-based, and radiographic variables were collected and included in a Cox regression analysis (CRA). Response to neoadjuvant therapy was characterized by a change in tumor thickness from pretherapy to preoperative scans using the modified RECIST criteria.
Results
In this study, 99 patients met the inclusion criteria. The median age of the included patients was 64.7 years, who were predominantly men, had smoking and asbestos exposure, and who received neoadjuvant therapy. The median change in tumor thickness following neoadjuvant therapy was –16.5% (interquartile range of -49.7% to +14.2%). CRA demonstrated reduced OS associated with non-epithelioid histology hazard ratio (HR): 3.06, 95% confidence interval (CI): 1.62–5.78, p < 0.001 and a response to neoadjuvant therapy inferior to the median (HR: 2.70, CI: 1.55–4.72, p < 0.001). Patients who responded poorly (below median) to neoadjuvant therapy had lower median survival (15.8 months compared to 38.2 months, p < 0.001).
Conclusion
Poor response to neoadjuvant therapy in patients with MPM is associated with poor outcomes even following maximum surgical cytoreduction and should warrant a patient-centered discussion regarding goals of care and may therefore help guide further therapeutic decisions.
In malignant pleural mesothelioma, targeting angiogenesis with cediranib, a vascular endothelial growth factor receptor and platelet-derived growth factor receptor inhibitor, may have therapeutic ...potential.
S0905 phase I combined cediranib (two dose cohorts 30 mg and 20 mg daily) with cisplatin-pemetrexed for six cycles followed by maintenance cediranib in unresectable chemonaive patients with malignant pleural mesothelioma of any histologic subtype. The primary end point established the maximum tolerated dose in combination with cisplatin-pemetrexed in a dose deescalation scheme.
A total of 20 patients were enrolled (seven to the 30-mg cohort and 13 to the 20-mag cohort). In the cediranib 30-mg cohort, two of the initial six patients reported dose-limiting toxicities and the dose was deemed too toxic to continue. In the next cohort, two patients experienced dose-limiting toxicities, and thus, the maximum tolerated dose of cediranib was established as 20 mg. During the six cycles of cisplatin-pemetrexed-cediranib, 20 mg, there were grade 3 toxicities (neutropenia and gastrointestinal) and grade 4 thrombocytopenia. No patients had any significant episodes of bleeding. According to the Response Evaluation Criteria in Solid Tumors (n = 17 evaluable patients), the median progression-free survival was 12.8 months (95% confidence interval CI: 6.9–17.2); according to the Modified Response Evaluation Criteria in Solid Tumors (n = 19 evaluable patients), the median progression-free survival was 8.6 months (95% CI: 6.1–10.9). For all patients, the disease control rate at 6 weeks was 90% and median overall survival time was 16.2 months (95% CI: 10.5–28.7).
Cediranib combined with cisplatin-pemetrexed has a reasonable toxicity profile and preliminary promising efficacy. The phase II S0905 trial will evaluate the efficacy of the triplet regimen compared with the current standard of care, cisplatin-pemetrexed.
Lessons Learned
Treatment with the Aurora kinase A inhibitor yields often durable disease control, but limited tumor regression, in heavily pretreated patients with unresectable malignant pleural or ...peritoneal mesothelioma.
In a limited sample size, MYC copy‐number gain or gene amplification, a candidate predictive biomarker for alisertib, did not correlate with improved response numbers or patient outcomes.
Background
Malignant mesothelioma is an aggressive disease for which few effective therapies are available. The Aurora family kinases are critical for mitotic fidelity and highly expressed in mesothelioma, wherein their inhibition leads to growth arrest in vitro. We evaluated the efficacy of alisertib, an Aurora A kinase inhibitor, in relapsed malignant mesothelioma.
Methods
Twenty‐six patients with previously treated, unresectable pleural or peritoneal mesothelioma were enrolled on a single‐arm, single‐institution phase II trial of alisertib at a dosage of 50 mg twice daily for 7 of every 21 days. The primary endpoint was 4‐month disease control rate. Secondary endpoints included overall response rate, progression free survival, overall survival, safety/toxicity, and correlation of endpoints with MYC copy number.
Results
Of the 25 evaluable patients treated on study, 8 (32%) experienced 4‐month disease control, surpassing the futility endpoint. There were no confirmed partial or complete responses. Median progression‐free and overall survival were 2.8 months and 6.3 months, respectively. No associations between MYC copy number and outcomes were observed.
Conclusion
Alisertib has modest activity in this unselected malignant mesothelioma population. Several patients achieved durable disease control. Although the study did meet its prespecified futility endpoint, the sponsor elected to close the trial at the interim analysis.
Epidemiologic and preclinical data support the oral cancer prevention potential of green tea extract (GTE). We randomly assigned patients with high-risk oral premalignant lesions (OPL) to receive GTE ...at 500, 750, or 1,000 mg/m(2) or placebo thrice daily for 12 weeks, evaluating biomarkers in baseline and 12-week biopsies. The OPL clinical response rate was higher in all GTE arms (n = 28; 50%) versus placebo (n = 11; 18.2%; P = 0.09) but did not reach statistical significance. However, the two higher-dose GTE arms 58.8% (750 and 1,000 mg/m(2)), 36.4% (500 mg/m(2)), and 18.2% (placebo); P = 0.03 had higher responses, suggesting a dose-response effect. GTE treatment also improved histology (21.4% versus 9.1%; P = 0.65), although not statistically significant. GTE was well tolerated, although higher doses increased insomnia/nervousness but produced no grade 4 toxicity. Higher mean baseline stromal vascular endothelial growth factor (VEGF) correlated with a clinical (P = 0.04) but not histologic response. Baseline scores of other biomarkers (epithelial VEGF, p53, Ki-67, cyclin D1, and p16 promoter methylation) were not associated with a response or survival. Baseline p16 promoter methylation (n = 5) was associated with a shorter cancer-free survival. Stromal VEGF and cyclin D1 expression were downregulated in clinically responsive GTE patients and upregulated in nonresponsive patients at 12 weeks (versus at baseline). An extended (median, 27.5 months) follow-up showed a median time to oral cancer of 46.4 months. GTE may suppress OPLs, in part through reducing angiogenic stimulus (stromal VEGF). Higher doses of GTE may improve short-term (12-week) OPL outcome. The present results support longer-term clinical testing of GTE for oral cancer prevention.
Introduction: Targeted therapy and immune checkpoint inhibitors (ICI) have drastically improved outcomes of metastatic non-small cell lung cancer (NSCLC) patients in outpatient settings. Because ...trials on critically ill patients are improbable, little is known about their efficacy among patients admitted to intensive care units (ICU). Methods: We retrospectively analyzed the clinical outcomes of critically-ill NSCLC patients receiving either ICI or targeted therapy during ICU admission at the MD Anderson Cancer Center from April 2016 to August 2020. We collected data on ICU admission diagnoses, sequential organ failure assessment (SOFA), previous cancer therapies, tumor gene mutations or translocations, and PD-L1 expression. Overall survival (OS) was calculated from the date of drug initiation using the Kaplan-Meier method. Results: Of 9898 ICU admissions, 9 patients with metastatic NSCLC who received either targeted therapy (5) or PD-1 ICI (4) during ICU admission were included. The most common reasons for ICU admissions were tumor visceral crisis (3/9) and sepsis (3/9). The median (range) admission SOFA was 4 (2-11). Six patients were naïve to systemic therapy. Five patients required mechanical ventilation. The median OS was 77 days (95%CI, 36-NA), and 5 patients were discharged alive (all received targeted therapy). The median OS of patients who received ICI was 25.5 days (95%CI, 8-NA) and for those who received targeted therapy was 218 days (95%CI, 77-NA). At 6 and 12 months follow-up, 3 and 2 patients who received targeted therapy were still alive, respectively. Conclusions: Our exploratory findings indicate a possible benefit of targeted therapy but suggest a lack of clinical utility of PD-1 ICI for critically ill metastatic NSCLC patients. Because of the small sample size, further studies are needed to expand on this topic.
Malignant pleural mesothelioma (MPM) is a deadly disease with few systemic treatment options. One potential therapeutic target,
the non–receptor tyrosine kinase c-Src, causes changes in ...proliferation, motility, invasion, survival, and angiogenesis in
cancer cells and may be a valid therapeutic target in MPM. To test this hypothesis, we determined the effects of c-Src inhibition
in MPM cell lines and examined c-Src expression and activation in tissue samples. We analyzed four MPM cell lines and found
that all expressed total and activated c-Src. Three of the four cell lines were sensitive by in vitro cytotoxicity assays to the c-Src inhibitor dasatinib, which led to cell cycle arrest and increased apoptosis. Dasatinib also
inhibited migration and invasion independent of the cytotoxic effects, and led to the rapid and durable inhibition of c-Src
and its downstream pathways. We used immunohistochemical analysis to determine the levels of c-Src expression and activation
in 46 archived MPM tumor specimens. The Src protein was highly expressed in tumor cells, but expression did not correlate
with survival. However, expression of activated Src (p-Src Y419) on the tumor cell membrane was higher in patients with advanced-stage
disease; the presence of metastasis correlated with higher membrane ( P = 0.03) and cytoplasmic ( P = 0.04) expression of p-Src Y419. Lower levels of membrane expression of inactive c-Src (p-Src Y530) correlated with advanced
N stage ( P = 0.02). Activated c-Src may play a role in survival, metastasis, and invasion of MPM, and targeting c-Src may be an important
therapeutic strategy. Mol Cancer Ther 2007;6(7):1962–72
Opinion statement
Malignant pleural mesothelioma (MPM) is a challenging disease to treat with median overall survival times ranging between 9-17 months for all stages of disease. Recent clinical ...trials have improved our understanding of the biology of MPM. However, survival results are still not ideal. For early-stage MPM, patients should be evaluated for trimodality therapy in an experienced cancer center. If treating off-protocol, MPM patients should receive a surgical staging evaluation. The decision to proceed with surgical resection also should be considered after an extensive and thorough pulmonary and cardiac evaluation. If deemed a good surgical candidate, patients should receive surgical resection (pleurectomy/decortication or extrapleural pneumonectomy), adjuvant radiation therapy (hemithoracic external beam or intensity modulated radiation therapy), and either neoadjuvant or adjuvant chemotherapy (cisplatin-pemetrexed for 4 cycles). The optimal precise sequence of the trimodality is unclear and should be decided upon by a multidisciplinary consensus for each individual patient. In general, clinical trial participation should be encouraged. Several trials are currently underway to examine intraoperative therapies, vaccines, immunotherapy additions, and novel radiation therapy techniques. Advances in the field of MPM are reliant on participation in clinical trials and identifying biomarkers that are predictive for response to systemic therapies and prognostic for survival benefit.
PDF
