|Year : 2015 | Volume
| Issue : 5 | Page : 32-36
Toxicity and adverse effects of everolimus in the treatment of advanced nonsmall cell lung cancer pretreated with chemotherapy-Chinese experiences
Y Ju, Y Hu, S Sun, J Wang, S Jiao
Department of Oncology, Chinese PLA General Hospital, Beijing, China
|Date of Web Publication||3-Nov-2015|
Department of Oncology, Chinese PLA General Hospital, Beijing
Department of Oncology, Chinese PLA General Hospital, Beijing
Source of Support: None, Conflict of Interest: None
Background: There is not more treatment selection for advanced nonsmall-cell lung cancer (NSCLC) patients who had disease progression after two previous treatments. Everolimus is an oral inhibitor of the mammalian target of rapamycin pathway, which is aberrantly activated in NSCLC. Patients and Methods: Stage IV NSCLC patients, with one or multiple prior chemotherapy regimens, received everolimus 5–10 mg/day with or without chemotherapy until progression or unacceptable toxicity. The primary objective were toxicity of everolimus and overall disease control rate (DCR). Results: 22 patients were enrolled. Common ≥grade3 events were stomatitis, dyspnea, vomiting, thrombocytopenia. Overall disease control rate was 54.5% among 22 patients, 1 had a partial response, and 11 had disease stabilization. Common ≥Grade 3 events were stomatitis, dyspnea, vomiting, and thrombocytopenia. Conclusion: Everolimus was well tolerated, showing the modest clinical activity in heavily pretreated advanced NSCLC.
Keywords: Everolimus, NSCLC, treatment, toxicity
|How to cite this article:|
Ju Y, Hu Y, Sun S, Wang J, Jiao S. Toxicity and adverse effects of everolimus in the treatment of advanced nonsmall cell lung cancer pretreated with chemotherapy-Chinese experiences. Indian J Cancer 2015;52, Suppl S1:32-6
|How to cite this URL:|
Ju Y, Hu Y, Sun S, Wang J, Jiao S. Toxicity and adverse effects of everolimus in the treatment of advanced nonsmall cell lung cancer pretreated with chemotherapy-Chinese experiences. Indian J Cancer [serial online] 2015 [cited 2022 Jul 4];52, Suppl S1:32-6. Available from: https://www.indianjcancer.com/text.asp?2015/52/5/32/168954
| » Introduction|| |
Lung cancer is the most common cause of cancer-related death worldwide, accounting for over 1 million deaths each year. Approximately >80% of lung cancer are nonsmall-cell lung cancer (NSCLC). Most patients have advanced disease at diagnosis. The prognosis for patients with advanced NSCLC remains poor. Conventional treatment of NSCLC has reached a plateau of effectiveness in improving the survival of NSCLC patients. Now, no standard treatment option exists for advanced patients in whom three lines of systemic therapy have failed. Hence, new treatment approaches are needed.
Mammalian target of rapamycin (mTOR), a serine/threonine kinase, is a downstream mediator in the phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway, which plays a critical role in regulating basic cellular functions including cellular growth and proliferation. It is aberrantly activated in a variety of cancers including NSCLC.
Everolimus, an inhibitor of mTOR, approved for the treatment of renal cell carcinoma, has shown antitumor effects in cancer cell lines and xenograft models including lung, pancreatic, melanoma, and colon cancer.
Inhibition of the mTOR pathway has emerged as a novel strategy for the treatment of cancer. Everolimus has resulted in objective tumor responses in patients with NSCLC when used as monotherapy and in combination with epidermal growth factor receptor inhibitor.,, To explore more effective treatment for patients with advanced NSCLC, we observed the effectiveness and safety of everolimus when used as monotherapy or combined with chemotherapy for patients with NSCLC heavily pretreated before.
| » Patients and Methods|| |
Patients with pathologically confirmed, advanced NSCLC (Stage IV), aged ≥18 years, and with a World Health Organization performance status (PS) two or fewer were enrolled. All patients were required to have documented evidence of disease progression following treatment with one or more chemotherapeutic regimens. Adequate bone marrow, liver, and renal function was required.
Patients who had no good tolerance to chemotherapy were treated with everolimus 5 or 10 mg orally daily until disease progression or unacceptable toxicity (PS score 1–2). In the earlier time, 5 patients received everolimus 10 mg daily. All the 5 patients experience obvious adverse events and could not tolerate the treatment. Hence, patients were treated with everolimus 5 mg daily at the later time. Patients who had good status were treated with everolimus and chemotherapy (PS score 0–1). Considering the adverse events of everolimus, patients were treated with everolimus 5 mg every 3 days combined with chemotherapy in the earlier time. Patients had good tolerance to the treatment. So, in the later time patients were treated with everolimus 5 mg daily combined with chemotherapy. Drugs of chemotherapy included pemetrexed, docetaxel, albumin-bound paclitaxel, gemcitabine -cisplatin, and tegafur. Toxicity was graded by the National Cancer Institute Common Terminology Criteria version 3.0.
Patients were required to undergo a history and physical examination, assessment of PS, complete blood count with differential count, and serum chemistry. A computed tomography (CT) scan was performed at baseline. All subsequent assessments were performed with a CT scan every two cycles of therapy. Responses were assessed by the Response Evaluation Criteria in Solid Tumors version 1.0.
| » Results|| |
Twenty-two patients were accrued between June 2013 and November 2014. All patients were evaluated for safety. All patients were Asion. 81.8% were men, and the median age was 56 years. Most patients (95%) had adenocarcinomas. All patients had Stage IV NSCLC, and two-third had a World Health Organization PS of 1 [Table 1]. Most patients discontinued everolimus because of disease progression (13.6%) or adverse events (41%).
Patients' exposure to everolimus with or without chemotherapy is shown in [Table 2]. For patients who received everolimus only in the treatment, patients who received everolimus 5 mg/day had the longer exposure, with a median of 2 months (range, 0.3–8) and a mean of 2.87 months (standard deviation, 2.65). The duration of exposure for 5 patients who received everolimus 10 mg/day monotherapy were not over 1.5 months. Among 5 patients, 4 patients experienced dose interruption of everolimus because of adverse events. Everolimus combined with chemotherapy was well tolerated. Patients who received everolimus 5 mg/3 days had a longer exposure, with a median of 3.6 months (range, 2.5–5). Four patients who received everolimus combined with pemetrexed had a long duration of exposure. The duration of exposure was over 2 months. In the following treatment, 1 patient received everolimus 5 mg every 2 days because of adverse events. The patient had 6 months duration of exposure. Three patients received everolimus combined with albumin-bound paclitaxel. The duration of exposure is 2 months (everolimus 5 mg/day) and 5 months (everolimus 5 mg/3 days), respectively.
Toxicities and safety
Most of the 22 patients experienced one or more adverse events suspected to be related to everolimus and/or chemotherapy. Five patients (23%) experienced possible drug-related Grade 3 or 4 events during treatment; the most common events were stomatitis (n = 2), dyspnea (n = 1), thrombocytopenia (n = 1), and vomiting (n = 2). All other possible drug-related Grade 3 or 4 events that occurred in more than 1 patient are listed in [Table 3] and [Table 4]. Of all the patients, the most common adverse events were stomatitis (n = 8), leucopenia (n = 4), rash (n = 3), cough (n = 3), dyspnea (n = 3), vomiting (n = 3), anorexia (n = 4), alanine aminotransferase increased (n = 2), and hyperglycemia (n = 3). Among these events, stomatitis, dyspnea, cough, and anorexia were suspected to be related to everolimus. Leukopenia and vomiting were suspected to be related to chemotherapy.
|Table 3: Adverse events of everolimus (occurring in at least 1 patients)|
Click here to view
|Table 4: Adverse events of everolimus and chemotherapy (occurring in at least 1 patients)|
Click here to view
The results of the final analysis are based on the total number of patients. No CR was recorded. Disease control rate (DCR) (partial response [PR] and stable disease [SD]) was 54.5% of patients overall after 2 months administration of everolimus [Table 5],[Table 6],[Table 7]. Of the 12 responders, 10 were men, all the patients had adenocarcinomas. PR was observed in 1 and SD in 11. A 61-year-old male patient was an adenocarcinoma of the lung that had failed three prior systemic therapy regimens experienced a PR. There was a regression in the primary tumor mass in the lung after two cycles of combination therapy (everolimus and chemotherapy). Before adding everolimus, the prior chemotherapy had no efficacy. DCR was 22.7% of patients overall after 3 months treatment, with 16.6% of patients that received everolimus only, with 40% of patients that received combined therapy.
| » Discussion|| |
Lung cancer is the leading cause of cancer-related death worldwide. NSCLC represents ~80% of all lung cancer cases., Only a minor patients have the chance of radical resection. Many patients with the advanced disease need to receive systemic therapy. Platinum-based chemotherapy is one of the selection for patients with advanced NSCLC as first-line therapy. Adding targeted therapy such as bevacizumab or cetuximab to platinum-based chemotherapy has improved overall survival.,, If patients relapse after the first-line treatment, they have to receive the second-line therapy (i.e., docetaxel, pemetrexed, or erlotinib). Second-line treatment options offer a modest survival benefit., No further standard options exist for patients after two lines of therapy. Hence, a combination of chemotherapy and targeted therapy is an area deserving further exploration in patients with progressing disease after previous treatment for NSCLC.
mTOR, a ubiquitous serine-threonine kinase and a downstream component of the PI3K/Akt-signaling pathway, plays a critical role in the regulation of protein synthesis, cell growth, proliferation, survival, and angiogenesis., The deregulated PI3K/Akt/mTOR pathway was reported to contribute to lung cancer development and maintenance. Frequent Akt activation and mTOR phosphorylation were found in 74% of NSCLC cell lines and 51% of NSCLC patient samples. So, inhibition of mTOR might represent a potential target of treatment for NSCLC.
Everolimus, an inhibitor of mTOR, have demonstrated antitumor effects in NSCLC models in preclinical studies.,,,, Everolimus is currently under clinical investigation as an anticancer agent.
In a Phase II study of everolimus 10 mg daily in patients with previously treated, advanced NSCLC, disease control was achieved in 47% of patients. Overall response rate was 4.7%. Common ≥Grade 3 events were fatigue, dyspnea, stomatitis, anemia, and thrombocytopenia. Pneumonitis, mainly Grade 1/2, occurred in 25%.
In the current study, patients achieved a DCR of 54.5% (12/22) in the full analysis set, with 1 patient experiencing a PR as the best overall response. Almost all the patients treated with everolimus had have multiple line therapy. Two patients had have six regimens of therapy before administration of everolimus. Although most patients had been heavily pretreated, preliminary DCR observed in the current study seems to compare favorably to that reported in a previous clinical study of everolimus monotherapy as second- or third-line therapy for advanced NSCLC. Duration of SD is over 3 months for 2 patients with everolimus monotherapy at a dose of 5 mg daily. One patient received SD and lasted over 8 months. Most patients had SD. No PR was observed in patients with everolimus monotherapy. Maybe the mechanism of action should be considered. Everolimus is not a cytotoxic drug. The disease control rather than tumor regression might be its primary clinical effect.
The present study demonstrated that treatment with 5 mg daily doses of everolimus is relatively well tolerated. The commonly adverse events were mild-to-moderate stomatitis, dyspnea, cough, and anorexia. However, the treatment with 10 mg daily doses of everolimus is not well tolerated. Five patients received 10 mg daily everolimus monotherapy. All the 5 patients had treatment interruptions because of adverse events. Moreover, duration of administration was shorter than 1.5 months. Maybe the tolerance of eastern patients is different from the west. Probably the tolerance of patients degraded after multiple lines of treatment.
In the past, researchers studied the combination therapy of everolimus and chemotherapy (i.e., pemetrexed or docetaxel). Pemetrexed, a folate antimetabolite, exerts its anticancer action primarily by inhibiting enzymes used in purine and pyrimidine synthesis, such as thymidylate synthase., The combination of everolimus plus pemetrexed had demonstrated enhanced antitumor activity in a xenograft model of NSCLC compared with pemetrexed monotherapy.
A Phase I study was initiated to establish the recommended daily or weekly dose of everolimus in combination with pemetrexed in the second-line treatment of patients with NSCLC. Everolimus in combination with pemetrexed generally was well tolerated, and everolimus could be administered at doses within the range of the single-agent standard doses with an acceptable safety profile. Three PRs were observed with everolimus 5 mg/day and two with 50 mg/week. Everolimus 5 mg/day or 50 mg/week with the standard regimen of pemetrexed are the recommended doses for further clinical study.
In the present study, there were 3 patients achieved SD in the patients that received everolimus (5 mg/day) combined with pemetrexed, with 1 patient experienced a PR. The patient had three lines of chemotherapy before adding everolimus. In the fourth line therapy, the patient received a PR after two cycle's combination therapy of everolimus and pemetrexed. Everolimus may be played an important role in the reversal of chemotherapy resistance. From the results of the gene mutation analysis, we found that the patient have the STK11 gene mutation. STK11 gene mutation is related to activation of mTOR signal transduction. Everolimus as an mTOR inhibitor, maybe inhibit the activation of mTOR signal transduction. Furthermore, in the clinic we observed a patient received 10 mg/day everolimus combined with pemetrexed. The combination was well tolerated. Moreover, the duration of administration was over 4 months with SD. So, everolimus combined with pemetrexed maybe provide a good option for advanced NSCLC after multiple lines of chemotherapy.
Researchers found that up-regulation of p-Akt had been noted in response to exposure to tubulin-interactive agents, such as taxanes and vincristine, and is postulated as contributing to resistance to the anticancer effects of these agents. Inhibition of mTOR in cancer cells with up-regulated p-Akt was associated with sensitization to tubulin-interactive agents. In a Phase I study, patients with recurrent/refractory NSCLC were treated with everolimus combined with docetaxel. Promising anticancer activity had been noted. Among 21 patients evaluable, 1 had a PR, and 10 had disease stabilization. In Phase II study of docetaxel in combination with everolimus for second- or third-line therapy of advanced NSCLC, 28 patients were enrolled, 28 patients experienced PR and 15 had SD.,
In our study, we observed 3 patients treated with a combination of everolimus and albumin-bound paclitaxel. Two patients had SD. One patient heavily pretreated had 5 months SD after six cycles of combination therapy. SD might be considered of clinical benefit. Interpretation of the tumor responses is limited by the small sample size.
In the combination therapy, patients who received everolimus 5 mg/3 days had the longer duration of exposure, with a median of 3.6 months (range, 2.5–5). However, no PR was observed in these patients. Patients who received everolimus 5 mg/day had the shorter duration of exposure, with a median of 2 months (range, 0.3–4). In these patients, one PR was observed. More patients should be observed in the future.
In the future, studies on predictive markers for the efficacy of everolimus in combination with chemotherapy will be useful because these markers may identify patients with NSCLC, who are most likely to benefit from this combination therapy. In order to select predict markers, next-generation sequence, and proteome technology can be used to analyze relevant gene and protein in the PI3K/Akt/mTOR pathway.
In summary, everolimus administered orally at a daily dose of 5 mg with or without chemotherapy (i.e., pemetrexed, albumin-bound paclitaxel) was well tolerated and showed the modest clinical activity in heavily pretreated patients with advanced-stage NSCLC. Patients received everolimus only in the treatment maybe reduce the costs.
| » Conclusion|| |
In summary, everolimus administered orally at a daily dose of 5mg with or without chemotherapy (i.e., pemetrexed, albumin bound paclitaxel) was well tolerated and showed modest clinical activity in heavily pretreated patients with advanced-stage NSCLC. Patients received everolimus only in the treatment maybe reduce the costs.
| » References|| |
Ferlay J, Shin HR, Bray F, Forman D, Mathers C, Parkin DM. Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. Int J Cancer 2010;127:2893-917.
O'Donnell A, Faivre S, Burris HA 3rd
, Rea D, Papadimitrakopoulou V, Shand N, et al.
Phase I pharmacokinetic and pharmacodynamic study of the oral mammalian target of rapamycin inhibitor everolimus in patients with advanced solid tumors. J Clin Oncol 2008;26:1588-95.
Soria JC, Shepherd FA, Douillard JY, Wolf J, Giaccone G, Crino L, et al.
Efficacy of everolimus (RAD001) in patients with advanced NSCLC previously treated with chemotherapy alone or with chemotherapy and EGFR inhibitors. Ann Oncol 2009;20:1674-81.
Papadimitrakopoulou V, Blumenschein GR, Leighl NB, Bennouna J, Soria JC, Burris HA, et al
. A phase 1/2 study investigating the combination of RAD001 (R) (everolimus) and erlotinib (E) as 2nd
line therapy in patients (pts) with advanced non-small cell lung cancer (NSCLC) previously treated with chemotherapy (C): Phase 1 results. J Clin Oncol 2008;26 20 Suppl: 8051.
Page NC, Read W, Tierney RM,et al
. The epidemiology of small cell lung carcinoma. Proc Am Soc Clin Oncol 2002;21:305a. [Abstr. 1216].
Alvarez M, Roman E, Santos ES, Raez LE. New targets for non-small-cell lung cancer therapy. Expert Rev Anticancer Ther 2007;7:1423-37.
Reck M, von Pawel J, Zatloukal P, Ramlau R, Gorbounova V, Hirsh V, et al.
Phase III trial of cisplatin plus gemcitabine with either placebo or bevacizumab as first-line therapy for nonsquamous non-small-cell lung cancer: AVAil. J Clin Oncol 2009;27:1227-34.
Lynch TJ, Patel T, Dreisbach L, McCleod M, Heim WJ, Hermann RC, et al.
Cetuximab and first-line taxane/carboplatin chemotherapy in advanced non-small-cell lung cancer: Results of the randomized multicenter phase III trial BMS099. J Clin Oncol 2010;28:911-7.
Pirker R, Pereira JR, Szczesna A, von Pawel J, Krzakowski M, Ramlau R, et al.
Cetuximab plus chemotherapy in patients with advanced non-small-cell lung cancer (FLEX): An open-label randomised phase III trial. Lancet 2009;373:1525-31.
Hanna N, Shepherd FA, Fossella FV, Pereira JR, De Marinis F, von Pawel J, et al.
Randomized phase III trial of pemetrexed versus docetaxel in patients with non-small-cell lung cancer previously treated with chemotherapy. J Clin Oncol 2004;22:1589-97.
Shepherd FA, Rodrigues Pereira J, Ciuleanu T, Tan EH, Hirsh V, Thongprasert S, et al.
Erlotinib in previously treated non-small-cell lung cancer. N Engl J Med 2005;353:123-32.
Sabatini DM. mTOR and cancer: Insights into a complex relationship. Nat Rev Cancer 2006;6:729-34.
Bjornsti MA, Houghton PJ. The TOR pathway: A target for cancer therapy. Nat Rev Cancer 2004;4:335-48.
Pisick E, Jagadeesh S, Salgia R. Receptor tyrosine kinases and inhibitors in lung cancer. Scientific World Journal 2004;4:589-604.
Balsara BR, Pei J, Mitsuuchi Y, Page R, Klein-Szanto A, Wang H, et al.
Frequent activation of AKT in non-small cell lung carcinomas and preneoplastic bronchial lesions. Carcinogenesis 2004;25:2053-9.
Boulay A, Zumstein-Mecker S, Stephan C, Beuvink I, Zilbermann F, Haller R, et al
. Antitumor efficacy of intermittent treatment schedules with rapamycin derivative RAD001 correlates with prolonged inactivation of ribosomal protein S6 kinase 1 in peripheral blood mononuclear cells. Cancer Res 2004;64:252-61.
Mabuchi S, Altomare DA, Cheung M, Zhang L, Poulikakos PI, Hensley HH, et al.
RAD001 inhibits human ovarian cancer cell proliferation, enhances cisplatin-induced apoptosis, and prolongs survival in an ovarian cancer model. Clin Cancer Res 2007;13:4261-70.
Buck E, Eyzaguirre A, Brown E, Petti F, McCormack S, Haley JD, et al.
Rapamycin synergizes with the epidermal growth factor receptor inhibitor erlotinib in non-small-cell lung, pancreatic, colon, and breast tumors. Mol Cancer Ther 2006;5:2676-84.
Beuvink I, Boulay A, Fumagalli S, Zilbermann F, Ruetz S, O'Reilly T, et al.
The mTOR inhibitor RAD001 sensitizes tumor cells to DNA-damaged induced apoptosis through inhibition of p21 translation. Cell 2005;120:747-59.
Majumder PK, Febbo PG, Bikoff R, Berger R, Xue Q, McMahon LM, et al.
mTOR inhibition reverses Akt-dependent prostate intraepithelial neoplasia through regulation of apoptotic and HIF-1-dependent pathways. Nat Med 2004;10:594-601.
Sigmond J, Backus HH, Wouter D, Temmink OH, Jansen G, Peters GJ. Induction of resistance to the multitargeted antifolate pemetrexed (ALIMTA) in Widr human colon cancer cells is associated with thymidylate synthase overexpression. Biochem Pharmacol 2003;66:431-8.
Giovannetti E, Mey V, Nannizzi S, Pasqualetti G, Marini L, Del Tacca M, et al.
Cellular and pharmacogenetics foundation of synergistic interaction of pemetrexed and gemcitabine in human non-small-cell lung cancer cells. Mol Pharmacol 2005;68:110-8.
O Reilly T, Brandt R, Knohr F, et al
Antitumor Activity of RAD001 Combined with Taxol ®
/Carboplatinum or Pemetrexed against Human Lung Tumor Xenograft Models. Presented at the 99th
Annual Meeting of the American Association for Cancer Research, San Diego, CA; 12-16, April 2008. [Abstract 4007].
VanderWeele DJ, Zhou R, Rudin CM. Akt up-regulation increases resistance to microtubule-directed chemotherapeutic agents through mammalian target of rapamycin. Mol Cancer Ther 2004;3:1605-13.
Ramalingam SS, Harvey RD, Saba N, Owonikoko TK, Kauh J, Shin DM, et al.
Phase 1 and pharmacokinetic study of everolimus, a mammalian target of rapamycin inhibitor, in combination with docetaxel for recurrent/refractory nonsmall cell lung cancer. Cancer 2010;116:3903-9.
Ramalingam SS, Owonikoko TK, Behera M, Subramanian J, Saba NF, Kono SA, et al.
Phase II study of docetaxel in combination with everolimus for second- or third-line therapy of advanced non-small-cell lung cancer. J Thorac Oncol 2013;8:369-72.
Ustundag S, Zencirci AD. Factors affecting the quality of life of cancer patients undergoing chemotherapy: A questionnaire study. Asia Pac J Oncol Nurs 2015;1:17-25.
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6], [Table 7]