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C. Barrios
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MS 16 - Novel SCLC Therapies (ID 34)
- Event: WCLC 2015
- Type: Mini Symposium
- Track: Small Cell Lung Cancer
- Presentations: 6
- Moderators:C. Barrios, N. Saijo
- Coordinates: 9/08/2015, 14:15 - 15:45, Mile High Ballroom 4a-4f
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MS16.01 - PARP Inhibitors and DNA Damage (ID 1916)
14:20 - 14:33 | Author(s): L. Byers
- Abstract
- Presentation
Abstract:
A leading cause of death in small cell lung cancer (SCLC) is the rapid emergence of drug resistance following an initial phase of chemotherapy and radiation sensitivity. Currently, response rates to existing second-line regimens (e.g., topotecan and other single-agent chemotherapies) are less than 20%. Because of this overall poor response to subsequent therapy, average survival for relapsed disease ranges between 4-6 months. As such, there is a critical need for the development of novel, active therapies for SCLC. Drugs that target DNA damage response (DDR), including PARP inhibitors, have shown promising activity against SCLC in pre-clinical models and in early clinical trials. Previously, we performed proteomic profiling of a large panel of SCLC cell lines which led to the observation that PARP1, Chk1, and several other DNA repair proteins are expressed at high levels in SCLC[1]. PARP1 overexpression was confirmed in patient tumors at the protein level by immunohistochemistry and at the mRNA level. Based on this finding, several PARP inhibitors were tested in pre-clinical models of SCLC. Olaparib, rucaparib, and talazoparib (previously BMN-673) all demonstrated striking single agent activity in a majority of SCLC cell lines tested. Furthermore, the addition of a PARP inhibitor to standard chemotherapies (e.g., cisplatin, etoposide and/or topotecan) and radiation further potentiated their effect[1][,][2]. In animal models including xenografts and patient-derived xenografts (PDXs), talazoparib has demonstrated significant anti-tumor activity as a single agent, comparable or superior to cisplatin[3][,][4]. Following these observations, several clinical trials were initiated to investigate the effects of PARP inhibition in SCLC patients. The first two studies to complete enrollment investigated the use of PARP inhibitors in relapsed SCLC. In the first study, single-agent talazoparib (BMN-673) was tested in an expansion cohort of patients with platinum-sensitive SCLC relapse (NCT01286987). Preliminary data from this trial demonstrated 2/23 patients with RECIST confirmed partial responses and 3/23 with stable disease lasting more than 24 weeks (clinical benefit rate of 25%). More than half of patients treated had some tumor volume reduction as their best response[5]. In the second study, the oral alkylating drug temozolomide with or without veliparib (ABT-888) was studied in 100 patients with sensitive or refractory relapse (NCT01638546). This trial recently completed enrollment and analysis of the results are ongoing. The use of PARP inhibitors in combination with chemotherapy builds upon prior pre-clinical data in lung cancer and other malignancies supporting the notion that PARP inhibitors potentiate the effect of other DNA damaging therapies. Currently, there are two studies investigating the use of veliparib (ABT-888) in combination with standard frontline chemotherapy (NCT01642251 and NCT02289690). E2511 (NCT01642251) is a Phase I/II trial of cisplatin, etoposide, and veliparib conducted through the ECOG-ACRIN Cancer Research Group in which treatment naïve SCLC patients receive the combination for up to 4 cycles. Published results from the Phase I portion support the safety and tolerability of the combination, with partial or complete responses observed in 5/7 evaluable patients[6]. More recently, another first-line study was initiated to investigate carboplatin in combination with etoposide and veliparib which will also address the question of veliparib maintenance (NCT02289690). To date, the activity of PARP inhibitors are best established in cancers with mutations in BRCA1/2 and other DNA repair genes that result in synthetic lethality in the setting of PARP inhibition (which provides a second “hit” to the DNA repair machinery). In fact, olaparib monotherapy was FDA-approved last year for patients with advanced, BRCA-mutated ovarian cancer who have received three or more lines of chemotherapy. This was based on a trial that demonstrated a response rate of 34% and a median duration of response or 7.9 months. Studies of other PARP inhibitors have also shown striking single-agent activity with this class of drugs in a mutation-selected population. However, in SCLC, the mechanism of action and identification of potential biomarkers of response to these drugs is an area of active investigation. Likely the universal loss of RB1, with resulting dependence on E2F1, plays a role, as may the PARP-trapping effects of several of these drugs which cause direct cytotoxicity[7]. Our group has demonstrated that expression levels of several DNA repair proteins – both individually and as a “DNA repair signature” – are associated with response in pre-clinical models of lung cancer[3]. However, further validation in the clinical setting is warranted. Additional DNA damage response (DDR) targets also show significant potential as therapeutic targets in SCLC. These include checkpoint kinases that are activated in response to DNA damage and facilitate S and G2 checkpoint arrest, such as Chk1 (Checkpoint kinase 1), Wee1, and ATR (Ataxia Telangiectasia and Rad3 related). Similar to PARP1, in our previous work we demonstrated elevated expression of Chk1 in SCLC[1]. SCLC may be particularly susceptible to inhibitors of Chk1 and other checkpoint kinases due to the near universal loss of TP53 in these cancers which make them dependent on other checkpoint controls in the cell cycle. Several drugs targeting these DDR proteins have entered clinical trials. For example, based on pre-clinical data demonstrating the potentiation of topoisomerase inhibitors by ATR inhibition, a Phase I/II trial of topotecan with VX970 (an ATR kinase inhibitor) has recently been initiated for SCLC (NCT02487095). Ongoing trials of PARP inhibitors and other molecules targeting DDR will help us to understand the activity of these compounds in patients with SCLC. Important questions that require further investigation include the optimal combinations of these drugs with existing therapies or other targeted inhibitors, strategies to manage associated toxicities (especially combinations with overlapping hematologic toxicities), and further development of candidate predictive biomarkers.REFERENCES 1. Byers LA, Wang J, Nilsson MB, et al. Proteomic profiling identifies dysregulated pathways in small cell lung cancer and novel therapeutic targets including PARP1. Cancer discovery 2012;2:798-811. 2. Owonikoko TK, Zhang G, Deng X, et al. Poly (ADP) ribose polymerase enzyme inhibitor, veliparib, potentiates chemotherapy and radiation in vitro and in vivo in small cell lung cancer. Cancer medicine 2014;3:1579-94. 3. Cardnell RJ, Feng Y, Diao L, et al. Proteomic markers of DNA repair and PI3K pathway activation predict response to the PARP inhibitor BMN 673 in small cell lung cancer. Clinical cancer research : an official journal of the American Association for Cancer Research 2013;19:6322-8. 4. Y. Feng, R. Cardnell, L.A. Byers, B. Wang, Y. Shen. Talazoparib (BMN 673) as single agent and in combination with temozolomide or PI3K pathway inhibitors in small cell lung cancer and gastric cancer models. 26th EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics (abstract) 2014. 5. Wainberg ZA, Ramanathan RK, Mina LA, Byers LA, Chugh R, Goldman JW, Sachdev JC, Matei DE, Wheler JJ, Henshaw JW, Zhang C, Gallant G, De Bono JS. Safety and antitumor activity of the PARP inhibitor BMN673 in a phase 1 trial recruiting metastatic small-cell lung cancer (SCLC) and germline BRCA-mutation carrier cancer patients. 2014 ASCO Annual Meeting; J Clin Oncol 32:5s, (suppl; abstr 7522) 2014. 6. Owonikoko TK, Dahlberg SE, Khan SA, et al. A phase 1 safety study of veliparib combined with cisplatin and etoposide in extensive stage small cell lung cancer: A trial of the ECOG-ACRIN Cancer Research Group (E2511). Lung cancer 2015;89:66-70. 7. Murai J, Huang SY, Das BB, et al. Trapping of PARP1 and PARP2 by Clinical PARP Inhibitors. Cancer research 2012;72:5588-99.
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MS16.02 - Stem Cell/Notch/Hedgehog (ID 1917)
14:33 - 14:46 | Author(s): D.P. Carbone
- Abstract
- Presentation
Abstract not provided
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MS16.03 - PI3K/AKT/mTOR (ID 1918)
14:46 - 14:59 | Author(s): S. Umemura, K. Goto
- Abstract
- Presentation
Abstract:
Small cell lung cancer (SCLC) comprises approximately 15% of all lung cancers, and it is an exceptionally aggressive malignancy with a high proliferative index. Despite extensive basic and clinical research over the past 30 years, little progress has been made in treating this disease. A better understanding of the genomic changes in SCLC is essential to identify new therapeutic targets. However, a systematic genomic analysis of SCLC is difficult because this cancer subtype is rarely treated surgically, resulting in the lack of suitable tumor specimens for comprehensive analysis. Two reports regarding the comprehensive genomic analysis of SCLC have been published. These reports suggested that transcriptional deregulation might play a role in SCLC biology[1,2]. However, to date, attempts to develop targeted therapies toward these transcriptional deregulations have had limited success. Recently, we performed a comprehensive genomic analysis of 51 surgical resected SCLCs and found a high penetrance of genetic alterations in the PI3K/AKT/mTOR pathway[3]. MYC family amplifications are known oncogenic drivers in SCLC. PI3K/AKT/mTOR pathway alterations and MYC family amplifications were mutually exclusive in this study (Figure 1). However, the information regarding therapeutically relevant genomic alterations in advanced non-surgical SCLC is not well developed; so we performed targeted sequencing from 90 advanced SCLC. We identified that the PI3K/AKT/mTOR pathway was frequently altered in advanced SCLC in the same way as surgically resected SCLC. In advanced SCLC, PI3K/AKT/mTOR pathway alterations and MYC family amplifications were also mutually exclusive. The genomic profile of advanced SCLC was almost similar to that of resectable SCLC. To further investigate whether the PI3K/AKT/mTOR pathway could be a feasible therapeutic target in SCLC, we performed the in vitro drug sensitivity test using PI3K/mTOR dual inhibitor: NVP-BEZ235. NCI-H1048 cells harboring activating mutation in PIK3CA gene (H1047R), was the most sensitive to BEZ235, with IC50 value of 5.4 nM. Additionally, PIK3CA silencing induced a significant decrease in the proliferation of H1048 cells, suggesting that the proliferation of these cells was strongly dependent on the PI3K/AKT/mTOR pathway[3]. On the other hand, PTEN is a tumor suppressor gene working in PI3K/AKT/mTOR pathway. In murine model, Pten deletion accelerated SCLC by engineered deletion of two tumor suppressors (Rb and p53), suggesting that Pten was an important driver of tumor progression in SCLC[4]. Unlike other types of cancer, this is a unique phenomenon observed in SCLC, therefore targeting of PTEN signaling is reasonable in SCLC. There are many other reports which suggest that PI3K/AKT/mTOR pathway is the promising therapeutic target in SCLC. Although two specific inhibitors of mTORC1, everolimus and temsirolimus, have been tested against SCLC in a Phase II study, the antitumor activity was limited in unselected patients. To improve the response to these inhibitors, biomarker-based patient selection is first recommended. Secondly, the addition of PI3K inhibition might improve the response to specific inhibitors of mTORC1. The dual inhibition of PI3K and mTOR might be advantageous over the single inhibition of mTOR because of the suppression of the S6K feedback loop, which leads to the pathway reactivation. PF-05212384 is a novel potent dual inhibitor of PI3K and mTOR, which has demonstrated preliminary evidence of clinical activity in patients with solid malignancies[5]. However, dual inhibitor of PI3K and mTOR has not yet to be evaluated against SCLC in a phase II study. Thus, we planned the investigator initiated phase II study to investigate the efficacy of PF-05212384 in advanced recurrent SCLC patients harboring PI3K/AKT/mTOR pathway alteration. Key eligibility criteria include: advanced SCLC, harboring PI3K/AKT/mTOR pathway alteration, prior chemotherapy, aged ≥ 20 years, and ECOG PS 0-2. The primary endpoint is objective response rate. Patients receive weekly intravenous dose of PF-05212384 154 mg until disease progression. For screening SCLC patients harboring PI3K/AKT/mTOR pathway alteration, we use the multiplex next-generation sequencing tool enabling the analysis of about 150 genes in a single run. SCLC harboring PI3K/AKT/mTOR pathway alteration is a “Rare Cancer”. Therefore, patient recruitment is performed using the nationwide lung cancer genomic screening program, LC-SCRUM-Japan. LC-SCRUM-Japan is the largest molecular screening system in Japan. At the end of June 2015, around 180 institutes in all prefectures of Japan are participating this screening program. The prospective genomic screening of SCLC will be started in July 2015. In conclusion, the SCLC genome possesses distinguishable genetic features in the PI3K/AKT/mTOR pathway. Genetic alterations in the PI3K/AKT/mTOR pathway were noted as a top therapeutic priority in SCLC. Investigator initiated phase II study of PF-05212384 in advanced recurrent SCLC patients harboring molecular alterations in PI3K/AKT/mTOR pathway is planned to be started in January 2016.Figure 1 References 1. Peifer M, Fernández-Cuesta L, Sos ML, et al. Integrative genome analyses identify key somatic driver mutations of small-cell lung cancer. Nature genetics 2012; 44: 1104-1110. 2. Rudin CM, Durinck S, Stawiski EW et al. Comprehensive genomic analysis identifies SOX2 as a frequently amplified gene in small-cell lung cancer. Nature genetics 2012; 44: 1111-1116. 3. Umemura S, Mimaki S, Makinoshima H, et al. Therapeutic priority of the PI3K/AKT/mTOR pathway in small cell lung cancers as revealed by a comprehensive genomic analysis. J Thorac Oncol 2014; 9: 1324-31. 4. McFadden DG, Papagiannakopoulos T, Taylor-Weiner A, et al. Genetic and clonal dissection of murine small cell lung carcinoma progression by genome sequencing. Cell 2014; 156: 1298-1311. 5. Shapiro GI, Bell-McGuinn KM, Molina JR, et al. First-in-Human Study of PF-05212384 (PKI-587), a Small-Molecule, Intravenous, Dual Inhibitor of PI3K and mTOR in Patients with Advanced Cancer. Clin Cancer Res. 2015; 21: 1888-1895.
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MS16.04 - Immunotherapy (Checkpoint Inhibitors) (ID 1919)
14:59 - 15:12 | Author(s): M. Reck
- Abstract
- Presentation
Abstract:
Small cell lung cancer (SCLC), which accounts for 15 – 20% of all lung cancer cases, represents one of the most aggressive subtypes based on rapid growth and early metastasis. Only limited therapeutic progress has been achieved in the recent decades and despite multiple mutations no targeted therapy for SCLC has been available by now. Based on preclinical data that revealed a relevant correlation between the immune system and SCLC the exploration of immune modulating agents appears to be attractive. First signals coming from randomized phase II trials showed an enhanced activity for the combination of the anti cytotoxic T-lymphocyte antigen-4 (CTLA-4) antibody ipilimumab with chemotherapy compared to chemotherapy alone. This combination is now under investigation in a couple of extended randomised trials. Besides ipilimumab also antibodies inhibiting the axis of programmed cell death protein 1 (PD-1) and programmed cell death protein ligand 1 (PD-L1) like nivolumab or pembrolizumab have shown encouraging results either alone or in combination with ipilimumab in heavily pre-treated patients with advanced SCLC. Ongoin or planned randomised trials will validate these signals in various therapeutic lines. A confirmation of these attractive early outcomes would have an substantial clinical impact. In particular in SCLC identification of new potential biomarkers will become of great importance because the PDL-1 status might not be the optimal predictive marker in this tumor entity.
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MS16.05 - Aurora Kinase and Cyclin Kinase Inhibitors (ID 1920)
15:12 - 15:25 | Author(s): C. Mathias
- Abstract
- Presentation
Abstract:
Introduction Small cell lung cancer (SCLC) represents approximately 13% of all lung cancer diagnoses and its incidence has reduced over the last 20 years, although the frequency is rising in women due to increased use of tobacco [1]. It is a highly malignant neuroendocrine tumor of the lung and treatment of SCLC remains challenging because of its rapid growth, early dissemination and development of drug resistance during the course of the disease [2]. Without treatment, SCLC has the most aggressive clinical course of any type of pulmonary tumor, with median survival from diagnosis of only 2 to 4 months [2]. With current chemotherapy regimens survival is prolonged, however, the overall survival at 5 years is only 5% to 10% [2]. Topotecan [3] is currently the only drug licensed in Europe and the Unites States for second-line treatment of SCLC, having been shown in a phase III trial to lead to longer overall survival and better quality of life than with best supportive care. In advanced SCLC, prognosis after failure of first-line treatment is very poor. No new targeted agents have shown meaningful benefit in this disease and, therefore, an urgent need exists for new active agents [4]. Cyclin Kinase Inhibitors Cyclin dependent kinases (CDK) belong to a family of serine/ threonine protein kinases that are associated with an activating cyclin regulatory subunit. CDKs are involved in the regulation of fundamental cellular processes such as cell division cycle and gene transcription. Cell-cycle CDKs 1, 2, 4, and 6 are required for the correct timing and order of the events of the cell-division cycle. CDK7 is a component of the CDK-activating complex that contributes to the assembly of CDK1/cyclin B. In addition, CDK7 functions as a transcriptional CDK, as well as CDKs 8 and 9, which have been shown to be involved in gene transcription via regulation of RNA polymerase II activity. Deregulated CDK activity results in loss of cell-cycle checkpoint function and increased expression of antiapoptotic proteins, which has been directly linked to the molecular pathology of cancer [5]. Roniciclib (BAY 1000394) is a CDK inhibitor with low nanomolar activity against cell-cycle CDKs and transcriptional CDKs. It was evaluated in cell line-derived and patient tumor derived SCLC xenograft models. The compound strongly reduced tumor growth with T/C values between 0.12 and 0.19 showing that roniciclib was similar or even more efficacious as compared with cisplatin (T/C values between 0.06 and 0.55) [6]. In vivo, studies showed that roniciclib has more than additive efficacy when combined with cisplatin and etoposide. This compound is currently under investigation in a double-blind, placebo controlled phase II CONCEPT-SCLC trial to assess the safety and efficacy of roniciclib in combination with etoposide and cisplatin or carboplatin as first line therapy in patients with extensive SCLC after results obtained in a multicenter phase I study that evaluated 25 pre-treated SCLC patients [7]. Aurora Kinase Inhibitors The aurora kinases (A, B, and C) are serine/threonine kinases that have a key role in mitosis; in particular, aurora kinase A is essential for centrosome function and maturation, spindle assembly, chromosome alignment, and mitotic entry. Aurora kinase A localizes to the centrosomes and spindle poles and recruits the cyclin B1–CDK1 complex. Inhibition of aurora kinase A leads to abnormal spindle formation, mitotic defects, and cell death. Overexpression or amplification of this enzyme has been noted across a range of different tumor types and is linked with tumor progression and poor prognosis. Thus, inhibition of aurora kinase A is a rational target for anticancer treatment [8]. Alisertib exhibits favorable pharmacokinetic parameters and displayed tumor growth inhibition [9]. In Phase I dose escalation studies with alisertib given orally on a twice daily schedule for seven consecutive days, the maximum tolerated dose was defined predominantly by the occurrence of grade 3 or grade 4 myelosuppression and stomatitis, consistent with the antiproliferative effects of Aurora A inhibition. In a phase II study, the small-cell lung cancer cohort (see figure 1), ten (21%; 95% CI 10–35) of 48 patients had an objective response to alisertib; all responders achieved a partial response. Response-assessable patients with small- cell lung cancer received a median of 2,5 cycles (range 1−21) of alisertib, with a median time on treatment of 1,5 months (range 0,1−11,7, IQR 0,9–3,7). The median duration of response was 4,1months (95% CI 3,1 not evaluable), median progression-free survival was 2,1 months (95% CI 1,4–3,4), and median time to progression was 2,6 months (95% CI 1,4–3,8). The adverse effects of alisertib were generally manageable and included anemia, fatigue, alopecia, and various gastrointestinal disorders, and consistent with those noted in earlier trials of alisertib. Neutropenia was the most frequent drug related grade 3–4 adverse event; however, febrile neutropenia was recorded much less frequently. The antitumor activity noted in the SCLC cohort in this study (objective response 21%) seems similar to that reported with the current standard of care, topotecan (objective response 7–24%) [3]. Although the initial signal of activity noted in both the chemotherapy sensitive relapse population and in patients with refractory and chemotherapy resistant relapse is encouraging, to achieve more meaningfully improved outcomes, combinations of alisertib with other anticancer drugs should be studied. A follow-up, randomized, global phase 2 trial of alisertib plus weekly paclitaxel versus placebo plus paclitaxel as second-line treatment for small cell lung cancer is currently enrolling. References [1] Youlden DR, et al. The International Epidemiology of Lung Cancer: Geographical Distribution and Secular Trends. Journal of Thoracic Oncology, Vol. 3, No. 8, 2008, pp. 819-831. [2] Govindan R, et al. Changing Epidemiology of Small-Cell Lung Cancer in the United States over the Last 30 Years: Analysis of the Surveillance, Epidemiologic, and End Results Database, Journal of Clinical Oncology, Vol. 24, No. 28, 2006, pp. 4539-4544. [3] Ormrod D and Spencer CM, Topotecan: A Review of Its Efficacy in Small Cell Lung Cancer, Drugs, Vol. 58, No. 3, pp. 533-551. [4] Joshi M, et al.. Small-cell lung cancer: an update on targeted therapies. Adv Exp Med Biol 2013; 779: 385–404. [5] Lapenna S,et al.. Cell cycle kinases as therapeutic targets for cancer. Nat Rev Drug Discov 2009;8:547–66. [6] Siemeister G, et al. . BAY1000394, a novel cyclin –dependent kinase inhibitor, with potent antitumor activity in mono and combination treatment upon oral application. Mol Cancer Ther, 2012 Oct 11 (10): 2285-73 [7] Bahleda R, et al. A first-in-human phase I study of oral pan-CDK inhibitor BAY 1000394 in patients with advanced solid tumors: Dose escalation with an intermittent 3 days on/4 days off schedule.. J Clin Oncol 30, 2012 (suppl; abstr 3012) [8] Bolanos-Garcia VM. Aurora kinases. Int J Biochem Cell Biol 2005; 37: 1572–77. [9] Sells TB, et al. MLN8054 and Alisertib (MLN8237): Discovery of Selective Oral Aurora A Inhibitors. ACS Med Chem Lett, 2015, 6, 630-4. [10] Melichar B, et al. Safety and activity of alisertib, an investigational aurora kinase A inhibitor, in patients with breast cancer, small-cell lung cancer, non-small-cell lung cancer, head and neck squamous-cell carcinoma, and gastro-oesophageal adenocarcinoma: a five-arm phase 2 study. Lancet Oncol, Vol16 April2015, 305-405 Figure 1
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MS16.06 - New Chemotherapies (Eribulin, Aldoxorubicin, Etirinotecan, MM398) (ID 1921)
15:25 - 15:38 | Author(s): R. Govindan, S. Devarakonda
- Abstract
- Presentation
Abstract:
Small cell lung cancer (SCLC) accounts for nearly 15% of newly diagnosed lung cancers.[1] With the advent of tyrosine kinase inhibitors, the last decade has witnessed remarkable improvements in the outcomes of patients with non-small cell lung cancer (NSCLC). However, outcomes in patients with SCLC continue to remain dismal. Currently approved targeted therapies have minimal role in the management of SCLC, since unlike NSCLC, targetable tyrosine kinase alterations are rarely witnessed in SCLC.[2,3] Cytotoxic chemotherapy has therefore continued to remain the standard of care for SCLC. SCLC is usually very sensitive to first-line platinum based therapies.[4] Nevertheless, these responses are seldom durable and majority of patients relapse within weeks to months of treatment completion. Relapsed SCLC is a tough disease to treat and barely responds to conventional therapies. There is hence is an urgent need to develop novel therapeutic strategies that are capable of improving survival in patients with SCLC - particularly those with relapsed disease. Several new chemotherapeutic agents are currently being developed and actively studied in various solid tumors. The objective of this article is to highlight some of these newer chemotherapies and discuss their potential relevance in the management of SCLC. Eribulin mesylate is a non-taxane halichondrin B analogue derived from the marine sponge Halichondria okadaic.[5] Eribulin sequesters tubulin and inhibits mitotic spindle formation, leading to cell cycle arrest in G2-M and eventually cell death. Eribulin is currently FDA approved in the United States for the management of metastatic breast cancer in patients receiving prior treatment with at least two chemotherapy regimens, including an anthracycline and a taxane. In the phase III EMBRACE trial, as a part of which 762 women with breast cancer were randomized to receive eribulin or chemotherapy of the treating physician’s choice, overall survival (OS) was significantly improved with eribulin (13.1 vs. 10.6 months, HR 0.81 p=0.041).[6] Eribulin as single agent and in combination with erlotinib were shown to be active and well tolerated in patients with NSCLC treated with prior platinum based therapies.[7] In the study by Spira and colleauges, eribulin was dosed at 1.4mg/m2 on days 1 and 8 of a 21 day cycle (similar to breast cancer dosing schedule) and in a second cohort of patients at 1.4 mg/m2 on days 1, 8 and 15 of a 28 day schedule.[8] Among these, the 21 day dosing schedule was shown to be better tolerated and active with a median OS of 9.4 months in the second line setting for NSCLC. However, when used in combination with a second agent, the maximum tolerated dose (MTD) of eribulin was much lower. In a phase Ib/II study involving pretreated NSCLC patients, the MTD of eribulin was 0.9mg/m2, with 500mg/m2 of pemetrexed, administered on day 1 of a 21 day cycle.[9] Unfortunately, the combination was tolerable but showed no therapeutic benefit at this dose. Aldoxorubicin, formerly known as INNO-206, combines a molecular linker that allows doxorubicin to bind covalently to serum albumin upon intravenous administration.[10] This formulation releases doxorubicin in the acidic tumor microenvironment. Aldoxorubicin is currently being actively investigated in the management of soft-tissue sarcomas and glioblastoma. In a phase Ib/II study by Chawla and colleagues, the MTD of aldoxorubicin was 350mg/m2 administered every 21 days.[11] The drug showed a partial response rate of 20% and stable disease rate of 40% in 25 patients with advanced chemotherapy refractory cancers, among which most patients (68%) had soft tissue sarcomas. Aldoxorubicin was considered to be safe and efficacious in these patients. Currently, aldoxorubicin is being studied as part of an ongoing randomized phase IIb trial in patients with relapsed/refractory SCLC (NCT02200757). This study will compare progression free survival (PFS) between patients receiving aldoxorubicin at a dose of 230mg/m2 every 21 days, with those receiving topotecan. Irinotecan is a chemotherapeutic agent known to be active in SCLC. SN38 is the active metabolite of irinotecan, which through its inhibitory action on DNA topoisomerase I induces DNA breaks and inhibits repair. Etirinotecan pegol is a formulation designed to provide prolonged systemic exposure to SN38.[12] In a phase I dose escalation study, 66 patients received etirinotecan on three different dosing schedules and 115mg/m2 administered on days 1, 8 and 15 of 21 day cycles was established as the MTD. Diarrhea was observed in 5 patients at the 115mg/m2 dose level, with one patient experiencing grade 3 or higher diarrhea. The cholinergic diarrhea that is seen with irinotecan was not observed with etirinotecan. The drug was also shown to induce partial responses in patients with various cancers including SCLC. Etirinotecan was also recently reported to be active in heavily pretreated ovarian cancer patients.[13] In this study etirinotecan was administered at 145mg/m2 every 14 or 21 days, and the 21 day dosing schedule was found to be better tolerated and selected for further study. A phase II study that plans to study the effect of etirinotecan dosed every 21 days on PFS in patients with relapsed SCLC is currently recruiting (NCT01876446). Another formulation of irinotecan, MM-398, which is a nanoliposomal encapsulated formulation that packs nearly 80,000 irinotecan molecules in a 100nm liposome, is also being actively investigated in pancreatic, gastrointestinal, and other solid tumors.[14] Results from the NAPOLI-1 trial, a phase III study in which patients with metastatic pancreatic cancer who were previously treated with gemcitabine, were randomized to receive either single agent MM-398 at 120mg/m2 every 3 weeks or a combination of 5-fluorouracil (5FU), leucovorin (LV) and MM-398 at 80mg/m2, or 5-FU/LV alone, were recently presented.[15] The primary objective of this study was OS and in the intention to treat analysis, this was significantly improved in the MM-398/5FU/LV combination arm compared to the 5FU/LV arm (median OS 6.1 months vs. 4.2 months, HR-0.57, p=0.0009). Although there is currently no clinical data regarding the efficacy or safety of these newer drugs in patients with SCLC, considering that taxanes, anthracyclines, and DNA topoisomerase inhibitors are each individually active in SCLC, and that newer agents such as these have shown some positive preliminary results in other cancers - there is hope and optimism that over the next few years we will witness substantial progress in the management of SCLC. Overall, the need for developing and implementing well-designed biomarker driven clinical studies to investigate the role of these and other novel agents in SCLC is now greater than ever. References 1. Govindan R, Page N, Morgensztern D, et al. Changing epidemiology of small-cell lung cancer in the United States over the last 30 years: analysis of the surveillance, epidemiologic, and end results database. J Clin Oncol 2006;24:4539-44. 2. Rudin CM, Durinck S, Stawiski EW, et al. Comprehensive genomic analysis identifies SOX2 as a frequently amplified gene in small-cell lung cancer. Nat Genet 2012;44:1111-6. 3. Peifer M, Fernández-Cuesta L, Sos ML, et al. Integrative genome analyses identify key somatic driver mutations of small-cell lung cancer. Nat Genet 2012;44:1104-10. 4. Kalemkerian GP, Akerley W, Bogner P, et al. Small cell lung cancer. J Natl Compr Canc Netw 2013;11:78-98. 5. Scarpace SL. Eribulin mesylate (E7389): review of efficacy and tolerability in breast, pancreatic, head and neck, and non-small cell lung cancer. Clin Ther 2012;34:1467-73. 6. Cortes J, O'Shaughnessy J, Loesch D, et al. Eribulin monotherapy versus treatment of physician's choice in patients with metastatic breast cancer (EMBRACE): a phase 3 open-label randomised study. Lancet 2011;377:914-23. 7. Mok TS, Geater SL, Iannotti N, et al. Randomized phase II study of two intercalated combinations of eribulin mesylate and erlotinib in patients with previously treated advanced non-small-cell lung cancer. Ann Oncol 2014;25:1578-84. 8. Spira AI, Iannotti NO, Savin MA, et al. A phase II study of eribulin mesylate (E7389) in patients with advanced, previously treated non-small-cell lung cancer. Clin Lung Cancer 2012;13:31-8. 9. Waller CF, Vynnychenko I, Bondarenko I, et al. An open-label, multicenter, randomized phase Ib/II study of eribulin mesylate administered in combination with pemetrexed versus pemetrexed alone as second-line therapy in patients with advanced nonsquamous non-small-cell lung cancer. Clin Lung Cancer 2015;16:92-9. 10. Kratz F. A clinical update of using albumin as a drug vehicle - a commentary. J Control Release 2014;190:331-6. 11. Chawla SP, Chua VS, Hendifar AF, et al. A phase 1B/2 study of aldoxorubicin in patients with soft tissue sarcoma. Cancer 2015;121:570-9. 12. Jameson GS, Hamm JT, Weiss GJ, et al. A multicenter, phase I, dose-escalation study to assess the safety, tolerability, and pharmacokinetics of etirinotecan pegol in patients with refractory solid tumors. Clin Cancer Res 2013;19:268-78. 13. Vergote IB, Garcia A, Micha J, et al. Randomized multicenter phase II trial comparing two schedules of etirinotecan pegol (NKTR-102) in women with recurrent platinum-resistant/refractory epithelial ovarian cancer. J Clin Oncol 2013;31:4060-6. 14. Saif MW. MM-398 achieves primary endpoint of overall survival in phase III study in patients with gemcitabine refractory metastatic pancreatic cancer. JOP 2014;15:278-9. 15. Dhindsa N, Bayever E, Li C, et al. NAPOLI-1: randomized phase 3 study of MM-398 (nal-iri), with or without 5-fluorouracil and leucovorin, versus 5-fluorouracil and leucovorin, in metastatic pancreatic cancer progressed on or following gemcitabine-based therapy. Annals of Oncology (2014) 25 (suppl_2): ii105-ii117. 10.1093/annonc/mdu193.
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Author of
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ORAL 27 - Care (ID 123)
- Event: WCLC 2015
- Type: Oral Session
- Track: Advocacy
- Presentations: 1
- Moderators:M.N. Mountain, J. Freeman-Daily
- Coordinates: 9/08/2015, 10:45 - 12:15, 708+710+712
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ORAL27.07 - Impact of Regulatory Delays in Approving Oncology Drugs in a Developing Country: Mortality Associated with Lack of Access to Crizotinib in Brazil (ID 2295)
11:50 - 12:01 | Author(s): C. Barrios
- Abstract
- Presentation
Background:
Strict legislation and regulatory standards for the approval of drugs represent a safety guarantee for the population of any country. However, inappropriate delays in the process of evaluation of new medications have potentially serious consequences that can be measured. The objective of this analysis is to estimate the impact of the delay in the registration of medicines by the Brazilian regulatory agency, ANVISA, on the life span and life with symptoms related to the disease of patients who might potentially benefit from treatment. We use the example of crizotinib (Xalcori® Pfizer, NY, USA), which had its registration refused by the agency in 2014.
Methods:
We arbitrarily selected the 3-year period from August 2011 (FDA approval) to June 2014 (refusal by ANVISA) for this analysis. The number and prevalence of NSCLC cases eligible for treatment were estimated according to data from the Brazilian National Cancer Institue (INCA). The percentage of patients with ALK-positive tumors was inferred from the literature. We assumed that every ALK-positive NSCLC patient in Brazil would have access to the drug regardless if seeking treatment through the private or public health systems. The benefits from treatment with crizotinib were considered according to the published literature available at the time of regulatory assessment.
Results:
We estimated 24.460 new cases of NSCLC/year in Brazil (INCA), 70,6% (17.269) of which are diagnosed as advanced disease. Approximately 4,3% (743) would qualify as ALK positive. In a phase III crossover trial, crizotinib treatment ensued an improved PFS (3.0 vs. 7.7 mo; HR 0.49, p<0.001) and a significant extension in the median time to deterioration of symptoms (1.4 vs. 5.6 mo; p<0.001) when compared to standard second line chemotherapy. Survival estimates were obtained from a retrospective analysis (Shaw et al. Lancet 2011) as follows: chemotherapy 6.0 vs. crizotinib 20.3 months. We estimated 707 prevalent cases of ALK+ NSCLC in Brazil at the start of our analysis and 62 new cases per month during the 3-year analysis period were projected. Applying the premises above we calculated 1.367 years of life lost, and 772 additional patients who would remain alive after the selected period between August 2011 and July 2014. Furthermore, a total of 846 years of life free of symptoms’ deterioration are lost with the associated human suffering during the same period of time.
Conclusion:
The delay in the analysis, approval and registration process of new medications in Brazil and other developing or developed countries has an important impact in terms of human lives that can be potentially measured or estimated. While this kind of scrutiny has clear methodological limitations to consider, our main objective in this analysis is to raise the issue of the urgent need for a detailed and transparent evaluation of all the steps involved in the evaluation and registration process to stall this unnecessary suffering and loss of human life.
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