- Email: [email protected]
Poly(ADP-Ribose) Polymerase Inhibitors
Journal of Thoracic Oncology • Volume 5, Number 12, Supplement 6, December 2010
Santa Monica Supplement
Poly(ADP-Ribose) Polymerase Inhibitors Edward B. Garon, MD, and Steven M. Dubinett, MD
T
his session not only described several poly(ADP-ribose) polymerase (PARP) inhibitors but also included talks on the science of nuclear excision repair, an oxidized glutathione, and a heat shock protein (HSP) 90 inhibitor.
SUMMARY OF PRESENTATIONS Science of Nuclear Excision Repair Dr. George Simon opened the session by presenting the science of nuclear excision repair. He reviewed preclinical data, including evidence that apoptosis increases in cell lines exposed to cisplatin when excision repair cross-complementation group 1 (ERCC1) siRNA is added. He also reviewed clinical data from the International Adjuvant Lung Trial, in which improved survival with adjuvant cisplatin-based chemotherapy was restricted to tumors with low ERCC1.1 He then focused on trials that designed to tailor therapy to repair genes. The Spanish Customized Adjuvant Treatment trial randomly assigns postresection patients with positive N1 or N2 nodes to docetaxel ⫹ cisplatin or an experimental arm. Based on data correlating higher breast cancer 1 (BRCA1) mRNA levels with cisplatin resistance and docetaxel sensitivity,2 the experimental arm assigns treatment by quartile expression for BRCA1 (lowest: gemcitabine ⫹ cisplatin; 2–3: docetaxel ⫹ cisplatin; and highest: docetaxel). The TAilored post-Surgical Therapy in Early-stage NSCLC (TASTE) trial randomizes postsurgical patients to cisplatin ⫹ pemetrexed or an experimental arm. In the experimental arm, mutations in the epidermal growth factor receptor (EGFR) lead to treatment with erlotinib, whereas treatment for EGFR wild-type patients are assigned based on ERCC1 status (cisplatin ⫹ pemetrexed versus observation). He then discussed the MADe IT Trail, in which patients with metastatic disease were assigned treatment regimen based on ERCC1 and ribonucleotide reductase M1 (RRM1) levels (Figure 1). Outcomes in this trial exceeded selected historical controls, and the difference was more apparent for
FIGURE 1. The algorithm.
survival than for progression-free survival.3,4 Dr. Simon hypothesized that up-regulation of ERCC1 or RRM1 in response to therapy could alter tumor biology toward a more indolent phenotype. A phase III trial has been designed to randomize patients to the MADe IT algorithm or gemcitabine ⫹ carboplatin.
NOV-002 Phase III Trial Results Lynch et al. discussed data from a phase III openlabeled trial of carboplatin and paclitaxel ⫾ NOV-002. This agent alters cellular redox status and alters the activity of redox-sensitive proteins. This drug was marketed in Russia based on a randomized phase II trial of 68 patients who showed a 1-year survival of 17% for chemotherapy alone, compared with 63% for chemotherapy ⫹ NOV-002. A phase I/II study in the United States showed a response rate of 33% for chemotherapy alone as opposed to 69% for chemotherapy plus NOV-002. This 907-patient study in frontline patients with stage IIIB/IV NSCLC using a carboplatin ⫹ paclitaxel backbone completed accrual in March 2008. Unfortunately, the primary end point of overall survival improvement was not met (as was presented at the recently concluded meeting of the American Society of Clinical Oncology), and the future of the drug is uncertain.
IPI-504 Division of Hematology/Oncology, David Geffen School of Medicine at University of California, Los Angeles, Santa Monica, California. Disclosure: The authors declare no conflicts of interest. Address for correspondence: Edward B. Garon, MD, Department of Medicine, Division of Hematology/Oncology, David Geffen School of Medicine at University of California, Los Angeles, 2825 Santa Monica Blvd., Suite 200, Santa Monica, CA 90404. E-mail: [email protected] Copyright © 2010 by the International Association for the Study of Lung Cancer. ISSN: 1556-0864/10/0512-0433
Dr. Lecia Sequist discussed IPI-504 (retaspimycin hydrochloride), an HSP-90 inhibitor. As will be discussed in more detail in this issue, HSP90 is being extensively evaluated as a target for therapy, based on its role as a chaperone for multiple proteins with important functions in oncogenesis (including human epithelial growth factor receptor 2 (HER2), EML4-anaplastic lymphoma kinase, and mutant EGFR). The agent is a potent, water-soluble agent that interconverts with
Copyright © 2010 by the International Association for the Study of Lung Cancer
S455
Santa Monica Supplement
Journal of Thoracic Oncology • Volume 5, Number 12, Supplement 6, December 2010
17-AAG. In a clinical trial in patients with tissue available who failed a previous EGFR tyrosine kinase inhibitor (TKI), the toxicity profile seemed favorable. No responses were seen in 19 patients with EGFR mutant tumors, but 4 of 28 (14%) patients with WT EGFR experienced a partial response.5
PARP Inhibitors Poly-ADP ribosylation is a posttranslational modification that covalently adds varying numbers of ADP residues to proteins. PARP-1 is the most ubiquitous member of the PARP family and is activated by DNA strand breaks. PARP inhibition leads to the accumulation of single-strand DNA breaks, and recent data demonstrated clinical activity of PARP inhibitors, particularly in the setting of other errors in DNA repair pathways. Dr. Ramaswamy Govindan briefly discussed a group of agents that are not being actively pursued in development at this time, but the bulk of the discussion revolved around four compounds discussed below. Dr. Shapiro discussed a phase I study of AZD2281 (KU0059436, olaparib). After maximum tolerated dose was determined to be 400 mg twice daily, a cohort of patients with germline BRCA mutations were enrolled. Approximately half of BRCA mutant patients (breast, ovarian, and prostate cancer) derived benefit, defined by radiographic or tumor marker response or stable disease for at least 4 months.6 More than 1/3 of patients in two single-agent phase II studies in BRCA-deficient breast and ovarian cancer met prespecified criteria for clinical benefit. Active clinical trials at the time of the meeting included studies in triple-negative breast, ovarian, gastric, and colon cancer. Dr. Patricia LoRusso discussed the PARP inhibitor ABT 888, describing it as a potent, orally bioavailable agent that crosses the blood brain barrier. Preclinical data were shown demonstrating potentiation of the effects of radiation, carboplatin, and temozolamide.7 In a phase I clinical trial, PARP inhibition was assessed in peripheral blood mononuclear cells at several time points and biopsy specimens pretreatment and 3 to 6 hours after treatment. High-level PARP inhibition was demonstrated in both the peripheral blood mononuclear cells and the tumor. Further clinical investigation is being pursued along with several different chemotherapeutics. Dr. Bradley discussed BSI-201, an intravenous small molecule inhibitor of PARP1 and other NAD⫹ binding enzymes. The agent is lipophilic and crosses the blood-brain barrier. Data demonstrating disparate levels of PARP1 (but not PARP2) between normal tissue and certain tumors were shown. A phase II study in triple-negative breast cancer demonstrated improved survival with a favorable safety profile.8 The clinical development plan for the agent was outlined, including a phase III trial with a carboplatin ⫹ gemcitabine backbone in squamous cell carcinoma of the lung.
S456
Dr. Maurizio Voi discussed PF-01367338 (formerly AG-014699). This agent has been most extensively tested along with temezolamide in metastatic melanoma.9 A phase 1 study evaluated pharmacodynamics and pharmacokinetics with a single dose on day 7. Evidence of activity was seen (greater than historical controls with temozolamide), and a phase II trial in melanoma was proposed. There is an ongoing phase I trial of the agent along with single agent carboplatin, carboplatin ⫹ paclitaxel, or cisplatin ⫹ pemetrexed.
CONCLUSION AND FUTURE DIRECTIONS In conclusion, several approaches were discussed, including tailored approaches and HSP90 inhibitors, both of which were discussed more thoroughly during other sessions. NOV-002, the proprietary formulation of oxidized glutathione, did not reach its end point in a phase III clinical trial after promising results in a randomized phase II trial. The most extensive discussion covered the PARP inhibitors. These agents are considered very promising antineoplastic agents, and clinical trials are being aggressively pursued in lung cancer and other types of malignancies. REFERENCES 1. Olaussen KA, Dunant A, Fouret P, et al. DNA repair by ERCC1 in non-small-cell lung cancer and cisplatin-based adjuvant chemotherapy. N Engl J Med 2006;355:983–991. 2. Wang L, Wei J, Qian X, et al. ERCC1 and BRCA1 mRNA expression levels in metastatic malignant effusions is associated with chemosensitivity to cisplatin and/or docetaxel. BMC Cancer 2008;8:97. 3. Simon G, Sharma A, Li X, et al. Feasibility and efficacy of molecular analysis-directed individualized therapy in advanced non-small-cell lung cancer. J Clin Oncol 2007;25:2741–2746. 4. Simon G. ERCC1 and RRM1—predictive vs. prognostic roles in nonsmall cell lung cancer (NSCLC). In 13th World Conference on Lung Cancer PD344 2009, San Francisco, CA, 2009. 5. Sequist LV, Gettinger S, Natale R, et al. A phase II trial of IPI-504 (retaspimycin hydrochloride), a novel Hsp90 inhibitor, in patients with relapsed and/or refractory stage IIIb or stage IV non-small cell lung cancer (NSCLC) stratified by EGFR mutation status. J Clin Oncol 2009;27:8073. 6. Fong PC, Boss DS, Yap TA, et al. Inhibition of poly(ADP-ribose) polymerase in tumors from BRCA mutation carriers. N Engl J Med 2009;361:123–134. 7. Donawho CK, Luo Y, Penning TD, et al. ABT-888, an orally active poly(ADP-ribose) polymerase inhibitor that potentiates DNA-damaging agents in preclinical tumor models. Clin Cancer Res 2007;13:2728 – 2737. 8. O’Shaughnessy J, Osborne C, Pippen J, et al. Updated results of a randomized phase II study demonstrating efficacy and safety of BSI-201, a PARP inhibitor, in combination with gemcitabine/carboplatin in metastatic triple-negative breast cancer. In SABCS 2009, San Antonio, TX, 2009. 9. Plummer R, Jones C, Middleton M, et al. Phase I study of the poly(ADPribose) polymerase inhibitor, AG014699, in combination with temozolomide in patients with advanced solid tumors. Clin Cancer Res 2008; 14:7917–7923.
Copyright © 2010 by the International Association for the Study of Lung Cancer
Santa Monica Supplement
Poly(ADP-Ribose) Polymerase Inhibitors Edward B. Garon, MD, and Steven M. Dubinett, MD
T
his session not only described several poly(ADP-ribose) polymerase (PARP) inhibitors but also included talks on the science of nuclear excision repair, an oxidized glutathione, and a heat shock protein (HSP) 90 inhibitor.
SUMMARY OF PRESENTATIONS Science of Nuclear Excision Repair Dr. George Simon opened the session by presenting the science of nuclear excision repair. He reviewed preclinical data, including evidence that apoptosis increases in cell lines exposed to cisplatin when excision repair cross-complementation group 1 (ERCC1) siRNA is added. He also reviewed clinical data from the International Adjuvant Lung Trial, in which improved survival with adjuvant cisplatin-based chemotherapy was restricted to tumors with low ERCC1.1 He then focused on trials that designed to tailor therapy to repair genes. The Spanish Customized Adjuvant Treatment trial randomly assigns postresection patients with positive N1 or N2 nodes to docetaxel ⫹ cisplatin or an experimental arm. Based on data correlating higher breast cancer 1 (BRCA1) mRNA levels with cisplatin resistance and docetaxel sensitivity,2 the experimental arm assigns treatment by quartile expression for BRCA1 (lowest: gemcitabine ⫹ cisplatin; 2–3: docetaxel ⫹ cisplatin; and highest: docetaxel). The TAilored post-Surgical Therapy in Early-stage NSCLC (TASTE) trial randomizes postsurgical patients to cisplatin ⫹ pemetrexed or an experimental arm. In the experimental arm, mutations in the epidermal growth factor receptor (EGFR) lead to treatment with erlotinib, whereas treatment for EGFR wild-type patients are assigned based on ERCC1 status (cisplatin ⫹ pemetrexed versus observation). He then discussed the MADe IT Trail, in which patients with metastatic disease were assigned treatment regimen based on ERCC1 and ribonucleotide reductase M1 (RRM1) levels (Figure 1). Outcomes in this trial exceeded selected historical controls, and the difference was more apparent for
FIGURE 1. The algorithm.
survival than for progression-free survival.3,4 Dr. Simon hypothesized that up-regulation of ERCC1 or RRM1 in response to therapy could alter tumor biology toward a more indolent phenotype. A phase III trial has been designed to randomize patients to the MADe IT algorithm or gemcitabine ⫹ carboplatin.
NOV-002 Phase III Trial Results Lynch et al. discussed data from a phase III openlabeled trial of carboplatin and paclitaxel ⫾ NOV-002. This agent alters cellular redox status and alters the activity of redox-sensitive proteins. This drug was marketed in Russia based on a randomized phase II trial of 68 patients who showed a 1-year survival of 17% for chemotherapy alone, compared with 63% for chemotherapy ⫹ NOV-002. A phase I/II study in the United States showed a response rate of 33% for chemotherapy alone as opposed to 69% for chemotherapy plus NOV-002. This 907-patient study in frontline patients with stage IIIB/IV NSCLC using a carboplatin ⫹ paclitaxel backbone completed accrual in March 2008. Unfortunately, the primary end point of overall survival improvement was not met (as was presented at the recently concluded meeting of the American Society of Clinical Oncology), and the future of the drug is uncertain.
IPI-504 Division of Hematology/Oncology, David Geffen School of Medicine at University of California, Los Angeles, Santa Monica, California. Disclosure: The authors declare no conflicts of interest. Address for correspondence: Edward B. Garon, MD, Department of Medicine, Division of Hematology/Oncology, David Geffen School of Medicine at University of California, Los Angeles, 2825 Santa Monica Blvd., Suite 200, Santa Monica, CA 90404. E-mail: [email protected] Copyright © 2010 by the International Association for the Study of Lung Cancer. ISSN: 1556-0864/10/0512-0433
Dr. Lecia Sequist discussed IPI-504 (retaspimycin hydrochloride), an HSP-90 inhibitor. As will be discussed in more detail in this issue, HSP90 is being extensively evaluated as a target for therapy, based on its role as a chaperone for multiple proteins with important functions in oncogenesis (including human epithelial growth factor receptor 2 (HER2), EML4-anaplastic lymphoma kinase, and mutant EGFR). The agent is a potent, water-soluble agent that interconverts with
Copyright © 2010 by the International Association for the Study of Lung Cancer
S455
Santa Monica Supplement
Journal of Thoracic Oncology • Volume 5, Number 12, Supplement 6, December 2010
17-AAG. In a clinical trial in patients with tissue available who failed a previous EGFR tyrosine kinase inhibitor (TKI), the toxicity profile seemed favorable. No responses were seen in 19 patients with EGFR mutant tumors, but 4 of 28 (14%) patients with WT EGFR experienced a partial response.5
PARP Inhibitors Poly-ADP ribosylation is a posttranslational modification that covalently adds varying numbers of ADP residues to proteins. PARP-1 is the most ubiquitous member of the PARP family and is activated by DNA strand breaks. PARP inhibition leads to the accumulation of single-strand DNA breaks, and recent data demonstrated clinical activity of PARP inhibitors, particularly in the setting of other errors in DNA repair pathways. Dr. Ramaswamy Govindan briefly discussed a group of agents that are not being actively pursued in development at this time, but the bulk of the discussion revolved around four compounds discussed below. Dr. Shapiro discussed a phase I study of AZD2281 (KU0059436, olaparib). After maximum tolerated dose was determined to be 400 mg twice daily, a cohort of patients with germline BRCA mutations were enrolled. Approximately half of BRCA mutant patients (breast, ovarian, and prostate cancer) derived benefit, defined by radiographic or tumor marker response or stable disease for at least 4 months.6 More than 1/3 of patients in two single-agent phase II studies in BRCA-deficient breast and ovarian cancer met prespecified criteria for clinical benefit. Active clinical trials at the time of the meeting included studies in triple-negative breast, ovarian, gastric, and colon cancer. Dr. Patricia LoRusso discussed the PARP inhibitor ABT 888, describing it as a potent, orally bioavailable agent that crosses the blood brain barrier. Preclinical data were shown demonstrating potentiation of the effects of radiation, carboplatin, and temozolamide.7 In a phase I clinical trial, PARP inhibition was assessed in peripheral blood mononuclear cells at several time points and biopsy specimens pretreatment and 3 to 6 hours after treatment. High-level PARP inhibition was demonstrated in both the peripheral blood mononuclear cells and the tumor. Further clinical investigation is being pursued along with several different chemotherapeutics. Dr. Bradley discussed BSI-201, an intravenous small molecule inhibitor of PARP1 and other NAD⫹ binding enzymes. The agent is lipophilic and crosses the blood-brain barrier. Data demonstrating disparate levels of PARP1 (but not PARP2) between normal tissue and certain tumors were shown. A phase II study in triple-negative breast cancer demonstrated improved survival with a favorable safety profile.8 The clinical development plan for the agent was outlined, including a phase III trial with a carboplatin ⫹ gemcitabine backbone in squamous cell carcinoma of the lung.
S456
Dr. Maurizio Voi discussed PF-01367338 (formerly AG-014699). This agent has been most extensively tested along with temezolamide in metastatic melanoma.9 A phase 1 study evaluated pharmacodynamics and pharmacokinetics with a single dose on day 7. Evidence of activity was seen (greater than historical controls with temozolamide), and a phase II trial in melanoma was proposed. There is an ongoing phase I trial of the agent along with single agent carboplatin, carboplatin ⫹ paclitaxel, or cisplatin ⫹ pemetrexed.
CONCLUSION AND FUTURE DIRECTIONS In conclusion, several approaches were discussed, including tailored approaches and HSP90 inhibitors, both of which were discussed more thoroughly during other sessions. NOV-002, the proprietary formulation of oxidized glutathione, did not reach its end point in a phase III clinical trial after promising results in a randomized phase II trial. The most extensive discussion covered the PARP inhibitors. These agents are considered very promising antineoplastic agents, and clinical trials are being aggressively pursued in lung cancer and other types of malignancies. REFERENCES 1. Olaussen KA, Dunant A, Fouret P, et al. DNA repair by ERCC1 in non-small-cell lung cancer and cisplatin-based adjuvant chemotherapy. N Engl J Med 2006;355:983–991. 2. Wang L, Wei J, Qian X, et al. ERCC1 and BRCA1 mRNA expression levels in metastatic malignant effusions is associated with chemosensitivity to cisplatin and/or docetaxel. BMC Cancer 2008;8:97. 3. Simon G, Sharma A, Li X, et al. Feasibility and efficacy of molecular analysis-directed individualized therapy in advanced non-small-cell lung cancer. J Clin Oncol 2007;25:2741–2746. 4. Simon G. ERCC1 and RRM1—predictive vs. prognostic roles in nonsmall cell lung cancer (NSCLC). In 13th World Conference on Lung Cancer PD344 2009, San Francisco, CA, 2009. 5. Sequist LV, Gettinger S, Natale R, et al. A phase II trial of IPI-504 (retaspimycin hydrochloride), a novel Hsp90 inhibitor, in patients with relapsed and/or refractory stage IIIb or stage IV non-small cell lung cancer (NSCLC) stratified by EGFR mutation status. J Clin Oncol 2009;27:8073. 6. Fong PC, Boss DS, Yap TA, et al. Inhibition of poly(ADP-ribose) polymerase in tumors from BRCA mutation carriers. N Engl J Med 2009;361:123–134. 7. Donawho CK, Luo Y, Penning TD, et al. ABT-888, an orally active poly(ADP-ribose) polymerase inhibitor that potentiates DNA-damaging agents in preclinical tumor models. Clin Cancer Res 2007;13:2728 – 2737. 8. O’Shaughnessy J, Osborne C, Pippen J, et al. Updated results of a randomized phase II study demonstrating efficacy and safety of BSI-201, a PARP inhibitor, in combination with gemcitabine/carboplatin in metastatic triple-negative breast cancer. In SABCS 2009, San Antonio, TX, 2009. 9. Plummer R, Jones C, Middleton M, et al. Phase I study of the poly(ADPribose) polymerase inhibitor, AG014699, in combination with temozolomide in patients with advanced solid tumors. Clin Cancer Res 2008; 14:7917–7923.
Copyright © 2010 by the International Association for the Study of Lung Cancer