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Summary Report From the 13th Annual Targeted Therapies of the Treatment of Lung Cancer Meeting
Commentary Daniel Morgensztern
Clinical Lung Cancer, Vol. 15, No. 1, 16-20
Division of Medical Oncology, Washington University School of Medicine, St. Louis, MO Alvin J. Siteman Cancer Center, St. Louis, MO
Ramaswamy Govindan Division of Medical Oncology, Washington University School of Medicine, St. Louis, MO Alvin J. Siteman Cancer Center, St. Louis, MO
Summary Report From the 13th Annual Targeted Therapies of the Treatment of Lung Cancer Meeting Introduction The 13th Annual Targeted Therapies of the Treatment of Lung Cancer Meeting, which was held February 20 to 23, 2013, in Santa Monica, CA, under the auspices of the International Association for the Study of Lung Cancer (IASLC), featured several presentations on novel therapies for thoracic malignancies. The summary reported here highlights selected presentations from the Santa Monica meeting.
Epidermal Growth Factor Receptor, Human Epidermal Growth Factor Receptor 2, and Human Epidermal Growth Factor Receptor 3 Dr Fred Hirsch presented data on antieepidermal growth factor receptor (EGFR) monoclonal antibodies for the treatment of advanced nonesmall-cell lung cancer (NSCLC). The ongoing SWOG 0819 phase III trial is comparing chemotherapy with carboplatin plus paclitaxel (and bevacizumab in eligible patients) either alone or in combination with cetuximab in the frontline setting. The fully humanized EGFR antibody necitumumab has been studied in 2 phase III randomized clinical trials for patients with previously untreated NSCLC. The INSPIRE study comparing treatment with cisplatin plus pemetrexed with and without necitumumab in patients with stage IV nonsquamous NSCLC was terminated by the Independent Data Monitoring Committee after enrollment of 634 patients, because of the increased risk for thromboembolism in the experimental arm. The SQUIRE study, comparing cisplatin plus gemcitabine with and without necitumumab in patients with squamous cell carcinoma completed accrual on February 22, 2012, with 1097 patients enrolled. Dr Lecia Sequist presented data on MM-121, a fully humanized antiehuman epidermal growth factor receptor (HER)3 antibody. Preclinical data from mouse xenografts with A549 cells showed synergy between MM-121 and erlotinib. The dose-finding phase I study enrolled 3 different cohorts of patients with advanced NSCLC: wild-type EGFR without previous treatment with EGFR tyrosine kinase inhibitor (TKI) (group A), mutant EGFR without prior EGFR TKI
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treatment (group B), and mutant EGFR resistant to EGFR TKI (group C). In a phase II study, erlotinib-naive patients will be randomized to erlotinib therapy alone or in combination with MM0121, whereas patients previously treated with erlotinib will receive the combination regimen. Dr. Geoffrey Oxnard presented updates on studies involving U3-1287, a fully human anti-HER3 monoclonal antibody. In a phase I study involving patients with solid tumors, there were no responses among the 17 patients with NSCLC. In a phase Ib/II trial (HERALD), U3-1287 was combined with erlotinib to treat patients with advanced NSCLC who had been previously treated with 1 or 2 lines of chemotherapy. In the phase Ib portion of this study, although no response was seen in 7 patients, 4 patients achieved stable disease (SD) lasting more than 60 days. A phase II study with 3 arms, including 2 different regimens of U3-1287 in combination with erlotinib or erlotinib alone, completed accrual on May 29, 2012. Despite impressive response to the reversible EGFR TKIs erlotinib and gefitinib, virtually all patients eventually develop acquired resistance. Several new EGFR TKIs have been developed, including second-generation inhibitors such as afatinib and dacomitinib and third-generation inhibitors such as CO-1685 and WZ4002. Afatinib has been recently approved for use in the United States as a frontline therapy for patients with EGFR-mutant NSCLC based on the results from the LUX-3 trial.1 Dr Thomas Lynch discussed the rationale for a randomized phase II/III trial comparing afatinib plus cetuximab therapy with single-agent afatinib therapy in treatment-naive patients with sensitizing EGFR mutation. Dr Ross Camidge presented data for dacomitinib, a pan-HER inhibitor with anti-T790M activity in vitro. The phase IIa study A7471017 enrolled patients with advanced NSCLC who were nonsmokers or former light-smokers and had tumors with EGFR mutation, HER2 mutation, or HER2 amplification. All 45 patients with exon 19 or 21 mutations had tumor reduction, with 37 (82%) achieving partial response (PR). Median progression-free survival (PFS) for patients with EGFR exon 19 or 21 mutation were 16.4 and 18.3 months, respectively. Among the initial 18 patients with HER2 mutation,
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3 patients (16.6%) achieved PR, 13 (72.2%) had SD, and 2 (11.2%) had progressive disease (PD). A randomized phase III trial (ARCHER 1009) comparing dacomitinib with erlotinib as treatment for molecularly unselected advanced NSCLC with 1 to 2 prior lines of therapy is ongoing. Two additional studies are being planned: a phase III study comparing dacomitinib therapy with gefitinib therapy in patients with sensitizing EGFR mutations and a phase IIa study using pulse dosing of dacomitinib to treat patients with EGFR T790M mutations. Dr Jonathan Goldman reviewed data on CO-1686, a third-generation EGFR TKI that inhibits the key activating and T790M resistance mutations. The planned phase I trial will enroll patients with acquired resistance to EGFR TKI, and the recommended dose will be used in the expansion phase limited to patients with T790M mutations. The management of patients with EGFR-mutant NSCLC who develop PD after therapy with an EGFR TKI remains quite challenging. Dr Paul Paik argued that it is not safe to stop TKI therapy at progression, because of the risk of disease flare. Dr Joel Neal suggested second-line chemotherapy followed by reintroduction of a TKI as third-line therapy as a possible option for these patients.
Anaplastic Lymphoma Kinase Dr Alice Shaw presented the update on the PROFILE 1007, a phase III study comparing crizotinib with chemotherapy using either pemetrexed or docetaxel previously treated in patients with advanced anaplastic lymphoma kinaseepositive (ALKþ) NSCLC. Median PFS, the primary endpoint, was significantly higher for patients in the crizotinib arm than for those in the chemotherapy arm (7.7 vs. 3 mo; hazard ratio [HR] 0.49; P < .0001). Interestingly, when the analysis was subdivided by type of chemotherapy, patients receiving pemetrexed had improved PFS compared with those receiving docetaxel (4.2 vs. 2.6 mo; HR 0.30; P < .0001), whereas PFS for patient who received crizotinib remained significantly higher than that for patients in either chemotherapy arm. Crizotinib was also associated with a significant improvement in the quality of life. Nevertheless, 111 of 174 patients (63%) in the chemotherapy arm received crizotinib outside of the trial, and there was no differences in overall survival (OS), which reached 20.3 months for patients in the crizotinib arm and 22.8 months for patients in the chemotherapy arm. Dr Shaw also presented data on the second-generation ALK inhibitor LDK378. A phase I study enrolled patients with advanced ALKþ tumors, regardless of previous use of ALK inhibitors. The median PFS was 8.6 months, there was activity in central nervous system lesions, and the treatment was well tolerated, with nausea, diarrhea, vomiting, and fatigue reported as the most common toxicities. Dr Paul Bunn reviewed the design of SWOG 1300, in which patients with advanced ALKþ and pemetrexed-naive NSCLC progressing on crizotinib therapy are being randomized to treatment with pemetrexed plus crizotinib or treatment with single-agent pemetrexed followed by reintroduction of crizotinib at progression, with PFS as the primary endpoint.
Mesenchymal Epithelial Transition Factor Dr David Spigel presented data on onartuzumab, an antibody against the MET receptor. In the phase II study, 137 patients
with advanced NSCLC were randomized to treatment with erlotinib alone or in combination with onartuzumab. Among patients with MET positive tumors, defined as 50% cells with moderate or strong staining intensity by immunohistochemistry, the combination therapy was associated with a significant increase in PFS (2.9 vs. 1.5 mo; HR 0.53; P ¼ .04) and OS (12.6 vs. 3.8 mo; HR 0.37; P ¼ .37). Ongoing first-line trials with onartuzumab include the GO27821 trial comparing chemotherapy (platinum plus pemetrexed or carboplatin plus paclitaxel and bevacizumab) with or without onartuzumab in patients with nonsquamous histology, the GO27820 trial comparing treatment with carboplatin and paclitaxel with or without onartuzumab in patients with squamous cell carcinoma, and a phase III study comparing treatment with erlotinib alone or in combination with onartuzumab in patients with MET positive tumors and EGFR mutation. Dr Mark Socinski reviewed data on rilotumumab (AMG 102), a fully human monoclonal IgG2 antibody against hepatocyte growth factor, the only known ligand of the MET receptor. The maximum tolerated dose (MTD) was not reached in the phase I trial. An ongoing phase I/II trial is evaluating the combination of rilotumumab with erlotinib as treatment for previously treated stage IV NSCLC patients. In the initial evaluation, there was no dose-limiting toxicity (DLT) among the 8 patients treated in the phase I portion of the study nor unexpected toxicity among the first 13 patients treated at the recommended dose of erlotinib 150 mg daily plus rilotumumab 15 mg/kg every 3 weeks. Dr Alan Sandler presented data on tivantinib (ARQ 197), a noneadenosine triphosphate competitive inhibitor of MET. Preclinical data have shown greater inhibition with the combination of tivantinib and EGFR inhibitors than with either agent alone, and the combination therapy was considered safe in a phase I trial. The phase II trial randomized 167 previously treated patients with advanced NSCLC to treatment with erlotinib alone or in combination with tivantinib.2 Although the difference in median PFS favored the combination arm, it was not significantly different (3.8 vs. 2.3 mo; HR 0.81; P ¼ .24). Nevertheless, the exploratory analysis suggested a significant benefit from the addition of tivantinib in the KRAS-mutant population. The MARQUEE phase III trial comparing erlotinib alone or in combination with tivantinib using a similar eligibility to the phase II study was closed following a planned interim analysis showing that the primary endpoint of OS improvement was not expected to be met. Dr Geoffrey Oxnard presented the design of an ongoing phase II study comparing treatment with erlotinib plus tivantinib to chemotherapy in patients with previously treated advanced NSCLC with documented KRAS mutation. Dr Heather Wakelee presented data on cabozantinib (XL184), an oral inhibitor of MET, vascular endothelial growth factor receptor (VEGFR)2, and rearranged during transfection (RET) protein. In the phase I trial combining cabozantinib with erlotinib for patients with previously treated NSCLC, 4 (8%) out of 53 evaluable patients achieved PR. The ongoing ECOG 1512 is comparing erlotinib to cabozantinib or the combination regimen in patients with predominantly nonsquamous stage IV NSCLC without EGFR mutation or prior treatment with erlotinib.
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Targeted Therapy for Lung Cancer Poly (Adenosine DiphosphateeRibose) Polymerase Poly (adenosine diphosphateeribose) polymerase (PARP) plays a significant role in repairing single strand breaks (SSBs), whereas homologous repair (HR) is the preferred repair mechanism for double strand breaks (DSBs). PARP inhibition impairs the repair of SSBs, which are converted to DSBs during replication, increasing the burden for HR. In the presence of HR abnormalities such as breast cancer susceptibility (BRCA) protein or ataxia telangiectasia mutated (ATM) protein deficiency, the DSBs are repaired by nonhomologous end-joining (NHEJ) protein, which, unlike HR, is error prone, leading to genomic instability and cell death. Dr Geoffrey Shapiro reviewed the current strategies to sensitize HR-proficient cells to PARP inhibition, including combinations with HSP90 inhibitors, proteasome inhibition, checkpoint kinase inhibition, and histone deacetylase (HDAC) inhibition. Dr Phillip Bonomi presented results from a phase II study of iniparib, a PARP inhibitor. In this study, 119 patients with advanced squamous cell carcinoma of the lung were randomized to treatment with carboplatin and gemcitabine with or without iniparib. Modest improvements in median PFS (5.7 vs. 4.3 mo) and median OS (11.2 vs. 8.5 mo) were noted with the addition of iniparib. A phase III study with the same design has enrolled 780 patients with the primary endpoint of improving OS. Results from this study are still pending. Dr Giuseppe Giaccone reported that treatment with the combination of olaparib with cisplatin and gemcitabine was associated with significant myelosuppression. Ongoing trials with PARP inhibitor in advanced NSCLC include the phase II PIN (PARP Inhibition in Advanced NSCLC) study, the randomized trial of olaparib maintenance compared with placebo in patients without progressive disease after induction chemotherapy, and the phase III PIPSeN (PARP Inhibitor Maintenance in Platinum-Sensitive Advanced NSCLC) study.
Heat Shock Protein 90 Heat-shock proteins (HSPs) are molecular chaperones that help nascent polypeptides fold correctly.3 HSP90 participates in the stabilization and activation of multiple proteins, usually called “client proteins,” including receptor tyrosine kinases and transcription factors. Cancer cells may use the HSP90 chaperone complex, which includes HSP70 and co-chaperones, to protect mutated and overexpressed proteins from misfolding and degradation. Dr Suresh Ramalingan reviewed data on ganetespib, which accumulates preferentially in the tumors and does not have the common ocular toxicity observed with earlier generation HSP inhibitors. Preclinical data with ganetespib have shown synergy with docetaxel, cisplatin, bevacizumab, and the BRAF inhibitor vemurafenib. The initial monotherapy trial accrued 99 previously treated patients with advanced NSCLC with mutant EGFR, mutant KRAS, or wild types for both genes.4 Among the 8 patients positive for ALK translocation and crizotinib naive, 4 patients achieved PR, 3 had SD ranging from 121 to 218 days, and 1 had PD. The 2 patients with ALK translocation and previous use of crizotinib had PD. No other patient from any other cohort achieved PR. The most common toxicities were diarrhea, fatigue, nausea, and anorexia. In a phase I study evaluating the combination of ganetespib with
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docetaxel, the DLTs were myelosuppression and diarrhea, with the recommended phase II doses of docetaxel 75 mg/m2 on day 1 and ganetespib 150 mg/m2 on days 1 and 15. The GALAXY-1 study was a randomized phase II trial comparing docetaxel alone or in combination with ganetespib as therapy for patients with advanced NSCCL and 1 prior line of therapy. The combination therapy was associated with a significant increase in the risk of diarrhea (42% vs. 12%) and febrile neutropenia (10% vs. 2%). The efficacy results with the first 172 patients showed improved response rate (16% vs. 8%, P ¼ .078) and PFS (4.2 vs. 2.8 mo; P ¼ .076) for the combination arm. Dr Frederic Levy presented data on Debio 0932, an orally available HSP90 inhibitor. In a phase I trial evaluating the administration of Debio 0932 daily or every 2 days, the recommended dose was 1000 mg daily, whereas the every-2-day regimen is ongoing. There were 2 PRs among the 20 patients treated every 2 days (10%) and no responder in the daily-dosing arm. Dr Geoffrey Shapiro presented data on the HSP90 inhibitor AT13387. In a phase I study involving 57 patients, there were no responders among the 9 patients with NSCLC. An ongoing phase II study is evaluating AT13387 alone or in combination with crizotinib in ALK positive tumors.
Fibroblast Growth Factor Receptor Fibroblast growth factor receptor (FGFR) signaling plays a significant role in several physiologic processes including embryogenesis, adult tissue homeostasis, and wound healing.5 The 2 main downstream pathways activated by FGFRs are the mitogenactivated protein kinase (MAPK) and phosphoinositide 3-kinase (PI3K). Two of the ligands, FGF1 and FGF2, stimulate angiogenesis, both through direct effects on the endothelial cells and through synergy with VEGF and platelet-derived growth factor (PDGF) pathways. FGFR1 amplifications have been reported in approximately 20% of patients with squamous cell lung cancer, making FGFR an attractive target for treatment.6 Dr Lecia Sequist presented data on BGJ398, a pan-FGFR kinase inhibitor. In a phase I trial involving 31 patients with FGFR mutation or amplification, the drug has been well tolerated and there were early signs of clinical activity. There is an ongoing expansion cohort for patients with squamous cell lung cancer and FGFR1 amplification. Dr Joel Neal presented the preliminary data on dovitinib, a potent tyrosine kinase inhibitor of FGFRs, VEGFRs, c-Kit and FLT3. In a phase I trial, the MTD was 500 mg 5 days per week, with the most common grade 3-4 toxicities being nausea (75%), diarrhea (64%) and vomiting (61%). Dr Ross Camidge presented data on ponatinib. Ongoing trials are evaluating the use of ponatinib in NSCLC harboring either FGFR amplification or RET mutation.
Phosphatidylinositol-3 KinaseeMammalian Target of Rapamycin The phosphatidylinositol-3 kinase (PI3K) pathway is important in cell proliferation and survival.7,8 Activation of PI3K by receptor tyrosine kinase or G-coupled receptors results in the phosphorylation of phosphatidylinositol-4,5 biphosphate (PIP2) to produce phosphatidylinositol-3,4,5 triphosphate (PIP3), which provides docking sites at the membrane for signaling proteins with
Daniel Morgensztern, Ramaswamy Govindan pleckstrin homology domains, including phosphoinositidedependent kinase-1 (PDK1) and AKT. PDK1 activates AKT, which in turn promotes cell survival by decreasing apoptosis. AKT also phosphorylates tuberous sclerosis (TSC)1, inhibiting the GTPase activity of the TSC1-TSC2 dimer, leading to the activation of mammalian target of rapamycin (mTOR), which increases protein synthesis through phosphorylation of eukaryotic initiation factor 4E and ribosomal S6 protein. Phosphate and tensin homolog (PTEN) antagonizes the PI3K pathway by dephosphorylating PIP3. The PI3K pathway is commonly altered in NSCLC. A TCGA (The Cancer Genome Atlas) study of squamous cell lung cancer showed several abnormalities in the PI3K pathway involving PTEN (15%), PIK3CA (16%), AKT (20%), and TSC (5%).9 Several drugs targeting the PI3K pathway are being actively studied. Dr Karen Reckamp reviewed the study design for the combination of BKM120, an oral inhibitor of PI3K, with carboplatin and pemetrexed in patients with advanced nonsquamous lung cancer. Patients will receive standard doses of chemotherapy with escalating doses of BKM120 from 60 to 100 mg daily. Dr Juliane Jurgensmeier presented data on AZD8186, a PI3Kbeta/delta inhibitor with increased activity against PTEN null cell lines with additive effects when combined with docetaxel. Dr Faye Johnson reviewed data on BEZ235, an oral inhibitor of PI3K, mTOR1, and mTOR2, which is synergistic with erlotinib, may circumvent erlotinib resistance in EGFR mutant NSCLC, and may have a role in combination with MEK inhibitors in KRAS-mutant tumors. In a phase I study, the DLTs were thrombocytopenia, fatigue, diarrhea, mucositis, and hyperglycemia.
Immunotherapy The melanoma-associated antigen-A3 (MAGE-A3) is a tumorspecific antigen encoded by the MAGE-A3 gene, which is expressed during embryogenesis but not in normal adult tissues, with the exception of testis and placenta tissue. Because neither testis nor placenta bear surface human leukocyte antigen molecules, MAGE-A3 represents a tumor-specific antigen. In a phase II study with adjuvant MAGE-A3, although the primary endpoint of improved disease-free interval (DFI) compared with that of the placebo arm was not met, the treatment was well tolerated, the DFI was numerically superior, and all patients showed a humoral immune response to the MAGE-A3 antigen.10 Dr Ramaswamy Govindan provided an update on the MAGRIT phase III trial, in which patients with completely resected MAGE-A3 positive NSCLC stage IB to IIIA were randomized to vaccine or placebo arms. Accrual of participants from 500 sites in 34 countries was completed in August 2012 with a total of 2315 patients. MAGEA3 expression was observed in 33% of the screened patients, including 47% of those with squamous tumors and 26% of those with nonsquamous tumors. Results from this large study are eagerly anticipated. Transforming growth factor beta 2 (TGFb2) has an immunosuppressive role, inhibiting cytotoxic T-cell activation and causing the conversion of naive T cells into regulatory T cells by the induction of Foxp3, helping tumors to evade immunosurveillance.11 Belagenpumatucel-L is an allogeneic tumor cell vaccine made with 4 irradiated NSCLC cell lines modified with TGF-b2 antisense plasmid. In a phase II study, 75 patients with NSCLC stages II to
IV received belagenpumatucel-L either monthly or every other month in 3 cohorts: 1.25, 2.5 and 5 107 cells per injection.12 Treatment was well tolerated, and outcomes were dose dependent, with improved survival for patients in cohorts 2 and 3 compared with that of patients in cohort 1. Dr Luda Bazhenova described the design of the phase III STOP trial, which randomized 532 patients with NSCLC stage IIIA (T3N2), IIIB, or IV who did not progress after first-line therapy with a platinum doublet, to belagenpumatucel-L 2.5 107 cells per injection monthly for 18 months followed by 2 quarterly boosters or placebo. The primary endpoint is OS. Accrual of participants occurred between October 2008 and June 2012, with 532 patients enrolled. L-BPL25 (emepepimut-S) is a liposome vaccine targeting mucin 1. In a phase IIB trial, patients with stage IIIB or IV disease who had PR or SD after first-line chemotherapy were randomized to L-BPL25 or supportive care.13 Treatment was well tolerated, but the improvement in median OS (13 mo to 17.4 mo) with the use of L-BPL25 did not reach statistical significance (HR 0.73; 95% CI 0.50-1.07; P ¼ .11). The greatest difference in survival was observed in patients with stage IIIB disease in which the median OS was not reached compared with a median OS of 13.3 months in patients in the best supportive care arm (HR 0.52; 95% CI 0.261.052; P ¼ .06). Therefore, the investigators decided to pursue a larger study evaluating maintenance vaccine therapy in patients with stage III disease. Dr Charles Butts presented the results of the START phase III trial, in which patients with unresectable stage III NSCLC were randomized to L-BLP25 weekly 8 followed maintenance once every 6 weeks until progression or placebo. The study did not meet the primary endpoint of statistically significant improvement in OS. Lorvotuzumab mertansine (LM) (IMGN901) is an antibodydrug conjugate composed of a CD56-targeting antibody combined to the maytansinoid DM1 attached via a disulfide linker. CD56 is expressed in virtually all patients with small-cell lung cancer (SCLC) and Merkel cell carcinoma (MCC) by immunohistochemistry. On binding to CD56, LM is rapidly internalized and cleaved, with the release of DM1, which disrupts tubulin polymerization and microtubule assembly. In a phase I trial enrolling patients with CD56þ patients, the MTD was 75 mg/m2 daily for 3 consecutive days every 21 days.14 Among the 26 patients with SCLC, there was 1 PR and 3 SD for more than 90 days. In a phase I/II study evaluating the combination of IMGN901 with carboplatin and etoposide, the recommended phase II dose was carboplatin area under the curve (AUC) 5, etoposide 100 mg/m2 on days 1 to 3, and IMGN905 112 mg/m2 on days 1 and 8.15 The most common grade 3 or 4 toxicities were thrombocytopenia, leukopenia, and anemia. Although approximately half of the patients developed neuropathy, the vast majority was of grade 1 or 2. Among the 13 patients with SCLC, 6 achieved partial response (46%), including 4 out of 10 patients previously treated with platinum-based chemotherapy and 2 out of 3 chemotherapy naïve patients. Dr Daniel Morgensztern reviewed the phase II trial 0007, in which patients with chemotherapy-naive extensive SCLC are being randomized 2:1 to carboplatin plus etoposide and IMG907 or chemotherapy alone. The planned accrual is 120 patients with further development if more than 42 of the 80 patients in the experimental arm remain without PD at 6 months.
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Targeted Therapy for Lung Cancer The Seneca Valley virus 001 (SVV-001) is a naturally occurring replication-competent picornavirus with potent and selective tropism for neuroendocrine cancer cell types.16 In a phase I trial, 30 patients were treated, with no severe toxicity. Although there were no responders, 1 of the 6 patients with SCLC achieved disease stabilization for 10 months after rapid progression on first-line carboplatin plus etoposide therapy and second-line irinotecan therapy, remaining alive for more than 3 years after the SVV-001 treatment. Dr Charles Rudin presented the design for the phase II alliance N0923 trial in which patients with extensive-stage SCLC without progression after 4 cycles of platinum-based chemotherapy were randomized to SVV-001 or placebo. The trial, however, was closed to accrual based on interim futility analysis. The recognition of antigens presented by the major histocompatibility complex (MHC) to the T-cell receptor (TCR) is not enough to induce a T-cell response, which is instead regulated by multiple costimulatory and coinhibitory interactions.17 Under normal physiological conditions, coinhibitory molecules, which are broadly categorized as immune checkpoints, are crucial for the maintenance of self-tolerance and protection of tissues from damage during immune response to pathogenic infections. There are currently 2 key inhibitory pathways under clinical development for the treatment of lung cancer, the cytotoxic T-lymphocytee associated antigen 4 and the programmed cell death protein (PD1)e1. Results with the initial antibodies targeting PD1 and its ligand (PDL1) have been recently reported.18,19 Dr Roy Herbst described a phase Ia trial involving the anti-PDL1 agent MPDL3280A, in which the dose was escalated from 0.01 mg/kg to 20 mg/kg every 3 weeks, followed by the expansion phase involving patients with NSCLC, renal cell carcinoma, melanoma, or other tumor types. MPDL3280A is an engineered immunoglobulin G1 antibody without antibody-dependent cellular cytotoxicity that may have the advantage of leaving the PD1-PDL2 interaction in the lungs intact, possibly decreasing the risk for autoimmune pneumonitis.
Conclusion There has been a significant increase in the number of novel drugs being tested in clinical trials for patients with lung cancer over the past few years. Several promising targets were reviewed at the 2013 Annual Targeted Therapies of the Treatment of Lung Cancer Meeting, including the second-generation EGFR and ALK inhibitors and the checkpoint inhibitors. TCGA identified potential targetable genes in 114 out of 178 (64%) patients with squamous cell carcinoma. The preliminary data on genomic analysis of adenocarcinomas from TCGA are expected soon. With the rapid technologic advances and decreasing costs, the use of whole exome or a large panel of selected cancer genes may eventually replace singlegene mutation tests. Recent studies have also highlighted the value of serial biopsies in patients progressing through targeted therapy for
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identification of genomic alterations that confer acquired resistance. There are several ongoing studies evaluating anti-PD1 and antiPDL1 that target immune checkpoints in patients with NSCLC. Unfortunately, despite the large number of new drugs currently being tested for lung cancer, long-term disease control and cure remain elusive. Only through better understanding of tumor biology and innovative approaches will we be able to dramatically improve the outcomes of patients with metastatic NSCLC.
Disclosure The authors have stated that they have no conflicts of interest.
References 1. Sequist LV, Yang JC, Yamamoto N, et al. Phase III study of afatinib or cisplatin plus pemetrexed in patients with metastatic lung adenocarcinoma with EGFR mutations. J Clin Oncol 2013; 31:3327-34. 2. Sequist LV, von Pawel J, Garmey EG, et al. Randomized phase II study of erlotinib plus tivantinib versus erlotinib plus placebo in previously treated non-small-cell lung cancer. J Clin Oncol 2011; 29:3307-15. 3. Trepel J, Mollapour M, Giaccone G, et al. Targeting the dynamic HSP90 complex in cancer. Nat Rev Cancer 2010; 10:537-49. 4. Socinski MA, Goldman J, El-Hariry I, et al. A multicenter phase II study of ganetespib monotherapy in patients with genotypically defined advanced non-small cell lung cancer. Clin Cancer Res 2013; 19:3068-77. 5. Dieci MV, Arnedos M, Andre F, et al. Fibroblast growth factor receptor inhibitors as a cancer treatment: from a biologic rationale to medical perspectives. Cancer Discov 2013; 3:264-79. 6. Weiss J, Sos ML, Seidel D, et al. Frequent and focal FGFR1 amplification associates with therapeutically tractable FGFR1 dependency in squamous cell lung cancer. Sci Transl Med 2010; 2:62ra93. 7. Liu P, Cheng H, Roberts TM, et al. Targeting the phosphoinositide 3-kinase pathway in cancer. Nat Rev Drug Discov 2009; 8:627-44. 8. Courtney KD, Corcoran RB, Engelman JA. The PI3K pathway as drug target in human cancer. J Clin Oncol 2010; 28:1075-83. 9. Cancer Genome Atlas Research Network. Comprehensive genomic characterization of squamous cell lung cancers. Nature 2012; 489:519-25. 10. Vansteenkiste J, Zielinski M, Linder A, et al. Adjuvant MAGE-A3 immunotherapy in resected non-small-cell lung cancer: phase II randomized study results. J Clin Oncol 2013; 31:2396-403. 11. Chen W, Jin W, Hardegen N, et al. Conversion of peripheral CD4þCD25- naive T cells to CD4þCD25þ regulatory T cells by TGF-beta induction of transcription factor Foxp3. J Exp Med 2003; 198:1875-86. 12. Nemunaitis J, Dillman RO, Schwarzenberger PO, et al. Phase II study of belagenpumatucel-L, a transforming growth factor beta-2 antisense gene-modified allogeneic tumor cell vaccine in non-small-cell lung cancer. J Clin Oncol 2006; 24: 4721-30. 13. Butts C, Murray N, Maksymiuk A, et al. Randomized phase IIB trial of BLP25 liposome vaccine in stage IIIB and IV non-small-cell lung cancer. J Clin Oncol 2005; 23:6674-81. 14. Woll PJ, O’Brien M, Fossella F, et al. Phase I study of lorvotuzumab mertansine (Imgn901) in patients with Cd56-positive solid tumours. Ann Oncol 2010; 21: 175-6. 15. Spigel DR, Bendell J, Mita AC, et al. Phase I/II study to assess the safety, pharmacokinetics (PK) and efficacy of lorvotuzumab mertansine (LM, IMGN901) in combination with carboplatin/etoposide in patients with solid tumors including small-cell lung cancer (SCLC). Ann Oncol 2012; 23(suppl 9):ix498 (abstract 1543TiP). 16. Rudin CM, Poirier JT, Senzer NN, et al. Phase I clinical study of Seneca Valley Virus (SVV-001), a replication-competent picornavirus, in advanced solid tumors with neuroendocrine features. Clin Cancer Res 2011; 17:888-95. 17. Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer 2012; 12:252-64. 18. Topalian SL, Hodi FS, Brahmer JR, et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. New Engl J Med 2012; 366:2443-54. 19. Brahmer JR, Tykodi SS, Chow LQ, et al. Safety and activity of anti-PDL1 antibody in patients with advanced cancer. New Engl J Med 2012; 366: 2455-65.
Clinical Lung Cancer, Vol. 15, No. 1, 16-20
Division of Medical Oncology, Washington University School of Medicine, St. Louis, MO Alvin J. Siteman Cancer Center, St. Louis, MO
Ramaswamy Govindan Division of Medical Oncology, Washington University School of Medicine, St. Louis, MO Alvin J. Siteman Cancer Center, St. Louis, MO
Summary Report From the 13th Annual Targeted Therapies of the Treatment of Lung Cancer Meeting Introduction The 13th Annual Targeted Therapies of the Treatment of Lung Cancer Meeting, which was held February 20 to 23, 2013, in Santa Monica, CA, under the auspices of the International Association for the Study of Lung Cancer (IASLC), featured several presentations on novel therapies for thoracic malignancies. The summary reported here highlights selected presentations from the Santa Monica meeting.
Epidermal Growth Factor Receptor, Human Epidermal Growth Factor Receptor 2, and Human Epidermal Growth Factor Receptor 3 Dr Fred Hirsch presented data on antieepidermal growth factor receptor (EGFR) monoclonal antibodies for the treatment of advanced nonesmall-cell lung cancer (NSCLC). The ongoing SWOG 0819 phase III trial is comparing chemotherapy with carboplatin plus paclitaxel (and bevacizumab in eligible patients) either alone or in combination with cetuximab in the frontline setting. The fully humanized EGFR antibody necitumumab has been studied in 2 phase III randomized clinical trials for patients with previously untreated NSCLC. The INSPIRE study comparing treatment with cisplatin plus pemetrexed with and without necitumumab in patients with stage IV nonsquamous NSCLC was terminated by the Independent Data Monitoring Committee after enrollment of 634 patients, because of the increased risk for thromboembolism in the experimental arm. The SQUIRE study, comparing cisplatin plus gemcitabine with and without necitumumab in patients with squamous cell carcinoma completed accrual on February 22, 2012, with 1097 patients enrolled. Dr Lecia Sequist presented data on MM-121, a fully humanized antiehuman epidermal growth factor receptor (HER)3 antibody. Preclinical data from mouse xenografts with A549 cells showed synergy between MM-121 and erlotinib. The dose-finding phase I study enrolled 3 different cohorts of patients with advanced NSCLC: wild-type EGFR without previous treatment with EGFR tyrosine kinase inhibitor (TKI) (group A), mutant EGFR without prior EGFR TKI
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treatment (group B), and mutant EGFR resistant to EGFR TKI (group C). In a phase II study, erlotinib-naive patients will be randomized to erlotinib therapy alone or in combination with MM0121, whereas patients previously treated with erlotinib will receive the combination regimen. Dr. Geoffrey Oxnard presented updates on studies involving U3-1287, a fully human anti-HER3 monoclonal antibody. In a phase I study involving patients with solid tumors, there were no responses among the 17 patients with NSCLC. In a phase Ib/II trial (HERALD), U3-1287 was combined with erlotinib to treat patients with advanced NSCLC who had been previously treated with 1 or 2 lines of chemotherapy. In the phase Ib portion of this study, although no response was seen in 7 patients, 4 patients achieved stable disease (SD) lasting more than 60 days. A phase II study with 3 arms, including 2 different regimens of U3-1287 in combination with erlotinib or erlotinib alone, completed accrual on May 29, 2012. Despite impressive response to the reversible EGFR TKIs erlotinib and gefitinib, virtually all patients eventually develop acquired resistance. Several new EGFR TKIs have been developed, including second-generation inhibitors such as afatinib and dacomitinib and third-generation inhibitors such as CO-1685 and WZ4002. Afatinib has been recently approved for use in the United States as a frontline therapy for patients with EGFR-mutant NSCLC based on the results from the LUX-3 trial.1 Dr Thomas Lynch discussed the rationale for a randomized phase II/III trial comparing afatinib plus cetuximab therapy with single-agent afatinib therapy in treatment-naive patients with sensitizing EGFR mutation. Dr Ross Camidge presented data for dacomitinib, a pan-HER inhibitor with anti-T790M activity in vitro. The phase IIa study A7471017 enrolled patients with advanced NSCLC who were nonsmokers or former light-smokers and had tumors with EGFR mutation, HER2 mutation, or HER2 amplification. All 45 patients with exon 19 or 21 mutations had tumor reduction, with 37 (82%) achieving partial response (PR). Median progression-free survival (PFS) for patients with EGFR exon 19 or 21 mutation were 16.4 and 18.3 months, respectively. Among the initial 18 patients with HER2 mutation,
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3 patients (16.6%) achieved PR, 13 (72.2%) had SD, and 2 (11.2%) had progressive disease (PD). A randomized phase III trial (ARCHER 1009) comparing dacomitinib with erlotinib as treatment for molecularly unselected advanced NSCLC with 1 to 2 prior lines of therapy is ongoing. Two additional studies are being planned: a phase III study comparing dacomitinib therapy with gefitinib therapy in patients with sensitizing EGFR mutations and a phase IIa study using pulse dosing of dacomitinib to treat patients with EGFR T790M mutations. Dr Jonathan Goldman reviewed data on CO-1686, a third-generation EGFR TKI that inhibits the key activating and T790M resistance mutations. The planned phase I trial will enroll patients with acquired resistance to EGFR TKI, and the recommended dose will be used in the expansion phase limited to patients with T790M mutations. The management of patients with EGFR-mutant NSCLC who develop PD after therapy with an EGFR TKI remains quite challenging. Dr Paul Paik argued that it is not safe to stop TKI therapy at progression, because of the risk of disease flare. Dr Joel Neal suggested second-line chemotherapy followed by reintroduction of a TKI as third-line therapy as a possible option for these patients.
Anaplastic Lymphoma Kinase Dr Alice Shaw presented the update on the PROFILE 1007, a phase III study comparing crizotinib with chemotherapy using either pemetrexed or docetaxel previously treated in patients with advanced anaplastic lymphoma kinaseepositive (ALKþ) NSCLC. Median PFS, the primary endpoint, was significantly higher for patients in the crizotinib arm than for those in the chemotherapy arm (7.7 vs. 3 mo; hazard ratio [HR] 0.49; P < .0001). Interestingly, when the analysis was subdivided by type of chemotherapy, patients receiving pemetrexed had improved PFS compared with those receiving docetaxel (4.2 vs. 2.6 mo; HR 0.30; P < .0001), whereas PFS for patient who received crizotinib remained significantly higher than that for patients in either chemotherapy arm. Crizotinib was also associated with a significant improvement in the quality of life. Nevertheless, 111 of 174 patients (63%) in the chemotherapy arm received crizotinib outside of the trial, and there was no differences in overall survival (OS), which reached 20.3 months for patients in the crizotinib arm and 22.8 months for patients in the chemotherapy arm. Dr Shaw also presented data on the second-generation ALK inhibitor LDK378. A phase I study enrolled patients with advanced ALKþ tumors, regardless of previous use of ALK inhibitors. The median PFS was 8.6 months, there was activity in central nervous system lesions, and the treatment was well tolerated, with nausea, diarrhea, vomiting, and fatigue reported as the most common toxicities. Dr Paul Bunn reviewed the design of SWOG 1300, in which patients with advanced ALKþ and pemetrexed-naive NSCLC progressing on crizotinib therapy are being randomized to treatment with pemetrexed plus crizotinib or treatment with single-agent pemetrexed followed by reintroduction of crizotinib at progression, with PFS as the primary endpoint.
Mesenchymal Epithelial Transition Factor Dr David Spigel presented data on onartuzumab, an antibody against the MET receptor. In the phase II study, 137 patients
with advanced NSCLC were randomized to treatment with erlotinib alone or in combination with onartuzumab. Among patients with MET positive tumors, defined as 50% cells with moderate or strong staining intensity by immunohistochemistry, the combination therapy was associated with a significant increase in PFS (2.9 vs. 1.5 mo; HR 0.53; P ¼ .04) and OS (12.6 vs. 3.8 mo; HR 0.37; P ¼ .37). Ongoing first-line trials with onartuzumab include the GO27821 trial comparing chemotherapy (platinum plus pemetrexed or carboplatin plus paclitaxel and bevacizumab) with or without onartuzumab in patients with nonsquamous histology, the GO27820 trial comparing treatment with carboplatin and paclitaxel with or without onartuzumab in patients with squamous cell carcinoma, and a phase III study comparing treatment with erlotinib alone or in combination with onartuzumab in patients with MET positive tumors and EGFR mutation. Dr Mark Socinski reviewed data on rilotumumab (AMG 102), a fully human monoclonal IgG2 antibody against hepatocyte growth factor, the only known ligand of the MET receptor. The maximum tolerated dose (MTD) was not reached in the phase I trial. An ongoing phase I/II trial is evaluating the combination of rilotumumab with erlotinib as treatment for previously treated stage IV NSCLC patients. In the initial evaluation, there was no dose-limiting toxicity (DLT) among the 8 patients treated in the phase I portion of the study nor unexpected toxicity among the first 13 patients treated at the recommended dose of erlotinib 150 mg daily plus rilotumumab 15 mg/kg every 3 weeks. Dr Alan Sandler presented data on tivantinib (ARQ 197), a noneadenosine triphosphate competitive inhibitor of MET. Preclinical data have shown greater inhibition with the combination of tivantinib and EGFR inhibitors than with either agent alone, and the combination therapy was considered safe in a phase I trial. The phase II trial randomized 167 previously treated patients with advanced NSCLC to treatment with erlotinib alone or in combination with tivantinib.2 Although the difference in median PFS favored the combination arm, it was not significantly different (3.8 vs. 2.3 mo; HR 0.81; P ¼ .24). Nevertheless, the exploratory analysis suggested a significant benefit from the addition of tivantinib in the KRAS-mutant population. The MARQUEE phase III trial comparing erlotinib alone or in combination with tivantinib using a similar eligibility to the phase II study was closed following a planned interim analysis showing that the primary endpoint of OS improvement was not expected to be met. Dr Geoffrey Oxnard presented the design of an ongoing phase II study comparing treatment with erlotinib plus tivantinib to chemotherapy in patients with previously treated advanced NSCLC with documented KRAS mutation. Dr Heather Wakelee presented data on cabozantinib (XL184), an oral inhibitor of MET, vascular endothelial growth factor receptor (VEGFR)2, and rearranged during transfection (RET) protein. In the phase I trial combining cabozantinib with erlotinib for patients with previously treated NSCLC, 4 (8%) out of 53 evaluable patients achieved PR. The ongoing ECOG 1512 is comparing erlotinib to cabozantinib or the combination regimen in patients with predominantly nonsquamous stage IV NSCLC without EGFR mutation or prior treatment with erlotinib.
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Targeted Therapy for Lung Cancer Poly (Adenosine DiphosphateeRibose) Polymerase Poly (adenosine diphosphateeribose) polymerase (PARP) plays a significant role in repairing single strand breaks (SSBs), whereas homologous repair (HR) is the preferred repair mechanism for double strand breaks (DSBs). PARP inhibition impairs the repair of SSBs, which are converted to DSBs during replication, increasing the burden for HR. In the presence of HR abnormalities such as breast cancer susceptibility (BRCA) protein or ataxia telangiectasia mutated (ATM) protein deficiency, the DSBs are repaired by nonhomologous end-joining (NHEJ) protein, which, unlike HR, is error prone, leading to genomic instability and cell death. Dr Geoffrey Shapiro reviewed the current strategies to sensitize HR-proficient cells to PARP inhibition, including combinations with HSP90 inhibitors, proteasome inhibition, checkpoint kinase inhibition, and histone deacetylase (HDAC) inhibition. Dr Phillip Bonomi presented results from a phase II study of iniparib, a PARP inhibitor. In this study, 119 patients with advanced squamous cell carcinoma of the lung were randomized to treatment with carboplatin and gemcitabine with or without iniparib. Modest improvements in median PFS (5.7 vs. 4.3 mo) and median OS (11.2 vs. 8.5 mo) were noted with the addition of iniparib. A phase III study with the same design has enrolled 780 patients with the primary endpoint of improving OS. Results from this study are still pending. Dr Giuseppe Giaccone reported that treatment with the combination of olaparib with cisplatin and gemcitabine was associated with significant myelosuppression. Ongoing trials with PARP inhibitor in advanced NSCLC include the phase II PIN (PARP Inhibition in Advanced NSCLC) study, the randomized trial of olaparib maintenance compared with placebo in patients without progressive disease after induction chemotherapy, and the phase III PIPSeN (PARP Inhibitor Maintenance in Platinum-Sensitive Advanced NSCLC) study.
Heat Shock Protein 90 Heat-shock proteins (HSPs) are molecular chaperones that help nascent polypeptides fold correctly.3 HSP90 participates in the stabilization and activation of multiple proteins, usually called “client proteins,” including receptor tyrosine kinases and transcription factors. Cancer cells may use the HSP90 chaperone complex, which includes HSP70 and co-chaperones, to protect mutated and overexpressed proteins from misfolding and degradation. Dr Suresh Ramalingan reviewed data on ganetespib, which accumulates preferentially in the tumors and does not have the common ocular toxicity observed with earlier generation HSP inhibitors. Preclinical data with ganetespib have shown synergy with docetaxel, cisplatin, bevacizumab, and the BRAF inhibitor vemurafenib. The initial monotherapy trial accrued 99 previously treated patients with advanced NSCLC with mutant EGFR, mutant KRAS, or wild types for both genes.4 Among the 8 patients positive for ALK translocation and crizotinib naive, 4 patients achieved PR, 3 had SD ranging from 121 to 218 days, and 1 had PD. The 2 patients with ALK translocation and previous use of crizotinib had PD. No other patient from any other cohort achieved PR. The most common toxicities were diarrhea, fatigue, nausea, and anorexia. In a phase I study evaluating the combination of ganetespib with
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docetaxel, the DLTs were myelosuppression and diarrhea, with the recommended phase II doses of docetaxel 75 mg/m2 on day 1 and ganetespib 150 mg/m2 on days 1 and 15. The GALAXY-1 study was a randomized phase II trial comparing docetaxel alone or in combination with ganetespib as therapy for patients with advanced NSCCL and 1 prior line of therapy. The combination therapy was associated with a significant increase in the risk of diarrhea (42% vs. 12%) and febrile neutropenia (10% vs. 2%). The efficacy results with the first 172 patients showed improved response rate (16% vs. 8%, P ¼ .078) and PFS (4.2 vs. 2.8 mo; P ¼ .076) for the combination arm. Dr Frederic Levy presented data on Debio 0932, an orally available HSP90 inhibitor. In a phase I trial evaluating the administration of Debio 0932 daily or every 2 days, the recommended dose was 1000 mg daily, whereas the every-2-day regimen is ongoing. There were 2 PRs among the 20 patients treated every 2 days (10%) and no responder in the daily-dosing arm. Dr Geoffrey Shapiro presented data on the HSP90 inhibitor AT13387. In a phase I study involving 57 patients, there were no responders among the 9 patients with NSCLC. An ongoing phase II study is evaluating AT13387 alone or in combination with crizotinib in ALK positive tumors.
Fibroblast Growth Factor Receptor Fibroblast growth factor receptor (FGFR) signaling plays a significant role in several physiologic processes including embryogenesis, adult tissue homeostasis, and wound healing.5 The 2 main downstream pathways activated by FGFRs are the mitogenactivated protein kinase (MAPK) and phosphoinositide 3-kinase (PI3K). Two of the ligands, FGF1 and FGF2, stimulate angiogenesis, both through direct effects on the endothelial cells and through synergy with VEGF and platelet-derived growth factor (PDGF) pathways. FGFR1 amplifications have been reported in approximately 20% of patients with squamous cell lung cancer, making FGFR an attractive target for treatment.6 Dr Lecia Sequist presented data on BGJ398, a pan-FGFR kinase inhibitor. In a phase I trial involving 31 patients with FGFR mutation or amplification, the drug has been well tolerated and there were early signs of clinical activity. There is an ongoing expansion cohort for patients with squamous cell lung cancer and FGFR1 amplification. Dr Joel Neal presented the preliminary data on dovitinib, a potent tyrosine kinase inhibitor of FGFRs, VEGFRs, c-Kit and FLT3. In a phase I trial, the MTD was 500 mg 5 days per week, with the most common grade 3-4 toxicities being nausea (75%), diarrhea (64%) and vomiting (61%). Dr Ross Camidge presented data on ponatinib. Ongoing trials are evaluating the use of ponatinib in NSCLC harboring either FGFR amplification or RET mutation.
Phosphatidylinositol-3 KinaseeMammalian Target of Rapamycin The phosphatidylinositol-3 kinase (PI3K) pathway is important in cell proliferation and survival.7,8 Activation of PI3K by receptor tyrosine kinase or G-coupled receptors results in the phosphorylation of phosphatidylinositol-4,5 biphosphate (PIP2) to produce phosphatidylinositol-3,4,5 triphosphate (PIP3), which provides docking sites at the membrane for signaling proteins with
Daniel Morgensztern, Ramaswamy Govindan pleckstrin homology domains, including phosphoinositidedependent kinase-1 (PDK1) and AKT. PDK1 activates AKT, which in turn promotes cell survival by decreasing apoptosis. AKT also phosphorylates tuberous sclerosis (TSC)1, inhibiting the GTPase activity of the TSC1-TSC2 dimer, leading to the activation of mammalian target of rapamycin (mTOR), which increases protein synthesis through phosphorylation of eukaryotic initiation factor 4E and ribosomal S6 protein. Phosphate and tensin homolog (PTEN) antagonizes the PI3K pathway by dephosphorylating PIP3. The PI3K pathway is commonly altered in NSCLC. A TCGA (The Cancer Genome Atlas) study of squamous cell lung cancer showed several abnormalities in the PI3K pathway involving PTEN (15%), PIK3CA (16%), AKT (20%), and TSC (5%).9 Several drugs targeting the PI3K pathway are being actively studied. Dr Karen Reckamp reviewed the study design for the combination of BKM120, an oral inhibitor of PI3K, with carboplatin and pemetrexed in patients with advanced nonsquamous lung cancer. Patients will receive standard doses of chemotherapy with escalating doses of BKM120 from 60 to 100 mg daily. Dr Juliane Jurgensmeier presented data on AZD8186, a PI3Kbeta/delta inhibitor with increased activity against PTEN null cell lines with additive effects when combined with docetaxel. Dr Faye Johnson reviewed data on BEZ235, an oral inhibitor of PI3K, mTOR1, and mTOR2, which is synergistic with erlotinib, may circumvent erlotinib resistance in EGFR mutant NSCLC, and may have a role in combination with MEK inhibitors in KRAS-mutant tumors. In a phase I study, the DLTs were thrombocytopenia, fatigue, diarrhea, mucositis, and hyperglycemia.
Immunotherapy The melanoma-associated antigen-A3 (MAGE-A3) is a tumorspecific antigen encoded by the MAGE-A3 gene, which is expressed during embryogenesis but not in normal adult tissues, with the exception of testis and placenta tissue. Because neither testis nor placenta bear surface human leukocyte antigen molecules, MAGE-A3 represents a tumor-specific antigen. In a phase II study with adjuvant MAGE-A3, although the primary endpoint of improved disease-free interval (DFI) compared with that of the placebo arm was not met, the treatment was well tolerated, the DFI was numerically superior, and all patients showed a humoral immune response to the MAGE-A3 antigen.10 Dr Ramaswamy Govindan provided an update on the MAGRIT phase III trial, in which patients with completely resected MAGE-A3 positive NSCLC stage IB to IIIA were randomized to vaccine or placebo arms. Accrual of participants from 500 sites in 34 countries was completed in August 2012 with a total of 2315 patients. MAGEA3 expression was observed in 33% of the screened patients, including 47% of those with squamous tumors and 26% of those with nonsquamous tumors. Results from this large study are eagerly anticipated. Transforming growth factor beta 2 (TGFb2) has an immunosuppressive role, inhibiting cytotoxic T-cell activation and causing the conversion of naive T cells into regulatory T cells by the induction of Foxp3, helping tumors to evade immunosurveillance.11 Belagenpumatucel-L is an allogeneic tumor cell vaccine made with 4 irradiated NSCLC cell lines modified with TGF-b2 antisense plasmid. In a phase II study, 75 patients with NSCLC stages II to
IV received belagenpumatucel-L either monthly or every other month in 3 cohorts: 1.25, 2.5 and 5 107 cells per injection.12 Treatment was well tolerated, and outcomes were dose dependent, with improved survival for patients in cohorts 2 and 3 compared with that of patients in cohort 1. Dr Luda Bazhenova described the design of the phase III STOP trial, which randomized 532 patients with NSCLC stage IIIA (T3N2), IIIB, or IV who did not progress after first-line therapy with a platinum doublet, to belagenpumatucel-L 2.5 107 cells per injection monthly for 18 months followed by 2 quarterly boosters or placebo. The primary endpoint is OS. Accrual of participants occurred between October 2008 and June 2012, with 532 patients enrolled. L-BPL25 (emepepimut-S) is a liposome vaccine targeting mucin 1. In a phase IIB trial, patients with stage IIIB or IV disease who had PR or SD after first-line chemotherapy were randomized to L-BPL25 or supportive care.13 Treatment was well tolerated, but the improvement in median OS (13 mo to 17.4 mo) with the use of L-BPL25 did not reach statistical significance (HR 0.73; 95% CI 0.50-1.07; P ¼ .11). The greatest difference in survival was observed in patients with stage IIIB disease in which the median OS was not reached compared with a median OS of 13.3 months in patients in the best supportive care arm (HR 0.52; 95% CI 0.261.052; P ¼ .06). Therefore, the investigators decided to pursue a larger study evaluating maintenance vaccine therapy in patients with stage III disease. Dr Charles Butts presented the results of the START phase III trial, in which patients with unresectable stage III NSCLC were randomized to L-BLP25 weekly 8 followed maintenance once every 6 weeks until progression or placebo. The study did not meet the primary endpoint of statistically significant improvement in OS. Lorvotuzumab mertansine (LM) (IMGN901) is an antibodydrug conjugate composed of a CD56-targeting antibody combined to the maytansinoid DM1 attached via a disulfide linker. CD56 is expressed in virtually all patients with small-cell lung cancer (SCLC) and Merkel cell carcinoma (MCC) by immunohistochemistry. On binding to CD56, LM is rapidly internalized and cleaved, with the release of DM1, which disrupts tubulin polymerization and microtubule assembly. In a phase I trial enrolling patients with CD56þ patients, the MTD was 75 mg/m2 daily for 3 consecutive days every 21 days.14 Among the 26 patients with SCLC, there was 1 PR and 3 SD for more than 90 days. In a phase I/II study evaluating the combination of IMGN901 with carboplatin and etoposide, the recommended phase II dose was carboplatin area under the curve (AUC) 5, etoposide 100 mg/m2 on days 1 to 3, and IMGN905 112 mg/m2 on days 1 and 8.15 The most common grade 3 or 4 toxicities were thrombocytopenia, leukopenia, and anemia. Although approximately half of the patients developed neuropathy, the vast majority was of grade 1 or 2. Among the 13 patients with SCLC, 6 achieved partial response (46%), including 4 out of 10 patients previously treated with platinum-based chemotherapy and 2 out of 3 chemotherapy naïve patients. Dr Daniel Morgensztern reviewed the phase II trial 0007, in which patients with chemotherapy-naive extensive SCLC are being randomized 2:1 to carboplatin plus etoposide and IMG907 or chemotherapy alone. The planned accrual is 120 patients with further development if more than 42 of the 80 patients in the experimental arm remain without PD at 6 months.
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Targeted Therapy for Lung Cancer The Seneca Valley virus 001 (SVV-001) is a naturally occurring replication-competent picornavirus with potent and selective tropism for neuroendocrine cancer cell types.16 In a phase I trial, 30 patients were treated, with no severe toxicity. Although there were no responders, 1 of the 6 patients with SCLC achieved disease stabilization for 10 months after rapid progression on first-line carboplatin plus etoposide therapy and second-line irinotecan therapy, remaining alive for more than 3 years after the SVV-001 treatment. Dr Charles Rudin presented the design for the phase II alliance N0923 trial in which patients with extensive-stage SCLC without progression after 4 cycles of platinum-based chemotherapy were randomized to SVV-001 or placebo. The trial, however, was closed to accrual based on interim futility analysis. The recognition of antigens presented by the major histocompatibility complex (MHC) to the T-cell receptor (TCR) is not enough to induce a T-cell response, which is instead regulated by multiple costimulatory and coinhibitory interactions.17 Under normal physiological conditions, coinhibitory molecules, which are broadly categorized as immune checkpoints, are crucial for the maintenance of self-tolerance and protection of tissues from damage during immune response to pathogenic infections. There are currently 2 key inhibitory pathways under clinical development for the treatment of lung cancer, the cytotoxic T-lymphocytee associated antigen 4 and the programmed cell death protein (PD1)e1. Results with the initial antibodies targeting PD1 and its ligand (PDL1) have been recently reported.18,19 Dr Roy Herbst described a phase Ia trial involving the anti-PDL1 agent MPDL3280A, in which the dose was escalated from 0.01 mg/kg to 20 mg/kg every 3 weeks, followed by the expansion phase involving patients with NSCLC, renal cell carcinoma, melanoma, or other tumor types. MPDL3280A is an engineered immunoglobulin G1 antibody without antibody-dependent cellular cytotoxicity that may have the advantage of leaving the PD1-PDL2 interaction in the lungs intact, possibly decreasing the risk for autoimmune pneumonitis.
Conclusion There has been a significant increase in the number of novel drugs being tested in clinical trials for patients with lung cancer over the past few years. Several promising targets were reviewed at the 2013 Annual Targeted Therapies of the Treatment of Lung Cancer Meeting, including the second-generation EGFR and ALK inhibitors and the checkpoint inhibitors. TCGA identified potential targetable genes in 114 out of 178 (64%) patients with squamous cell carcinoma. The preliminary data on genomic analysis of adenocarcinomas from TCGA are expected soon. With the rapid technologic advances and decreasing costs, the use of whole exome or a large panel of selected cancer genes may eventually replace singlegene mutation tests. Recent studies have also highlighted the value of serial biopsies in patients progressing through targeted therapy for
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identification of genomic alterations that confer acquired resistance. There are several ongoing studies evaluating anti-PD1 and antiPDL1 that target immune checkpoints in patients with NSCLC. Unfortunately, despite the large number of new drugs currently being tested for lung cancer, long-term disease control and cure remain elusive. Only through better understanding of tumor biology and innovative approaches will we be able to dramatically improve the outcomes of patients with metastatic NSCLC.
Disclosure The authors have stated that they have no conflicts of interest.
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