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N. Saijo
Moderator of
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SC05 - Novel Drugs in Thoracic Cancers (ID 329)
- Event: WCLC 2016
- Type: Science Session
- Track: Chemotherapy/Targeted Therapy/Immunotherapy
- Presentations: 4
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SC05.01 - Immunotherapy in Malignant Pleural Mesothelioma (ID 6617)
11:00 - 11:20 | Author(s): R. Hassan
- Abstract
- Presentation
Abstract not provided
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SC05.02 - Novel Cytotoxic Drugs in Lung Cancer (ID 6618)
11:20 - 11:40 | Author(s): J. Soria
- Abstract
- Presentation
Abstract:
Even in the era of precision medicine and immunotherapy, cytotoxic chemotherapies remain an essential component of lung cancer treatment, both in resectable disease as well as in advanced/metastatic lung cancer. We have chosen to focus on 2 new cytotoxic compounds, which are likely to emerge as new players in the field of lung cancer management. One (named PM1183) has activity in small-cell lung cancer (SCLC), the other TAS-114 has activity in non-small cell lung cancer (NSCLC). PM1183 is a DNA-binding chemotherapy with a new mechanism of action. PM1183 acts as an inhibitor of transcription. Binding of PM1183 to CG-rich motifs, triggers sequential phosphorylation of Pol II and stalling of elongating Pol II. This leads to recruitment of the ubiquitin-proteasome machinery, RNA Pol II degradation, and recruitment of XPF, generation of DNA breaks and induction of apoptosis. PM1183 has been tested in a phase IB trial in combination with doxorubicine. In the dose-finding part: recommended dose (RD) was defined at PM1183 4.0 mg flat dose (FD) or 2.0 mg/m2 + DOX 50 mg/m2 both on day (D)1 every three weeks (q3w). Myelosuppression was dose-limiting (DLT). Compelling activity was observed during escalation phase. It was especially remarkable as 2nd line in SCLC patients: 5 of 7 evaluable pts (71%) had objective partial response (PR) as per RECIST v.1.1. In an expansion cohort of 20 patients, PM1183 and DOX showed outstanding clinical activity: 67% response rate, including 10% of CRs, as 2nd line treatment in SCLC patients. A randomized phase III trial testing PM1183 + DOX is planned and will compare this combination with topotecan or CAV. TAS-114 is a first-in-class oral deoxyuridine triphosphatase (dUTPase) inhibitor that acts as a modulator of the pyrimidine nucleotide metabolic pathway by blocking the conversion of 2’‑deoxyuridine-5’-triphosphate (dUTP; FdUTP) into 2’-deoxyuridine-5’-monophophate (dUMP; FdUMP) through reversible inhibition of dUTPase (gatekeeper protein), resulting in the enhanced incorporation of both uracil and fluorouracil into DNA. The activity of TAS-114, administered in combination with thymidine synthase (TS) inhibitors, 5-FU, S-1 or capecitabine, has been studied pre-clinically in various cancer cell lines and animal models. TAS-114 selectively inhibited dUTPase and showed a higher affinity than the substrates of dUTPase, dUTP and FdUTP, inhibition constant values of TAS-114 were 0.13 μM and 0.10 μM, respectively. The antitumor effect of TAS-114 combined with S-1 as compared to that of S-1 alone was investigated in vivo using a xenograft mouse model with NCI-H2228 (human NSCLC). Both regimens were administered orally (TAS-114: 600 mg/kg/day and S-1: 8.3 mg/kg/day vs S-1: 8.3 mg/kg/day through day 1 to 28) and resulted in relative tumor volumes of 1.61% vs 3.04%, p<0.01, inhibition rates of 52.7% vs 10.8%, and body weight changes of 6.8% vs 3.3%, respectively. A phase 1 clinical study of TAS-114 and S-1 combination treatment is currently ongoing to investigate the safety and to determine the maximum-tolerated dose (MTD) and recommended dose (RD) in patients (pts) with advanced refractory solid tumors. TAS-114 and S-1 are administrated orally twice a day for 14 days followed by 7 days resting period for a 21-days cycle at the starting dosage of 5 mg/m² with the fixed dosage of 25 mg/m², respectively. To date, a total of 96 pts were enrolled with 37 pts in the dose escalation and 59 pts in the MTD expansion stages. TAS-114 and S-1 were escalated up to 240 mg/m² and 36 mg/m², respectively, with 2 DLTs observed at the highest dose level (1 patient with G3 rash and 1 patient with G2 rash/G2 HFS), therefore TAS-114 at 240 mg/m² and S-1 at 30 mg/m² was determined to be the MTD and RD. The most common treatment related adverse events were anemia and rash. There were 4 confirmed partial responses observed in 2 non-small cell lung (NSCLC) pts, 1 pancreas pt and 1 colorectal cancer patient to date. Amongst 6 evaluable NSCLC pts to date, there was an overall response rate of 33% (2/6) with 2 confirmed PR and a disease control rate of 100% (6/6). Pharmacodynamics analysis performed on patient tumor specimens treated at MTD indicated TAS-114 target engagement by reductions in the amount of intra-tumoral dUMP, a “surrogate” metabolite indicative of dUTPase inhibition, following TAS-114/S-1 combination as compared to S-1 alone administration. When TAS-114 is administered in combination with S-1, an additional cytocidal antitumor effect to TTP depletion by TS inhibition is expected as TAS-114 inhibits a gatekeeper protein, thereby allowing increased DNA incorporation of both uracil and 5-FU resulting in DNA damage.
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SC05.03 - Novel Tyrosine Kinase Inhibitors in Lung Cancer (ID 6619)
11:40 - 12:00 | Author(s): C. Zhou
- Abstract
- Presentation
Abstract:
The invited talk will firstly talk about the recent advances in novel TKIs overcoming resistance during EGFR-TKI and ALK-TKI treatment. Afterwards, several novel TKIs with CNS penetration that may substantially change the prognosis and treatment strategy of patients with brain metastases will be discussed. Finally, we will take an overview about targeted therapy against rare and novel, potentially druggable oncogenic drivers either in preclinical settings or early-stage clinical trials. As we know, the presence of EGFR activating mutations and ALK chromosomic rearrangements with corresponding tyrosine kinase inhibitors (TKIs) has revolutionized the treatment strategies of patients with non-small cell lung cancer (NSCLC) [1, 2]. Although tremendously initial response and manageable toxicity profiles, however, acquired resistance inevitably develops after approximately 1 year treatment with EGFR-TKIs (erlotinib and gefitinib) and ALK inhibitor (crizotinib). Encouragingly, third-generation EGFR-TKIs including AZD9291, CO1686 and HM61713 have showed striking efficacy overcoming acquired resisitance driven by T790M secondary mutations [3, 4]. In patients who get acquired resistance to first-generation EGFR-TKIs with T790M mutations, the objective response rate (ORR) of AZD9291 was 61% and median progression-free survival (PFS) was 9.7 months [4]. Other novel third-generation EGFR-TKIs such as ASP8274, EGF816, PF-06747775 and avitinib are also being investigated in early-stage clinical trials and the survival and safety data will be released in the near future. Another promising novel EGFR-TKI, namely AZD3759 has showed promising response in patients with brain metastases and leptomeningeal disease, a major case leading to treatment failure. In BLOOM study, 11 out of 21 patients with measurable brain metastases and heavily pre-treated progressed both extracranially and intracranially had tumor shrinkage in the brain at dose ≥50mg BID. Recently, EAI045, an EGFR allosteric inhibitor, in combination with cetuxmab exhibit antitumor activity in mouse models of lung cancer driven by L858R/T790M/C797S, a common resistant mechanism of AZD9291 [5]. Meanwhile, second-generation ALK inhibitors (ceritinib, alectinib and brigatinib) have entered clinical applications for NSCLC patients with ALK rearrangements after failure of crizotinib and third-generation ALK inhibitors (lorlatinib and ASP3026) are also being evaluated in clinical trials overcoming known ALK resistant mutations[6, 7]. In patients who progress on crizotinib, the ORR and PFS of brigatinib at 180mg was 54% and 12.9 months. Lorlatinib, a third-generation ALK inhibitor, also demonstrated robust clinical activity in ALK-rearrangement patients with NSCLC. The ORR was 57% in patients who received 1 prior ALK-TKI and 42% in patients who received ≥2 prior ALK-TKIs. On the other hand, with the development of high-throughput sequencing, called next-generation sequencing (NGS) and genomic technologies, more novel molecular targets such as MET 14 exon skipping splicing mutations[8]have been identified as potential therapeutic targets and simultaneously analyzing hundreds of molecular alterations have turned out reality with limited tumor tissues. In the recent years, the emergence of numbers of oncogenic drivers other than EGFR mutations and ALK rearrangements has divided NSCLC into multiple distinct subtypes amenable to corresponding targeted therapy, including ROS1 rearrangement, RET arrangement, BRAF-V600E mutations, HER2 mutations and MET 14 exon skipping mutations et al. For instance, dabrafenib either as monotherapy or in combination with MEK inhibitor (trametinib) has displayed promising antitumor activity and manageable safety profile in patients with BRAF V600E mutations [9, 10]. In 57 previously treated metastatic NSCLC patients with BRAF-V600E mutations, 63.2% patients (36/57) achieved an overall response [9]. Other novel molecular targets maybe serving as oncogenic drivers including mutations in HER2 (neratinib and pyrotinib) and PI3KCA (BKM120 and GDC0941), ROS1 (entrectinib, foretinib and lorlatinib), RET (XL184) and NTRK (entrectinib) rearrangements and FGFR1 gene amplification (AZD4547, Lenvatinib and FP-1039) are being evaluated either in preclinical settings or early-stage clinical trials. Reference: 1. Mok TS, Wu YL, Thongprasert S, Yang CH, Chu DT, Saijo N, et al. Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N Engl J Med 2009;361: 947-957. 2. Solomon BJ, Mok T, Kim DW, Wu YL, Nakagawa K, Mekhail T, et al. First-line crizotinib versus chemotherapy in ALK-positive lung cancer. N Engl J Med 2014;371: 2167-2177. 3. Sequist LV, Soria JC, Goldman JW, Wakelee HA, Gadgeel SM, Varga A, et al. Rociletinib in EGFR-mutated non-small-cell lung cancer. N Engl J Med 2015;372: 1700-1709. 4. Janne PA, Yang JC, Kim DW, Planchard D, Ohe Y, Ramalingam SS, et al. AZD9291 in EGFR inhibitor-resistant non-small-cell lung cancer. N Engl J Med 2015;372: 1689-1699. 5. Jia Y, Yun CH, Park E, Ercan D, Manuia M, Juarez J, et al. Overcoming EGFR(T790M) and EGFR(C797S) resistance with mutant-selective allosteric inhibitors. Nature 2016;534: 129-132. 6. Ou SH, Ahn JS, De Petris L, Govindan R, Yang JC, Hughes B, et al. Alectinib in Crizotinib-Refractory ALK-Rearranged Non-Small-Cell Lung Cancer: A Phase II Global Study. J Clin Oncol 2016;34: 661-668. 7. Shaw AT, Kim DW, Mehra R, Tan DS, Felip E, Chow LQ, et al. Ceritinib in ALK-rearranged non-small-cell lung cancer. N Engl J Med 2014;370: 1189-1197. 8. Paik PK, Drilon A, Fan PD, Yu H, Rekhtman N, Ginsberg MS, et al. Response to MET inhibitors in patients with stage IV lung adenocarcinomas harboring MET mutations causing exon 14 skipping. Cancer Discov 2015;5: 842-849. 9. Planchard D, Besse B, Groen HJ, Souquet PJ, Quoix E, Baik CS, et al. Dabrafenib plus trametinib in patients with previously treated BRAF(V600E)-mutant metastatic non-small cell lung cancer: an open-label, multicentre phase 2 trial. Lancet Oncol 2016;17: 984-993. 10. Planchard D, Kim TM, Mazieres J, Quoix E, Riely G, Barlesi F, et al. Dabrafenib in patients with BRAF(V600E)-positive advanced non-small-cell lung cancer: a single-arm, multicentre, open-label, phase 2 trial. Lancet Oncol 2016;17: 642-650.
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SC05.04 - Lung Cancer Vaccines: An Update (ID 6620)
12:00 - 12:20 | Author(s): E. Quoix
- Abstract
- Presentation
Abstract:
Treatment of small-cell lung cancer (SCLC) has not been modified since decades : and consists in a chemotherapy (CT) with platin+etoposide+/-concurrent radiotherapy (RT) and prophylactic cranial irradiation in case of a (near)complete response to therapy. Non-small cell lung cancer (NSCLC) represents 85% of all lung cancers and around 50% are metastatic at presentation. Systemic treatment (platin-based doublets) has been implemented for stage IV NSCLC but also for locally advanced and early stages as a (neo)adjuvant therapy to surgery or RT. By the end of the XXth century, a plateau has been reached with CT in stage IV disease with similar results whatever the drug used in conjunction with platin-salt. Since the beginning of the XXIst century there have been tremendous innovations in the systemic treatment of NSCLC. First, adjunction of bevacizumab to CT for stage IV non-squamous cell carcinoma and the use of maintenance therapy have led to an improvement in median survival time (MST) exceeding now one year. Second, targeted therapies proved to be of major interest for patients with EGFR activating mutations leading to a MST>2 years. Other targets of interest have been found such as ALK and ROS1 translocations, V600EBRAF mutations leading to prolonged survival with appropriate treatments. Third, immunotherapy represents now an exciting approach especially for those patients without targetable mutations/translocations. Lung cancer has long been considered as a poor candidate for immunotherapy because of low content of tumor-infiltrating lymphocytes (TIL) compared to other tumors. On the other hand, in case of the presence of TIL the prognosis is better (1). The fact that incidence of lung cancer is especially high in patients who were transplanted (2)or in patients with HIV infection (3)is against the assumption of lung cancer being non immunogenic. There are two types of immunotherapy : the immune checkpoint blockers which aim at enhancing a T-cell response directed against tumoral cells and abrogate the immune tolerance and the therapeutic vaccines designed to induce or amplify an immune response directed against tumor-associated antigens (TAA). The immune checkpoint blockers in current development are anti CTLA4 monoclonal antibodies (ipilimumab), first used in the treatment of melanoma and now investigated in NSCLC and SCLC, anti PD1 (nivolumab, pembrolizumab) or anti PDL1 (avelumab, atezolizumab). All these molecules are now either at an advanced stage of development or already authorized (4). Therapeutic vaccines have already a long story beginning with Coley toxins at the end of the nineteenth century (5). The Coley's toxins, (cultures of streptococci) were infused in patients with bone and soft tissue sarcomas and some impressive regressions were observed. The hypothesis was that the immune reaction provoked by the infusion of the "toxins" present in the infectious material was able to destroy the tumoral cells. However, due to the reluctance of doctors to administer dangerous bacterial culture and the appearance of novel treatments of cancer (CT and RT), the Coley's toxin approach has been abandoned although numerous articles were devoted to this subject (6). Non specific vaccines using for example BCG to stimulate innate immunity have been disappointing as well in SCLC (7-8)and NSCLC (9). Specific immunotherapy aims at the stimulation of adaptive immunity against the vaccine components and thus induces or amplifies an immune response against TAA. These vaccines are either peptides (Tecemotide, MAGE-A3), cellular vaccines (Belagenpumatucel) or vaccines using viral vector (TG4010). Tecemotide and TG4010 are a MUC1 antigen-specific cancer immunotherapy. MUC1 is expressed at the apical surface of mucin-secreting normal epithelial cells of various tissues and can be overexpressed and aberrantly glycosylated in some tumors and thus is an attractive target for immunotherapy. Tecemotide is a liposomal vaccine. In a randomized phase II trial (10), 171 NSCLC patients who were not progressing after induction CT or CT-RT received subcutaneous tecemotide plus best supportive care (BSC) or BSC alone as maintenance therapy . Median survival time (MST) was longer in patients receiving tecemotide (17.2 vs. 13.0 months) but this did not reach statistical significance. As in a post hoc analysis the benefit appeared to be more important for patients with stage IIIB disease, it was decided to perform a phase III study in locally advanced NSCLC (11,12)comparing in non-progressing patients after CT with platin-based doublet and RT, tecemotide versus placebo. MST was 25.8 months with tecemotide versus 22.4 months with placebo (HR 0.89, 95%CI 0.77-1.03, p=0.111). In the concurrent CT-RT subgroup, there was a significant survival benefit in favor of tecemotide whereas in the sequential CT-RT subgroup, survival did not differ between the two arms. A similar study (13)was initiated in Asian people. This trial was prematurely terminated as the sponsor decided to discontinue program with tecemotide in NSCLC MAGE-A3 is an antigen expressed in 76% of melanoma and in 35% of NSCLC. It is absent from normal tissues except for testis and placenta. This vaccine, has been investigated in early stage of NSCLC as an adjuvant treatment. A randomized phase II study(14)compared the MAGE-3A vaccine to a placebo in 182 patients operated of a stage IB or II NSCLC with their tumor expressing MAGE-A3 antigen. The randomization was on a 2 :1 basis. The main objective was to compare the Disease Free Interval (DFI) defined as the time from resection to the date of recurrence (any type) or second primary lung neoplasm. Although there was a trend toward a numerically longer DFI in the MAGE-A3 vaccine group, the main objective was not met. Nevertheless, even if these trends were by far not significant, the results appear promising to the sponsors and a phase III trial was launched (MAGRIT trial) with the same scheme(15). Unfortunately, the biggest trial ever performed with the inclusion of 2312 NSCLC patients is negative regarding as well the primary objective: disease-free survival (DFS) but also the secondary objective, DFS in the group of patients not receiving adjuvant chemotherapy or other subgroups. Belagenpumatucel-L is a vaccine comprising 4 tranforming growth factor-β2-antisense gene-modified irradiated allogeneic NSCLC cell lines. A randomized phase III trial (16)comparing this vaccine to a placebo was performed after platinum-based CT for stage III/IV disease in non progressing patients. This trial was negative with no difference in overall survival and in PFS. However, in a prespecified multivariate analysis, there was an improved survival for patients who were randomized within 12 weeks after CT and for patients who received prior radiation therapy. TG4010 is a suspension of a recombinant modified vaccinia virus strain Ankara coding for the MUC1 TAA and IL2. Feasibility of either upfront combination of TG4010 with cisplatine-vinorelbine or TG4010 alone until progression has been demonstrated in a phase II study(17). Sixty-five patients were randomized. Response rate was 30 % in the combined upfront schedule, MST was 12.7 months and one-year survival rate 53%. Taking into account these results, a phase II randomized study (18)comparing CT with cisplatin and gemcitabine to the same CT + TG4010 was performed. One hundred and forty eight patients with stage IIIB or IV disease were included. The primary endpoint was 6-month PFS with the hypothesis that it will be at least 40% in the combined arm. This objective was met with a 6-months PFS of 43% compared to 35.1% in the CT alone arm. There was a non significant trend toward a higher response rate and a longer time to progression in the combined arm. An exploratory analysis of the subgroups defined by the level of activated NK cells (CD16+CD56+CD69+lymphocytes or TrPAL) shows that a better outcome was observed for those patients with normal level of TrPAL and that the vaccine might be deleterious for those with high level of TrPAL. A phase IIB was then performed to confirm the role of the level of TrPAL(19). 222 patients were randomly allocated to CT+TG4010 or CT+placebo. Median PFS was 5.9 months in the TG4010 group versus 5.1 months in the placebo group (HR 0.74, 95%CI 0.55-0.98, p= 0.019). In patients with TrPAL values less or equal ULN, the HR for PFS was 0.75 (95%CI 0.51-1.03) with a posterior probability of HR being <1 of 98.4% and thus the primary endpoint was met. In patients with high level of TrPAL, there was no deleterious effect but no benefit as the HR for PFS was 0.77 (95%CI 0.42-1.40). As a conclusion, all studies with vaccines have been quite disappointing. To the best of my knowledge, the only vaccine still under investigation remains TG4010, but....phase III trial is not implemented at this time. In each vaccine study some efficacy has been observed in subgroups of NSCLC patients but mostly in post hoc analyses. All vaccine studies have shown that there is no safety problems. The fact that nowadays, considerable interest has been developed toward checkpoint inhibitors, probably explains the disaffection toward vaccines. Hopefully it will be only transient and the already long story of therapeutic vaccines will continue.
Table 1 Phase II and III vaccine studies in NSCLC References 1. Kawai O, et al. Predominant infiltration of macrophages and CD8(+) T Cells in cancer nests is a significant predictor of survival in stage IV nonsmall cell lung cancer. Cancer 2008;113:1387–95. 2. Engels EA, et al. Spectrum of cancer risk among US solid organ transplant recipients. JAMA 2011;306:1891–901. 3. Hleyhel M, et al. Risk of non-AIDS-defining cancers among HIV-1-infected individuals in France between 1997 and 2009: results from a French cohort. AIDS 2014;28:2109–18. 4. El-Osta H,et al. Immune checkpoint inhibitors: the new frontier in non-small-cell lung cancer treatment. OncoTargets Ther. 2016;9:5101–16. 5. Coley WB. The Treatment of Inoperable Sarcoma by Bacterial Toxins (the Mixed Toxins of the Streptococcus erysipelas and the Bacillus prodigiosus). Proc R Soc Med. 1910;3(Surg Sect):1–48. 6. Zacharski LR, Sukhatme VP. Coley’s toxin revisited: immunotherapy or plasminogen activator therapy of cancer? J Thromb Haemost 2005;3:424–7. 7. Maurer LH, et al. Combined modality therapy with radiotherapy, chemotherapy, and immunotherapy in limited small-cell carcinoma of the lung: a Phase III cancer and Leukemia Group B Study. J Clin Oncol 1985;3:969–76. 8. Giaccone G, et al. Phase III study of adjuvant vaccination with Bec2/bacille Calmette-Guerin in responding patients with limited-disease small-cell lung cancer. J Clin Oncol 2005;23:6854–64. 9. Robinson E, et al.. Combined-modality treatment of inoperable lung cancer (i.v. immunotherapy, chemotherapy, and radiotherapy). Cancer Treat Rep. 1985;69:251–8. 10. Butts C, 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. 11. Butts C, et al. Tecemotide (L-BLP25) versus placebo after chemoradiotherapy for stage III non-small-cell lung cancer (START): a randomised, double-blind, phase 3 trial. Lancet Oncol. 2014;15:59–68. 12. Mitchell P, et al. Tecemotide in unresectable stage III non-small-cell lung cancer in the phase III START study: updated overall survival and biomarker analyses. Ann Oncol 2015;26:1134–42. 13. Wu Y-L, et al. INSPIRE: A phase III study of the BLP25 liposome vaccine in Asian patients with unresectable stage III non-small cell lung cancer. BMC Cancer. 2011;11:430. 14. Vansteenkiste J, 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. 15. Vansteenkiste JF, et al. Efficacy of the MAGE-A3 cancer immunotherapeutic as adjuvant therapy in patients with resected MAGE-A3-positive non-small-cell lung cancer (MAGRIT): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2016;17:822–35. 16. Giaccone G, et al. A phase III study of belagenpumatucel-L, an allogeneic tumour cell vaccine, as maintenance therapy for non-small cell lung cancer. Eur J Cancer 2015;51:2321–9. 17. Ramlau R, et al. A phase II study of Tg4010 (Mva-Muc1-Il2) in association with chemotherapy in patients with stage III/IV Non-small cell lung cancer. J Thorac Oncol 2008;3:735–44. 18. Quoix E, et al. Therapeutic vaccination with TG4010 and first-line chemotherapy in advanced non-small-cell lung cancer: a controlled phase 2B trial. Lancet Oncol. 2011;12:1125–33. 19. Quoix E, et al. TG4010 immunotherapy and first-line chemotherapy for advanced non-small-cell lung cancer (TIME): results from the phase 2b part of a randomised, double-blind, placebo-controlled, phase 2b/3 trial. Lancet Oncol. 2016;17:212–23.Product Trials conducted Author (ref) Tecemotide (Stimuvax*) Merck Serono Phase IIB maintenance study in stage III/IV NSCLC Phase III maintenance therapy after CT-RT in non resectable stage III disease Butts(10) Butts(11) Mitchell(12) Wu(13) MAGE A3 GSK Adjuvant treatment after surgery Phase II randomized study Phase III study (Magrit trial) Vansteenkiste(14) Vansteenkiste(15) Belagenpumatucel Lucanix* NovaRx Phase III study as maintenance in stage IV disease after 1st line CT Giaccone(16) TG4010 Transgene In combination with first line CT in stage IV disease NSCLC Phase II study Phase IIB randomized study Phase IIB/III randomized study Ramlau(17) Quoix(18) Quoix(19)
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PL05 - Closing Plenary Session: A Life in Thoracic Oncology - Reflections from Giants on Milestones in the Treatment Advances in Lung Cancer (ID 433)
- Event: WCLC 2016
- Type: Plenary
- Track:
- Presentations: 1
- Moderators:P.A. Bunn, Jr., T. Mok
- Coordinates: 12/07/2016, 16:00 - 18:00, Hall C1
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PL05.04 - Translational Lung Cancer Research (ID 6917)
16:55 - 17:10 | Author(s): N. Saijo
- Abstract
- Presentation
Abstract:
Lung cancer is a leading cause of cancer death in the world. The survival benefit of chemotherapy was rarely observed in NSCLC until the development of Cisplatin. Platinum doublets including 2nd/3rd generation cytotoxic drugs showed minor prolongation of survival but the effect reached a plateau. JCOG conducted key RCTs to develop new standards against SCLC but a breakthrough has not been observed yet. Two recent major therapeutic advancements in NSCLC are immunotherapies to inhibit immune checkpoints and development of targeted drugs for driver mutations. Translational Research in Immune Checkpoint inhibitors Immunotherapy of cancer has a long history without success because of wrong strategy of immune stimulation with non-specific immunostimulators, biological response modifiers and recently by peptide antigens. After introduction of idea on immune checkpoint inhibition by Dr. James Allison, the studies of this fields were dramatically activated. Currently two anti-PD-1 antibodies such as Nivolumab and Pembrolizumab have been approved for the treatment of NSCLC based on reproducible effects of tumor shrinkage and survival benefit. In second line treatment, both antibodies significantly improved survival compared with standard care of cytotoxic chemotherapy irrespective of patient selection. Recent press release announced that Nivolumab failed to demonstrate benefit for PFS compared to cytotoxic chemotherapy (CheckMate-026), on the other hand Pembrolizumab demonstrated superior PFS and OS (KEYNOTE-024). Both of the trials patient selection was done based on PD-L1 expression in lung cancer cells. In spite of positive data on survival, RR in various trials against advanced NSCLC with or without prior chemotherapy ranges from 15-25% for both drugs and median survival is almost same in anti-PD1 Ab and cytotoxic drugs. The most important issue will be how to concentrate responsive patient population or how to eliminate in effective patients. Although there is a tendency of correlation between PD-L1 expression and objective response/survival, responders to Ab are experienced even in PD-L1 negative patients. There are many problems in PD-L1 screening. There is no comparative data of various PD-1 tests used in various clinical trials. Each PD-1 test uses different antibody. Each test uses a different definition and cut off point that defines PD-1 positivity. There is no data on best sample, paraffin-fixed vs fresh tissue, primary site tumor vs metastatic tissue. PD-1 expression is not stable and influenced by many factors. There is no reliable validation and standardization. In tumor cells, mutation burden may influence on antigenicity. In colorectal cancer, microsatellite instability has related with response to anti-PD-1 antibody, but it is not yet clear whether mutation burden really increases antigenicity. CD8 lymphocytes infiltration is also considered to be one of the biomarkers for anti-PD-1 Ab response. However, it is too objective and seems to be quite difficult to quantify CD 8 lymphocytes infiltration. The most important thing will be the function of killer T lymphocytes which can respond to target antigens and to kill tumor cells. The best method may be quantitative measurements of cytotoxicity in killer T cell on tumor cells. The techniques to demonstrate this process are mandatory for successful patient selection in the treatment with anti-PD-1 antibody. Translational Drug Development for Precision Medicine Recent development of molecular target drugs in lung cancer really reflects progress of translational studies. EGFR-TKIs are one of the most important drugs and changed concept of treatment of lung cancer. Finding on many rare driver mutations forced to reclassify lung cancer to various genomic subtypes. Innovative technologies for genomic medicine changes one size fit medicine to precision medicine. For discovery of drugs to each genomic subtype of lung cancer, nationwide and global screening network should be mandatory. In Japan LC-SCRUM Japan leaded by Dr. Koichi Goto, National Cancer Center Hospital East, started in February 2013 to find out new seeds against lung cancer by the support of government.. At the beginning, tumor tissues were analyzed for ALK/ROS1/RET fusions using RT-PCR in EGFR –Mt negative patients and the detected fusions were confirmed by FISH. From March 2015, multiplex diagnostic kit using NGS was introduced and this project expanded as SCRUM-Japan including other histological types of lung cancer such as SQ and SM as well as GI malignancy. 14 pharmaceutical companies started to support this project. No. of institutions joined in the network increased to 200 In Non-SQ NSCLC, 159 and 96 for SQ and SM, respectively on March, 2016. More than 2,500 samples were analyzed. Rare mutations including ROS(91), RET(54) and ALK(40) fusions, ERB2 mutation/amplification(48), BRAF mutation(16), MET amplification/ex14 skip(16) and PIK3A mutation(22) have been screened in 287 Non-SQ-NSCLC patients and 67(23%) have been accrued to more than 12 clinical trials. In LURET trials against RET fusion gene + patients, 19 patients have been accrued and 17 are eligible. The response rate of vandetanib was 53%and PFS was 4.7 months. In 0012-01 trial against ROS fusion gene + patients, 129 patients (74 from china, 26 from Japan, 15 from Taiwan and 12 from Korea)has been accrued. Response rate of crizotinib was 69%in 127 evaluable patients. J-AlEX trial was a phase III randomized controlled trial comparing alectinib(ALE) and crizotinib(CRI) in ALK-positive NSCLC. Response rates for ALE and CRI were 85.4% and 70.2% respectively. PFS was not reached and 10.2 months(P<0.0001), respectively. Other clinical trials are ongoing. Samples from SQ and SM are increasing and interesting mutations and amplifications have been detected in these materials. Accordingly this nationwide and population enrichment screening system enabled various rare driver mutations to be efficiently detected in lung cancer, contributing to the rapid accrual of matched patients in translational clinical trials.
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