Virtual Library

Abstract not provided

Abstract:
NSCLC is a heterogenous disease withvariable molecular mutations. Vi-Ki-ras2 Kirsten rat sarcoma viral oncogene (KRAS) is one of the most common oncogenic drivers, especially in lung cancer, found in around 25-30% adenocarcinomas. The other molecular abnormalities related to RAS pathway are EGFR (10-23%), BRAF (2%), MET (2%), HER2 (1%) and NRAS (0.2%). Within KRAS, the most common mutations are G12C (40%), G12V (21%), G12D (17%), G12A (10%) and other (12%) G12 and G13 mutations [Dogan. Clinical Cancer Research 2012; 18: 6169-6177]. KRAS mutations are associated with poorer outcomes in NSCLC. Renaud et al, showed that KRAS mutant patients had worser outcomes compared to wild type cases[1]. KRAS may be a negative predictor of responsiveness to cytotoxic therapy based off of retrospective data. In addition, Renaud and colleagues have shown that KRAS mutations may be predictive of resistance to radiation therapy. Identifying ways to target these KRAS mutations may lead to benefit for patients in combination with other traditional means of treatment. Directly blocking RAS activity has remained difficult to attain, due to a variety of mechanisms and yet to demonstrate efficacy clinically. Therefore, much more focus has been spent on downstream targets of KRAS. Selumetinib an oral inhibitor of the mitogen-activated protein kinase kinase (MEK) 1/2 had promising phase II results in combination with docetaxel in comparison to docetaxel alone. Unfortunately, in the multicenter Phase III, SELECT-1 trial with 510 patients, PFS and OS were no different in the selumetinib and docetaxel arm versus docetaxel alone. This may be in part due to an increase in RAF-depedent MEK phosphorylation that may interfere with its efficacy. Combining inhibitors that target different components or parallel pathways have yielded success in other tumors like melanoma with combination MEK and BRAF inhibition. For KRAS mutant tumors, the PI3K-AKT- mTOR pathway has also been examined as it has been thought it can bypass resistance to MEK inhibition. The combination of MEK in addition to PI3K-aKT-mTOR has yet to yield any clinically impactful results. Inhibtion of the cysteine residue on KRAS G12C, which makes up more than 40% of KRAS mutants, has been shown to have some activity preclinically [2, 3] Our preliminary data shows that, KRAS is frequently associated with co-occuring mutations. The most common of these were TP53 (n=15, 25%), ATM (n=9, 15%), LRP1B (n=9, 15%), ARID1A (n=8, 13%), STK11 (n=8, 13%), ARID1B (n=7, 12%), TERT (n=7, 12%), EGFR (n=6, 10%), RBM10 (n=6, 10%), SPTA1 (n=6, 10%). We still are not clear on the role of co-mutations and their specific function as sensitizers or agents resistance. It was previously shown that KRAS plus TP-53 mutations had impaired response to docetaxel monotherapy. The addition of selumetinib provided substantial benefit in mice models [4]. Also, STK11 mutations in conjunction with KRAS mutant NSCLC has been shown to infer resistance to PD-1/PDL-1 blockade [5]. Lung cancer frequently exhibits upregulation of angiogenesis and has been reported to be associated with a negative prognostic factor. Over the past decade, novel insights into the role of angiogenesis in NSCLC tumor growth and progression have provided a rationale for the development of anti-angiogenic agents. The use of anti-angiogenic agents to treat NSCLC gained clinical interest in 2006, when the results of the Eastern Cooperative Oncology Group (ECOG) Trial 4599 were published in the New England Journal of Medicine and showed for the first-time improved overall survival(OS) and progression-free survival after the addition of bevacizumab (Avastin, Genentech), a humanized monoclonal antibody that inhibits the process of angiogenesis by binding to the vascular endothelial growth factor A (VEGF-A) protein, to treatment with carboplatin and paclitaxel in 878 patients who had recurrent or advanced NSCLC [6]. Since then, no other anti-angiogenic agent (such as sunitinib, sorafenib, etc.) has been able to demonstrate improved OS for patients with lung cancer. This may be in part because the mechanisms of actions for those drugs is completely different from bevacizumab; they work by inhibiting the internal tyrosine kinase domain of the VEGF receptor and are also not completely selective for the VEGF receptor and also hit other targets (such as PDGF, FGFR, etc.) [6]. This may play a role in the increased toxicity for these inhibitors and the subsequent lower OS. Since the recent positive data showing benefit of first-line carboplatin, pemetrexed, and pembrolizumab may lead to expedited FDA approval, the utility of anti-angiogenic drugs may enter a renaissance as a second-line therapeutic option. However, another consideration has to be made in the pursuit of improved anti-angiogenic drugs where the clinical and financial “value” for the patient are factored in clinical decision making. Though the VEGF/VEGFR pathway is seen as a crucial mediator of tumor survival and growth, the treatments currently available are overshadowed by excessive costs and several cost-effective analyses of bevacizumab have shown that the use of the drug can cost up to 350,000 per life-year gained [7]. References 1. Renaud, S., P.-E. Falcoz, M. Schaeffer, et al., Prognostic value of the KRAS G12V mutation in 841 surgically resected Caucasian lung adenocarcinoma cases. Br J Cancer, 2015. 113(8): p. 1206-1215. 2. Ostrem, J.M., U. Peters, M.L. Sos, J.A. Wells, and K.M. Shokat, K-Ras(G12C) inhibitors allosterically control GTP affinity and effector interactions. Nature, 2013. 503(7477): p. 548-51. 3. Patricelli, M.P., M.R. Janes, L.S. Li, et al., Selective Inhibition of Oncogenic KRAS Output with Small Molecules Targeting the Inactive State. Cancer Discov, 2016. 6(3): p. 316-29. 4. Chen, Z., K. Cheng, Z. Walton, et al., A murine lung cancer co-clinical trial identifies genetic modifiers of therapeutic response. Nature, 2012. 483(7391): p. 613-617. 5. Skoulidis, F., M.D. Hellmann, M.M. Awad, et al., STK11/LKB1 co-mutations to predict for de novo resistance to PD-1/PD-L1 axis blockade in KRAS-mutant lung adenocarcinoma, 2017, American Society of Clinical Oncology. 6. Socinski, M.A., ANGIOGENESIS INHIBITION FOR THE TREATMENT OF NON–SMALL CELL LUNG CANCER. CLINICAL ADVANCES IN HEMATOLOGY AND ONCOLOGY, 2016. 14(5): p. 336-338. 7. Goulart, B. and S. Ramsey, A trial-based assessment of the cost-utility of bevacizumab and chemotherapy versus chemotherapy alone for advanced non-small cell lung cancer. Value Health, 2011. 14(6): p. 836-45.

Abstract:
MET activation in non-small cell lung cancers (NSCLCs) can occur via mechanisms including mutation and amplification. MET exon 14 splicing alterations and MET amplification are clinically actionable genomic alterations. Response to MET-directed targeted therapy has been reported for both subsets. In a phase 1 study of crizotinib for patients with MET exon 14-altered NSCLCs, the overall response rate (ORR) was 39% and the median progression-free survival was 8 months (Drilon et al, ASCO 2016). In the same phase 1 study, the ORR for crizotinib in patients with MET-amplified NSCLC was 17% and 50% for tumors with a FISH MET/CEP7 ratio of >2.2 to <5 and ≥5, respectively (Camidge et al, ASCO 2014). Furthermore, acquired MET amplification is associated with resistance to EGFR tyrosine kinase inhibition in EGFR-mutant lung cancers. Response to combined EGFR- and MET-directed therapy has been reported in patients with EGFR-mutant lung cancers with acquired resistance to prior EGFR tyrosine kinase inhibitor therapy. Prospective clinical trials of various MET inhibitors as single-agents or in combination with other therapies are ongoing. A number of different MET inhibitors have been tested in the clinic, including multikinase inhibitors with activity against MET such as crizotinib and cabozantinib, MET-selective inhibitors such as capmatinib, and MET antibodies such as onartuzumab and embituzumab. Newer agents such as MET antibody-drug conjugates are being explored. Data on acquired resistance to MET-directed targeted therapy has begun to emerge. The MET D1228N and D1228V kinase domain mutations have been identified as acquired mechanisms of resistance to MET tyrosine kinase inhibition (Heist et al, J Thoracic Oncol 2016; Bachall et al, Cancer Discov 2017)). The detection of MET mutation and amplification in the clinic is thus important, but is associated with specific challenges, and requires a comprehensive approach to testing. Notably, molecular profiling should not be restricted to the classic population of younger, never or former light cigarette smoker patients with advanced lung adenocarcinomas where other drivers such as sensitizing EGFR mutations and ALK or ROS1 rearrangements are enriched; MET exon 14 alterations, for example, are found in older patients with a more substantial prior smoking history, and in sarcomatoid carcinomas of the lung. The role of MET immunohistochemistry in selecting patients for MET-directed targeted therapy in the absence of comprehensive molecular profiling remains controversial, although the experience with this approach in prior prospective clinical trials has been disappointing. Advances have clearly been made in the development of MET-directed targeted therapy for subsets of patients with advanced NSCLCs that are hopefully moving the field closer to the regulatory approval of one or more these agents in the future.

Abstract:
Aberrant activation of fibroblast growth factor (FGF) signaling due to up-regulation of FGF receptor gene (FGFR) expression, alternative splicing of FGFR transcripts, FGFR mutations or translocations, or increased availability of FGF has been found to contribute to prognosis in several types of tumors(1, 2). Our previous evidence suggest that these gene alterations increase the sensitivity to multi-kinase inhibitors (3, 4, 5). FGFR gene alterations are relatively frequent in lung squamous cell carcinoma (LSCC) and are a potential targets for therapy with FGFR inhibitors. However, little is known regarding the clinicopathologic features associated with FGFR alterations. The angiokinase inhibitor nintedanib has shown promising activity in preclinical and clinical studies for non-small cell lung cancer and other solid tumors (6,7,8). We have now applied next-generation sequencing (NGS) to characterize FGFR alterations in LSCC patients as well as examined the antitumor activity of nintedanib in LSCC cell lines positive for FGFR1 copy number gain (CNG). The effects of nintedanib on the proliferation of and FGFR signaling in LSCC cell lines were examined in vitro, and its effects on tumor formation were examined in vivo. A total of 75 clinical LSCC specimens were screened for FGFR alterations by NGS. Nintedanib inhibited the proliferation of FGFR1 CNG-positive LSCC cell lines in association with attenuation of the FGFR1-ERK signaling pathway in vitro and in vivo. FGFR1 CNG (10.7%), FGFR1 mutation (2.7%), FGFR2 mutation (2.7%), FGFR4 mutation (5.3%), and FGFR3 fusion (1.3%) were detected in LSCC specimens by NGS. Clinicopathologic features did not differ between LSCC patients positive or negative for FGFR alterations. However, among the 36 patients with disease recurrence after surgery, prognosis was significantly worse for those harboring FGFR alterations. Screening for FGFR alterations by NGS warrants further study as a means to identify patients with LSCC recurrence after surgery who might benefit from nintedanib therapy. 1) Mizukami T, et al. Mol Carcinog. 2017;56(1):106-117. 2) Matsumoto K, et al. Br J Cancer. 2012;106(4):727-32. 3) Arao T, et al. Hepatology. 2013;57(4):1407-15. 4) Sakai K, et al. Oncotarget. 2015;6(25):21636-44. 5) Kaibori M, et al. Oncotarget. 2016; 7(31):49091-49098. 6) Kudo K, et al. Clin Cancer Res. 2011; 17(6):1373-81. 7) Okamoto I, et al. Mol Cancer Ther. 2010; 9(10):2825-33. 8) M. Takeda K. et al. Ann Oncol. 2016; 27(4): 748–750.

Abstract:
Chromosomal rearrangements or deletions can generate novel gene fusions that lead to the expression of chimeric proteins with oncogenic activity in lung and other cancers. The paradigm for gene fusions in lung cancer is the EML4-ALK gene fusion which is found in approximately 5% of lung adenocarcinomas.[1] Once identified, drug development for this target proceeded rapidly and crizotinib was the first approved tyrosine kinase inhibitor for patients with ALK+ non-small cell lung cancer based on its ability to generate substation objective response rates and prolonged progression free survival (NSCLC).[3,4 ]The development of CNS penetrant and/or next generation ROS1 inhibitors including lorlatinib, entrectinib and TPX-0005 is ongoing. RET gene fusions are also found in 1-2% of NSCLC, but the use of multiple different RET inhibitors have failed to reproduce the success of targeting ALK or ROS1 fusions.[5 ]The development of more selective RET inhibitors such as LOXO-292, BLU-667, and RXDX-105 are currently in clinical trials for RET+ lung and other cancers. NTRK1 fusions were recently identified in NSCLC and homologous NTRK2 and NTRK3 fusions are found in multiple tumor types.[6,7, ]Early clinical trials of larotrectinib showed an impressive objective response rate of 76% for 12 different tumor histologies harboring NTRK1/2/3 fusions and the CNS-penetrant entrectinib is similarly being evaluated in a basket trial. Other rare, novel fusions have recently been identified in NSCLC including EGFR fusions or MET fusions.[7] Early evidence suggests that these fusions may also respond to cognate TKIs. EGFR fusions break the paradigm of ALK and ROS1 fusions in which the 5’ end of ALK or ROS1 is replaced with the 5’ portion of another gene. EGFR fusions retain most of the EGFR gene, with the unrelated gene sequencing fusing at the 3’ end of EGFR. A related oncogenic EGFR mutation in which the kinase domain of EGFR is duplicated in tandem has also been described and appears responsive to EGFR TKIs.[7] Additional fusions involving the receptor tyrosine kinase (RTK) encoding genes AXL, PDGFRA, and ERBB4 fusions have been described, but little is known about the true incidence in lung cancer.[8,9] The fusions described thus far all involve genes that encode RTKs, but additional gene fusions have also been identified in lung cancer including BRAF fusions.[7,9 ]BRAF fusions replace the 5’ region of BRAF, including the Ras-binding domain (RBD), with sequences from another gene. Anecdotal evidence suggest that these alterations may be responsive to MEK inhibition. Analogous splice alteration which remove a region including the RBD have also been described in cancer and are oncogenic. Finally, gene fusions involving NRG1, which encodes the HER3/4 ligand neuregulin-1, have been described, mostly in invasive mucinous adenocarcinomas of the lung.[9,10 ]Several challenges exist to the development of targeted therapies for these novel fusions. Even in the era of next-generation sequencing tests these alterations may go undetected due to limited testing of genes to those with approved therapies (ALK, ROS1, EGFR, and BRAF) and not all assays are designed to detect all of these alterations. Furthermore, the rarity of some of these alterations may make clinical trials for these novel fusions less appealing, although amalgamating some of these alterations with analogous mutations, e.g., MET gene fusions with MET exon 14 splice alterations or MET gene amplification, may allow for a more rapid path to approval. References 1. Chia PL, Mitchell P, Dobrovic A, et al: Prevalence and natural history of ALK positive non-small-cell lung cancer and the clinical impact of targeted therapy with ALK inhibitors. Clin Epidemiol 6:423-32, 2014 2. Camidge DR, Bang YJ, Kwak EL, et al: Activity and safety of crizotinib in patients with ALK-positive non-small-cell lung cancer: updated results from a phase 1 study. The lancet oncology 13:1011-9, 2012 3. Davies KD, Le AT, Theodoro MF, et al: Identifying and targeting ROS1 gene fusions in non-small cell lung cancer. Clinical cancer research : an official journal of the American Association for Cancer Research 18:4570-9, 2012 4. Shaw AT, Ou SH, Bang YJ, et al: Crizotinib in ROS1-rearranged non-small-cell lung cancer. N Engl J Med 371:1963-71, 2014 5. Gautschi O, Milia J, Filleron T, et al: Targeting RET in Patients With RET-Rearranged Lung Cancers: Results From the Global, Multicenter RET Registry. J Clin Oncol 35:1403-1410, 2017 6. Vaishnavi A, Capelletti M, Le AT, et al: Oncogenic and drug-sensitive NTRK1 rearrangements in lung cancer. Nature medicine 19:1469-72, 2013 7. Stransky N, Cerami E, Schalm S, et al: The landscape of kinase fusions in cancer. Nat Commun 5:4846, 2014 8. Seo JS, Ju YS, Lee WC, et al: The transcriptional landscape and mutational profile of lung adenocarcinoma. Genome Res 22:2109-19, 2012 9. Nakaoku T, Tsuta K, Ichikawa H, et al: Druggable oncogene fusions in invasive mucinous lung adenocarcinoma. Clin Cancer Res 20:3087-93, 2014 10. Fernandez-Cuesta L, Plenker D, Osada H, et al: CD74-NRG1 fusions in lung adenocarcinoma. Cancer Discov 4:415-22, 2014

Abstract:
Stage 4 NSCLC 1[st] line Rx: In addition to complete staging, all patients with any histology should have PD-L1 testing of their tumor. In addition patients with an adenocarcinoma histology and never smokers should have molecular testing that would include at least EGFR, ALK, ROS1 and BRAF. If NGS testing is selected that additional genes can be tested including MET,RET, HER2,and NTRK. Patients with a PD-L1 tumor proportion score (TPS) >49% who do not have a molecular driver can be treated with pembrolizumab as their first therapy. This therapy is continued for 2 years or until progression or unacceptable toxicity. For those with a TPS score of 1-49, concurrent chemotherapy plus pembrolizumab may be considered based on the results of a small phase II trial. However, larger phase III trials are in progress and may alter this choice. Patients with a molecular alteration in EGFR, ALK, ROS1, or BRAF are treated with the appropriate TKI or TKI combination in the case of v600E BRAF. Although all of the randomized trials comparing these new therapies to chemotherapy included only PS 0-1 patients, there is clear evidence that patients with PS 2 and even PS 3 and elderly patients may benefit from these therapies and should thus be tested. For patients with a lower TPS score or no molecular abnormality and PS0-1, the standard therapy is a platinum doublet chemotherapy with or without bevacizumab. For patients with adenocarcinoma, the most frequently used regimen is pemetrexed with platinum. In North America the platinum is most often carboplatin because of its preferred toxicity profile. PS 0-1 adenocarcinoma patients may also receive bevacizumab if there are no comorbid conditions that would increase toxicity. A taxane doublet with or without bevacizumab is also acceptable. For patients with squamous carcinoma the platinum doublet usually contains gemcitabine or a taxane with carboplatin with or without bevacizumab. Patients receiving chemotherapy are restaged after 2 cycles. Those with progressive disease are offered second line therapy. Patients with stable disease or response receive 2 additional cycles and are then restaged again. Those with acceptable toxicity and continued response are offered 2 additional cycles for a total of 6. Those without further response or additional toxicity are offered maintenance therapy after the 4 cycles. Patients receiving 6 cycles are also offered maintenance therapy. Maintenance therapy may consist of continued pemetrexed or continued bevacizumab for those responding to these. Switch therapy to pemetrexed or to erlotinib or gemcitabine may be considered. 2[nd] Line Rx. For patients receiving 1[st] line pembrolizumab, 2[nd] line rx is first line chemotherapy as discussed above. For patients progressing on a 1[st] line TKI, the 2[nd] line therapy is most often a 2[nd] or 3[rd] generation TKI. When therapy with a TKI is exhausted, the next line of therapy is standard first line chemotherapy as described above. For patients who receive 1[st] line chemotherapy, the second line therapy is most often immunotherapy which can be any of the 3 approved agents for patients with a TPS score of >1 or nivolumab or atezolizumab for patients with a TPS score of 0. 3[rd] Line Rx: Patients who receive 1[st] line I/O followed by chemo or who receive gene specific TKIs followed by 1[st] line chemotherapy, the 3[rd] line treatment would be what was previously considered 2nl line chemo such as docetaxel +/- ramicirumab. Other chemotherapy agents can also be considered such as gemcitabline, other taxanes or irinotecan. Clinical trials may be substituted for any of these treatments in any lines of therapy. Unresectable Stage III. The standard approach is currently concurrent chemotherapy with chest radiotherapy. This is likely to change as positive results of a trial comparing CT/RT alone to CT/RT followed by immunotherapy with durvalumab were announced in mid-2017. The chest RT is generally about 60 Gy given over 6 weeks. The chemotherapy is generally a platinum doublet with etoposide, paclitaxel or pemetrexed. At the time of progression the algorhythm described for stage 4 above can be instituted. Resectable stage I-IIIA. For stage 1A standard therapy is lobectomy alone or stereotactic body radiotherapy (SBRT) for those who are medically inoperable. Patients with stage IB, especially with poor prognostic features such as large size or vascular invasion may receive neoadjuvant or adjuvant chemotherapy with a cisplatin doublet and surgery is standard while other smaller stage IB tumors are treated with lobectomy alone. Stage II and IIIA patients may be treated with neoadjuvant chemotherapy or neoadjuvant CT/RT followed by surgery. They may also receive surgical resection first followed by adjuvant CT or CT/RT. The future: It is highly likely that immunotherapy combinations will prove to be superior to single checkpoint inhibitors so that the majority of sage IV patients without a molecular driver are likely to receive an immunotherapy combination, likely irrespective of TPS score. For stage IV patients with a molecular driver, it is likely that initial therapy will consist of the TKI plus another agent that can affect the cells that persist after initial TKI therapy. It is likely that immunotherapy combinations and molecular combinations will be used in unresectable stage III disease before, after or during CT/RT and will improve cure rates. I believe that a large change in approach to early stage patients will occur with the development of neoadjuvant immunotherapy and molecular therapy. In these approaches we have the opportunity to improve cure rates as well as to more rapidly develop new therapies based on pathologic complete response rates as we now do in breast cancer. The future is also likely to see new ways to define risk in both smokers and non-smokers so that we can detect patients early and so that we can develop new prevention strategies for those at high risk. Figure 1

Abstract:
Where we are now, and where we will be in 10 years:　From Asian Perspective Nagahiro Saijo, MD, PHD, Tokyo Medical University, Kinki University School Medicine Compared with 30 years ago non-small cell carcinoma(NSCLC) became a vast dominant type of lung cancer and majority of clinical trials focus on it. At the end of 20[th] century, effect of platinum doublet containing third generation cytotoxic drugs reached a plateau and thoracic oncologists felt skepticism to achieve the goal in lung cancer treatment. Development of EGFR-TKIs (Gefitinib and Erlotinib) was one of the biggest breakthroughs for rollback of chemotherapy in lung cancer. The EGFR mutation was discovered in 2004 but it took 5 years until there was general agreement that it was an important driver mutation which could predict for response to EGFR-TKI. Evolution of EGFR-TKI proceeds to irreversible 2[nd] (Afatinib and Dacomitinib) and mutation specific 3[rd] generation (Osimertinib) TKIs which can combat the issues of resistance. In Asia more than 50% of adenocarcinoma are EGFR-Mt+ and physicians experienced many long term survivors like surgical treatment in early stage lung cancer. In addition CTONG trial demonstrated that adjuvant EGFR-TKI (Gefitinib) delays recurrence in EGFR-positive surgically resected EGFR-Mt+ NSCLC. WJOG in Japan is conducting exactly the same schedules of trial. There will be a possibility to conduct study of EGFR-TKI combined with chemoradiotherapy in EGFR-Mｔ+ stage III NSCLC in Asian countries although this strategy was not successful in unselected population. Many driver mutations have been identified and its molecular classification made rapid progress in lung cancer, especially adenocarcinoma. The identification ALK and ROS rearrangement quickly followed by the development of active drugs (Crizotinib, Alectinib, Brigotinib, Lorlatinib ). J-ALEX and ALEX trials clearly showed that Alectinib was extremely active drug against ALK rearranged NSCLC. The Nation Wide Genomic Screening Project (LC-Scrum-Japan) leaded by K Goto has been started on February 2013 in Japan. Under this project many driver mutations have been identified not only in non-squamous cell carcinoma but also in squamous and small cell lung cancer. Many clinical trials are ongoing targeting genomic alterations screened in LC-SCRUM-Japan. Among them LURET trial demonstrated that Vandetanib could show 53% response rate (9/17) in RET+ lung cancer and Crizotinib produced 69% response rate (89/129) in ROS-1+ patients in OxOnc12-01 Asian Global trial. Driver mutation targeted drugs showed dramatic effect compared with standard cytotoxic chemotherapy, however, there is so far no positive data of their combination in spite of clear preclinical synergistic or additive effect. Human RAS oncogenes are the most commonly mutated gene family in Caucasian. About 35% (15% in Asian) of lung cancer are driven by activating mutations of KRAS. RAS is really an oncogenic driver and numerous preclinical studies suggest that KRAS is an excellent and well validated target. However, unlike EGFR, ALK, ROS, there is no effective drugs against KRAS. It will be extremely an important issue to develop KRAS targeting drugs. Robust negative data accumulate in immunotherapy for lung cancer including peptide vaccine therapy. Based on unique idea of Allison J. first immune checkpoint inhibitor, anti-CTLA4 antibody (ipillimumab) produced survival benefit in melanoma. PD-1 was cloned by Honjo T　(Japan) on 1992 and antitumor activity of anti-PD-1 antibody was reported on 2002. During past 7 years, immune checkpoint inhibitors have been an exciting new addition to the armamentarium fort lung cancer. Two anti-PD-1 antibodies such as Nivolumab and Pemblolizumab has become a standard for second line treatment of lung cancer based on durable response and marked increase in overall survival. In first line treatment Pemblolizumab prolonged OS and PFS compared with standard chemotherapy in NSCLC with high PD-L1 expression >50% (Keynote024). On the other hand, Nivolumab failed to show PFS benefit compared with cytotoxic agents because of poor patient selection. The most important issue will be how to concentrate responsive population and how to eliminate ineffective patients. Although there is a tendency of correlation between PD-L1 expression and objective response/PFS/OS, responders are experienced even in PD-L1 negative patients. Microsatellite instability has related with response to anti-PD-1 antibody in colorectal cancer. Mutation burden may influence on antigenicity of tumor cells. Infiltration of CD8+ lymphocytes is also considered to be a predictive biomarker but it is too objective for precise quantification. The successful patient selection for immune checkpoint inhibitors may depend on the development of methods for quantitative measurement of tumor specific cytotoxic activity of CD8+ lymphocytes. Can cytotoxic drugs survive as one of the modalities for lung cancer treatment? Combination of cytotoxic drugs and immune checkpoint inhibitors shows promising antitumor activity in lung cancer and gastric cancer. Antibody-drug conjugate (ADC) is a very interesting strategy for effective chemotherapy. DS-8201 targeting HER2, developed by Daiichi-Sankyo showed high response rate and favorable toxicity profile in previously treated HER2 positive gastric and breast cancer. ADC will be a potent strategy in future cytotoxic chemotherapy for lung cancer. Progress in the treatment of small cell lung cancer is very behind because of decrease in absolute number of SCLC patients and no discovery of driver mutations. JCOG conducted serial randomized clinical trials in SCLC. However, treatment result reached a plateau in both of limited and extensive diseases. Discovery of druggable targets in near future may have a significant impact in small cell lung cancer.

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