Recent Advancements of Monotherapy, Combination, and Sequential Treatment of EGFR/ALK-TKIs and ICIs in Non–Small Cell Lung Cancer

Dehua Liao , Lun Yu , Dangang Shangguan , Yongchang Zhang , Bowen Xiao , Ni Liu , and Nong Yang ^, ^*

Dehua Liao

Department of Pharmacy, The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, China

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Lun Yu

Department of PET-CT Center, Chenzhou NO. 1 People’s Hospital, Chenzhou, China

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Dangang Shangguan

Department of Pharmacy, The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, China

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Yongchang Zhang

Lung Cancer and Gastrointestinal Unit, Department of Medical Oncology, The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, China

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Bowen Xiao

Department of Pharmacy, The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, China

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Ni Liu

Department of Pharmacy, The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, China

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Nong Yang

Lung Cancer and Gastrointestinal Unit, Department of Medical Oncology, The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, China Department of Pharmacy, The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, China Department of PET-CT Center, Chenzhou NO. 1 People’s Hospital, Chenzhou, China Lung Cancer and Gastrointestinal Unit, Department of Medical Oncology, The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, China

Corresponding author.

Edited by: S. Paul Gao , Memorial Sloan Kettering Cancer Center, United States

Reviewed by: Huo Jiege , Jiangsu Provincial Hospital of Traditional Chinese Medicine, China

Xiaoqiang Yue , Shanghai Changzheng Hospital, China

*Correspondence: Nong Yang, moc.361@23gnongnay 13, newly diagnosed/maintenance LA/stage IV NSCLCConcurrentCrizotinibNivolumabI/IICompletedCAURAL Yang et al. (2019) 14, locally advanced or metastatic NSCLC EGFR + p. T790MConcurrentOsimertinibDurvalumabIIIActive, not recruitingTATTON Ahn et al. (2016) 11, advanced non–small cell lung cancerConcurrentOsimertinibDurvalumabIActive, not recruiting {"type":"clinical-trial","attrs":{"text":"NCT02088112","term_id":"NCT02088112"}} NCT02088112 Gibbons et al. (2016) Arm 1 10, arm 2 10, carcinoma, non–small cell lung cancerConcurrentGefitinibDurvalumabICompleted {"type":"clinical-trial","attrs":{"text":"NCT02013219","term_id":"NCT02013219"}} NCT02013219 Ma et al. (2016a) 20, non–small cell lung cancerConcurrentErlotinibAtezolizumabICompletedCheckMate-012 Hellmann et al. (2017) 21, non–small cell lung cancerConcurrentErlotinibNivolumabICompletedJAVELIN 101 Alice and Shaw (2018) 40, non–small cell lung cancerConcurrentCrizotinib and lorlatinibAvelumabIbCompleted Oshima et al. (2018) 20,516, NSCLCConcurrent and SequentialEGFR-TKIsNivolumab-- Kato et al. (2017) 155, stage IV cancer with post-immunotherapySequentialEGFR-TKIsCTLA-4, PD-1/PD-L1 inhibitors, or other agents-- Schoenfeld et al. (2019) 126, NSCLC, treated with PD-1/PD-L1 inhibitors and EGFR-TKIsConcurrent and sequentialEGFR-TKIsPD-1/PD-L1 inhibitors-- Kotake et al. (2017) 19, NSCLC EGFR + p.T790MSequentialOsimertinibNivolumab-- Mamesaya et al. (2017) 1, NSCLC EGFR + p.T790MSequentialOsimertinibNivolumab-- Uchida et al. (2019) 26, treatment with EGFR-TKIs immediately before and/or after PD-1 inhibitorsSequentialEGFR-TKIsPD-1 inhibitors-- Lin et al. (2019b) 453, NSCLC, treated with crizotinibSequentialCrizotinibICIs--

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PD-1/PD-L1 Inhibitor Treatment With TKI Pre-/Post-Treatment

Pre-clinical studies have shown that the intrinsic PD-L1 expression was upregulated in EGFR-sensitive mutation NSCLC cells, which induces the apoptosis of T cells and facilitates the immune escape. In addition, MHCI and class II molecules were enhanced after exposure to EGFR-TKIs, which will always be accompanied by the induction of IFN-γ and T-cell–mediated tumor killing. For progressive patients who have been pretreated with TKIs, sequential treatment with ICIs was widely reported ( Yang et al., 2019 ). KEYNOTE-001, a phase I trial, indicated that pembrolizumab was not suitable for EGFR-positive mutation patients who have been pretreated with TKIs (median OS 4 months and median PFS 5.3 months) ( Garon et al., 2019 ). The curative effect was significantly lower than that of other patients who received TKI treatment naive (median OS 18.6 months and median PFS 4 months). A randomized phase III trial, IMpower 150, investigated the efficacy of atezolizumab combined with bevacizumab and chemotherapy in NSCLC, and key subgroup analyses were conducted for patients with EGFR-sensitive mutations ( Reck et al., 2019 ). It is noteworthy that it showed a favorable response for this combination pattern when compared with bevacizumab combined with the chemotherapy group (median duration of response: 11.1 vs. 5.6 months).

On the other hand, several clinical studies have demonstrated that EGFR/ALK-positive mutation NSCLC was not suitable for ICI monotherapy or TKIs combined with ICIs. In advanced NSCLC patients with sensitive mutations, the response rate of PD-1 inhibitors was less than 5%, while the response rate of corresponding TKIs was 70%. In the combination therapy of ICIs and EGFR-TKIs, the incidence of side effects was significantly increased ( Hsu et al., 2019 ). A retrospective study conducted in Japan showed that among 20,516 advanced NSCLC patients with EGFR-sensitive mutation, the total incidence rate of ILD or immune pneumonia was 4.8%; the incidence rates of pneumonia were 4.6% and 6.4% when treated with TKIs or nivolumab, respectively, and 25.7% in the combination therapy. When further stratified the patients by treatment with and without nivolumab, the odds ratios of EGFR-TKI-associated immune pneumonia in cases with and without nivolumab treatment were 5.09 and 1.22, respectively ( Oshima et al., 2018 ). Nivolumab even developed explosive disease progression in two patients with lung adenocarcinoma who were resistant to chemotherapy and EGFR-TKI therapy (out of 155 participants). Within 2 months, the tumors increased by 53.6% and 125%, respectively, several times faster than before ICI was introduced ( Kato et al., 2017 ). In other words, high risk and probability of adverse events severely limit the options for the sequential therapy of ICIs and TKIs.

In clinical practice, it is often the case that a short time of immunotherapy or immunochemotherapy was conducted at first, and then, patients were changed to small-molecule targeted therapy. This is due to the fact that the advanced NSCLC patients often need an urgent therapy to control the progression of disease and fill the gap while waiting for the genetic test results. Schoenfeld et al. (2019) have reported that in NSCLC patients with EGFR-sensitive mutations, the treatment of osimertinib within 3 months after ICIs increased the incidence of grades 3–5 adverse reactions (interstitial pneumonia or enterocolitis). By contrast, no severe adverse reactions were observed among patients treated with either osimertinib followed by PD-1/PD-L1 (0 of 29) or PD-1/PD-L1 followed by other EGFR-TKIs (afatinib or erlotinib, 0 of 27). It was considered that it appears to be drug-specific, rather than class-specific, the interaction between osimertinib and PD-1 inhibitors. In addition, there were also a number of other studies on the sequential treatment with osimertinib and ICIs. Both Kotake et al. (2017) and Mamesaya et al. (2017) have all found a high incidence of interstitial pneumonia in retrospective case collections with nivolumab prior to osimertinib. Uchida et al. (2019) have reported the same phenomenon that interstitial pneumonia occurred in the sequential treatment of ICIs followed by osimertinib; however, it was not the case in the sequential treatment of ICIs followed by first- or second-generation EGFR-TKIs. The administration of osimertinib immediately after treatment with PD-1 inhibitors was observed in three patients. In addition, Oshima et al. (2018) have investigated the relationship between the types of ICIs and the occurrence of interstitial pneumonia. In comparison with monotherapy, a higher proportion of interstitial pneumonia was observed for concurrent or sequential treatment of nivolumab and EGFR-TKIs. Lin JJ. et al. (2019 ) have also reported that the risk of hepatotoxicity morbidity experienced an increase in their analysis in a series of patients who received immunotherapy before crizotinib. Jia et al. (2019b) have demonstrated that the combination treatment of EGFR-TKIs and ICIs may induce overlapping toxicities in an EGFR-mutated mouse model. Based on these findings, we should soberly realize that when TKIs were combined with ICIs, the sequence and the timing may influence the severity of pneumonitis. An overview of the studies mentioned earlier is shown in Table 1 .

Discussion

Nowadays, accumulating therapies with efficacy are available clinically for patients with NSCLC. Apart from surgery and conventional chemotherapy, targeted therapies could achieve significant efficacy and low adverse events and improve the quality of life for patients with specific genetic mutations. The particular system of targeted therapies elucidates the possibility of long-term treatment in the future, yet the development of new generations of targeted TKIs to overcome the acquired resistance is still an urgent task. Immunotherapy, as a novel therapy for the treatment of NSCLC in recent years, has demonstrated significant efficacy in clinical practice as monotherapy or combined with chemotherapy, and higher ORR will be achieved in long-term treatment. Several clinical trials are exploring the clinical application of ICIs at different stages of NSCLC as monotherapy or combination therapy. As of 2021, there are thousands of clinical trials at clinicaltrials.gov about different kinds of ICIs for the treatment of lung cancer, such as pembrolizumab, nivolumab, and atezolizumab . Although a long-term survival could be achieved for ICIs, a series of immune-related adverse events could not be ignored. It has been reported that the activation of the oncogenic EGFR pathway enhances the susceptibility of the lung tumors to PD-1 blockade in the mouse model, suggesting the combination of the PD1 blockade with EGFR TKIs may be a promising therapeutic strategy. Hence, in order to acquire maximum benefit for patients, the combination of TKIs and ICIs has been explored in previous clinical studies. Unfortunately, when small-molecule TKIs were combined with ICIs, the original treatment effect was not significantly improved, whereas the probability of grade 3 and 4 adverse reactions was increased. In the TATTON study, the combination use of osimertinib and durvalumab induces the high incidence of interstitial lung disease, which led to the mandatory discontinuation of several similar clinical studies ( Ahn et al., 2016 ). The combination of gefitinib combined with durvalumab demonstrated encouraging activity but higher incidence of grade 3/4 liver enzyme elevation (40–70%) ( Gibbons et al., 2016 ). The treatment-related grade 3–4 adverse events were observed in 39% of patients when treated with atezolizumab combined with erlotinib ( Ma et al., 2016b ). The phase 1b JAVELIN 101 Lung trial evaluated the second-line combination of avelumab and crizotinib in ALK-negative NSCLC patients, and 2 out of 12 patients (16.7%) had dose-limiting hepatotoxicity. Other notable dose-limiting toxicities included rash, febrile neutropenia, and QT prolongation. However, in the cohort of ALK-translocation–positive NSCLC in this study, no dose-limiting toxicities were observed when avelumab was combined with lorlatinib ( Alice and Shaw, 2018 ). Numerous studies have shown that the expression of TME and PD-L1 will be affected by pretreatment with TKIs, thus affecting the efficacy of immunotherapy. Previous studies have reported that the high expression of PD-L1 may be related to the acquired resistance of EGFR-TKI. Hence, EGFR-TKI may not be suitable for patients with wild-type EGFR or high expressions of PD-L1 ( Su et al., 2018 ; Hsu et al., 2019 ). The changes in the TME may influence the selection of EGFR-TKIs and ICI combination therapy, and the development of the TME during treatment may also render the most effective treatment ( Gettinger et al., 2018 ; Yoshida et al., 2018 ; Yamada et al., 2019 ). It is possible to dynamically monitor the immune activity of the TME for a long time to maximize the impact of immunotherapy on patients. Based on previous studies, the safety profiles associated with concurrent TKIs and ICIs are quite variable among studies. It is of note that most of these combinations have generally shown somewhat higher toxicity than expected, and this unexpected high incidence of adverse events results in the limitation to further active investigation. Also, it reflects the potential exacerbation of intrinsic but typically minimal toxicities of various TKIs. To the best of our knowledge, no concurrent combination therapy of TKIs and ICI phase 3 clinical trial in TKI-naive patients is currently planned or actively accruing.

In addition to concurrent therapy, sequential therapy is also another important pattern of combination therapy. As it is known to us, the prior selection for patients with sensitive mutation (EGFR/ALK) is still TKIs. However, acquired resistance is inevitable and severely limits its clinical application. Based on the positive results of IMpower 150 and other phaseⅠ/Ⅱ trials, this sensitive mutation (EGFR/ALK) NSCLC will always conduct immunotherapy (monotherapy or combined with chemotherapy) after failure from first-/second-line targeted therapy. The sequential treatment as ICI pre-treatment with TKIs is the most common pattern in clinical practice, and ICI post-treatment with TKIs also exists. Most of the sequential treatment of TKIs and ICIs could achieve a longer OS, and drug-induced toxicity is tolerable. However, a previous study has also shown that ILD was observed in the treatment sequence of an anti-PD-1 antibody followed by osimertinib but not with first- or second-generation EGFR-TKIs. Jia et al. (2019b) have reported that osimertinib, rather than gefitinib combined with anti-PD-L1 treatment, could lead to lung injury in an EGFR-mutated tumor-bearing mouse model. This may be due to the durable immune response of the PD-(L)1 antibody. In contrast, EGFR-TKIs such as osimertinib take effect in a short period of time. They also speculated that the mechanism of ILD development is different between first-/second-generation TKIs and osimertinib, and the activation of T-cell effects by ICIs may upregulate this effect synergistically to cause ILD with osimertinib but not first- or second-generation TKIs. Jia et al. (2019a) have also reported that EGFR-targeted therapy alters the tumor microenvironment in EGFR-driven lung tumors. The optimal sequence of the treatment and strategies that modulate the tumor microenvironment to a state that may favor antitumor immune responses need to be considered when designing clinical trials. As it is known to us, the treatment of NSCLC is a “multi-station” manner, including the sequential therapy of TKIs and ICIs, which could provide a pivotal benefit for advanced NSCLC. However, further studies are still needed to explore the mechanism of adverse events and optimal sequence of the treatment and strategies.

In conclusion, the combination treatment of EGFR/ALK-TKIs and ICIs in NSCLC should be considered investigational; the specific drug, optimal dosing, sequence of the treatment schedule, interval time, treatment-related toxicities, and efficiency should all be considered in this type of combination therapy.

Author Contributions

DL and NY designed the study and wrote the protocol. DL, DS, YZ, and BX drafted the manuscript. LY, DL, NL, and NY revised the manuscript content. All the authors read and approved the final manuscript.

Funding

This study was supported by the Hunan Medical Association Foundation (NO: HMA202001005), the Project of Changsha City Science and Technology Department (NO: kq2004129), the Hunan Pharmaceutical Association Foundation (NO: 2020YXH001), Hunan Provincial Natural Science Foundation of China (No. 2021JJ70025), and the Climbing Plan of Hunan Cancer Hospital (NO: 2021NSFC-A003).

Conflict of Interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Publisher’s Note

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors, and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.

References

Ahn M.-J., Yang J., Yu H., Saka H., Ramalingam S., Goto K., et al. (2016). 136O: Osimertinib Combined with Durvalumab in EGFR-Mutant Non-small Cell Lung Cancer: Results from the TATTON Phase Ib Trial . J. Thorac. Oncol. 11 ( 4 ), S115. 10.1016/s1556-0864(16)30246-5 [ CrossRef ] [ Google Scholar ]
Akbay E. A., Koyama S., Carretero J., Altabef A., Tchaicha J. H., Christensen C. L., et al. (2013). Activation of the PD-1 Pathway Contributes to Immune Escape in EGFR-Driven Lung Tumors . Cancer Discov. 3 ( 12 ), 1355–1363. 10.1158/2159-8290.CD-13-0310 [ PMC free article ] [ PubMed ] [ CrossRef ] [ Google Scholar ]
Alice T., Shaw S.-H. L. (2018). Avelumab (Anti– PD-L1) in Combination with Crizotinib or Lorlatinib in Patients with Previously Treated Advanced NSCLC Phase 1b Results from JAVELIN Lung 101 . Clin. Trial 18 ( 5 ), 599–610. [ Google Scholar ]
Azuma K., Ota K., Kawahara A., Hattori S., Iwama E., Harada T., et al. (2014). Association of PD-L1 Overexpression with Activating EGFR Mutations in Surgically Resected Nonsmall-Cell Lung Cancer . Ann. Oncol. 25 ( 10 ), 1935–1940. 10.1093/annonc/mdu242 [ PubMed ] [ CrossRef ] [ Google Scholar ]
Azzoli C. G., Baker S., Jr, Temin S., Pao W., Aliff T., Brahmer J., et al. (2009). American Society of Clinical Oncology Clinical Practice Guideline Update on Chemotherapy for Stage IV Non-small-cell Lung Cancer . J. Clin. Oncol. 27 ( 36 ), 6251–6266. 10.1200/JCO.2009.23.5622 [ PMC free article ] [ PubMed ] [ CrossRef ] [ Google Scholar ]
Barber D. L., Wherry E. J., Masopust D., Zhu B., Allison J. P., Sharpe A. H., et al. (2006). Restoring Function in Exhausted CD8 T Cells during Chronic Viral Infection . Nature 439 ( 7077 ), 682–687. 10.1038/nature04444 [ PubMed ] [ CrossRef ] [ Google Scholar ]
Baumeister S. H., Freeman G. J., Dranoff G., Sharpe A. H. (2016). Coinhibitory Pathways in Immunotherapy for Cancer . Annu. Rev. Immunol. 34 , 539–573. 10.1146/annurev-immunol-032414-112049 [ PubMed ] [ CrossRef ] [ Google Scholar ]
Bremnes R. M., Al-Shibli K., Donnem T., Sirera R., Al-Saad S., Andersen S., et al. (2011). The Role of Tumor-Infiltrating Immune Cells and Chronic Inflammation at the Tumor Site on Cancer Development, Progression, and Prognosis: Emphasis on Non-small Cell Lung Cancer . J. Thorac. Oncol. 6 ( 4 ), 824–833. 10.1097/JTO.0b013e3182037b76 [ PubMed ] [ CrossRef ] [ Google Scholar ]
Chen N., Fang W., Zhan J., Hong S., Tang Y., Kang S., et al. (2015). Upregulation of PD-L1 by EGFR Activation Mediates the Immune Escape in EGFR-Driven NSCLC: Implication for Optional Immune Targeted Therapy for NSCLC Patients with EGFR Mutation . J. Thorac. Oncol. 10 ( 6 ), 910–923. 10.1097/JTO.0000000000000500 [ PubMed ] [ CrossRef ] [ Google Scholar ]
Costa D. B., Halmos B., Kumar A., Schumer S. T., Huberman M. S., Boggon T. J., et al. (2007). BIM Mediates EGFR Tyrosine Kinase Inhibitor-Induced Apoptosis in Lung Cancers with Oncogenic EGFR Mutations . PLoS Med. 4 ( 10 ), 1669–1680. 10.1371/journal.pmed.0040315 [ PMC free article ] [ PubMed ] [ CrossRef ] [ Google Scholar ]
Cui J. J., Rogers E., Zhai D., Deng W., Ung J., Nguyen V., et al. (2020). TPX-0131: A Next Generation Macrocyclic ALK Inhibitor that Overcomes ALK Resistant Mutations Refractory to Current Approved ALK Inhibitors". AACR) . Mol. Cancer Ther. 20 ( 9 ), 1499–1509. [ PMC free article ] [ PubMed ] [ Google Scholar ]
Doebele R. C., Pilling A. B., Aisner D. L., Kutateladze T. G., Le A. T., Weickhardt A. J., et al. (2012). Mechanisms of Resistance to Crizotinib in Patients with ALK Gene Rearranged Non-small Cell Lung Cancer . Clin. Cancer Res. 18 ( 5 ), 1472–1482. 10.1158/1078-0432.CCR-11-2906 [ PMC free article ] [ PubMed ] [ CrossRef ] [ Google Scholar ]
Dong Z. Y., Zhang J. T., Liu S. Y., Su J., Zhang C., Xie Z., et al. (2017). EGFR Mutation Correlates with Uninflamed Phenotype and Weak Immunogenicity, Causing Impaired Response to PD-1 Blockade in Non-small Cell Lung Cancer . Oncoimmunology 6 ( 11 ), e1356145. 10.1080/2162402X.2017.1356145 [ PMC free article ] [ PubMed ] [ CrossRef ] [ Google Scholar ]
Fehrenbacher L., Spira A., Ballinger M., Kowanetz M., Vansteenkiste J., Mazieres J., et al. (2016). Atezolizumab versus Docetaxel for Patients with Previously Treated Non-small-cell Lung Cancer (POPLAR): a Multicentre, Open-Label, Phase 2 Randomised Controlled Trial . Lancet 387 ( 10030 ), 1837–1846. 10.1016/S0140-6736(16)00587-0 [ PubMed ] [ CrossRef ] [ Google Scholar ]
Fossella F., Pereira J. R., von Pawel J., Pluzanska A., Gorbounova V., Kaukel E., et al. (2003). Randomized, Multinational, Phase III Study of Docetaxel Plus Platinum Combinations versus Vinorelbine Plus Cisplatin for Advanced Non-small-cell Lung Cancer: the TAX 326 Study Group . J. Clin. Oncol. 21 ( 16 ), 3016–3024. 10.1200/JCO.2003.12.046 [ PubMed ] [ CrossRef ] [ Google Scholar ]
Gainor J. F., Shaw A. T., Sequist L. V., Fu X., Azzoli C. G., Piotrowska Z., et al. (2016). EGFR Mutations and ALK Rearrangements Are Associated with Low Response Rates to PD-1 Pathway Blockade in Non-small Cell Lung Cancer: A Retrospective Analysis . Clin. Cancer Res. 22 ( 18 ), 4585–4593. 10.1158/1078-0432.CCR-15-3101 [ PMC free article ] [ PubMed ] [ CrossRef ] [ Google Scholar ]
Gandhi L., Rodríguez-Abreu D., Gadgeel S., Esteban E., Felip E., De Angelis F., et al. (2018). Pembrolizumab Plus Chemotherapy in Metastatic Non-small-cell Lung Cancer . N. Engl. J. Med. 378 ( 22 ), 2078–2092. 10.1056/NEJMoa1801005 [ PubMed ] [ CrossRef ] [ Google Scholar ]
Garon E. B., Hellmann M. D., Rizvi N. A., Carcereny E., Leighl N. B., Ahn M. J., et al. (2019). Five-Year Overall Survival for Patients with Advanced Non‒Small-Cell Lung Cancer Treated with Pembrolizumab: Results from the Phase I KEYNOTE-001 Study . J. Clin. Oncol. 37 ( 28 ), 2518–2527. 10.1200/JCO.19.00934 [ PMC free article ] [ PubMed ] [ CrossRef ] [ Google Scholar ]
Gettinger S., Horn L., Jackman D., Spigel D., Antonia S., Hellmann M., et al. (2018). Five-Year Follow-Up of Nivolumab in Previously Treated Advanced Non-small-cell Lung Cancer: Results from the CA209-003 Study . J. Clin. Oncol. 36 ( 17 ), 1675–1684. 10.1200/JCO.2017.77.0412 [ PubMed ] [ CrossRef ] [ Google Scholar ]
Gibbons D. L., Chow L. Q., Kim D.-W., Kim S.-W., Yeh T., Song X., et al. (2016). 57O Efficacy, Safety and Tolerability of MEDI4736 (Durvalumab [D]), a Human IgG1 Anti-programmed Cell Death-Ligand-1 (PD-L1) Antibody, Combined with Gefitinib (G): A Phase I Expansion in TKI-Naïve Patients (Pts) with EGFR Mutant NSCLC . J. Thorac. Oncol. 11 ( 4 ), S79. 10.1016/s1556-0864(16)30171-x [ CrossRef ] [ Google Scholar ]
Hellmann M. D., Rizvi N. A., Goldman J. W., Gettinger S. N., Borghaei H., Brahmer J. R., et al. (2017). Nivolumab Plus Ipilimumab as First-Line Treatment for Advanced Non-small-cell Lung Cancer (CheckMate 012): Results of an Open-Label, Phase 1, Multicohort Study . Lancet Oncol. 18 ( 1 ), 31–41. 10.1016/S1470-2045(16)30624-6 [ PMC free article ] [ PubMed ] [ CrossRef ] [ Google Scholar ]
Hellmann M. D., Paz-Ares L., Bernabe Caro R., Zurawski B., Kim S.-W., Carcereny Costa E., et al. (2019). Nivolumab Plus Ipilimumab in Advanced Non-small-cell Lung Cancer . N. Engl. J. Med. 381 ( 21 ), 2020–2031. 10.1056/nejmoa1910231 [ PubMed ] [ CrossRef ] [ Google Scholar ]
Hirano F., Kaneko K., Tamura H., Dong H., Wang S., Ichikawa M., et al. (2005). Blockade of B7-H1 and PD-1 by Monoclonal Antibodies Potentiates Cancer Therapeutic Immunity . Cancer Res. 65 ( 3 ), 1089–1096. [ PubMed ] [ Google Scholar ]
Horn L., Spigel D. R., Vokes E. E., Holgado E., Ready N., Steins M., et al. (2017). Nivolumab versus Docetaxel in Previously Treated Patients with Advanced Non-small-cell Lung Cancer: Two-Year Outcomes from Two Randomized, Open-Label, Phase III Trials (CheckMate 017 and CheckMate 057) . J. Clin. Oncol. 35 ( 35 ), 3924–3933. 10.1200/JCO.2017.74.3062 [ PMC free article ] [ PubMed ] [ CrossRef ] [ Google Scholar ]
Hsu K. H., Huang Y. H., Tseng J. S., Chen K. C., Ku W. H., Su K. Y., et al. (2019). High PD-L1 Expression Correlates with Primary Resistance to EGFR-TKIs in Treatment Naïve Advanced EGFR-Mutant Lung Adenocarcinoma Patients . Lung Cancer 127 , 37–43. 10.1016/j.lungcan.2018.11.021 [ PubMed ] [ CrossRef ] [ Google Scholar ]
Huang S. H., Li Y., Zhang J., Rong J., Ye S. (2013). Epidermal Growth Factor Receptor-Containing Exosomes Induce Tumor-specific Regulatory T Cells . Cancer Invest. 31 ( 5 ), 330–335. 10.3109/07357907.2013.789905 [ PubMed ] [ CrossRef ] [ Google Scholar ]
Inoue A., Kobayashi K., Maemondo M., Sugawara S., Oizumi S., Isobe H., et al. (2013). Updated Overall Survival Results from a Randomized Phase III Trial Comparing Gefitinib with Carboplatin-Paclitaxel for Chemo-Naïve Non-small Cell Lung Cancer with Sensitive EGFR Gene Mutations (NEJ002) . Ann. Oncol. 24 ( 1 ), 54–59. 10.1093/annonc/mds214 [ PubMed ] [ CrossRef ] [ Google Scholar ]
Iwai Y., Ishida M., Tanaka Y., Okazaki T., Honjo T., Minato N. (2002). Involvement of PD-L1 on Tumor Cells in the Escape from Host Immune System and Tumor Immunotherapy by PD-L1 Blockade . Proc. Natl. Acad. Sci. U. S. A. 99 ( 19 ), 12293–12297. 10.1073/pnas.192461099 [ PMC free article ] [ PubMed ] [ CrossRef ] [ Google Scholar ]
Jamal-Hanjani M., Spicer J. (2012). Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors in the Treatment of Epidermal Growth Factor Receptor-Mutant Non-small Cell Lung Cancer Metastatic to the Brain . Clin. Cancer Res. 18 ( 4 ), 938–944. 10.1158/1078-0432.CCR-11-2529 [ PubMed ] [ CrossRef ] [ Google Scholar ]
Jia Y., Li X., Jiang T., Zhao S., Zhao C., Zhang L., et al. (2019a). EGFR-targeted Therapy Alters the Tumor Microenvironment in EGFR-Driven Lung Tumors: Implications for Combination Therapies . Int. J. Cancer 145 ( 5 ), 1432–1444. 10.1002/ijc.32191 [ PubMed ] [ CrossRef ] [ Google Scholar ]
Jia Y., Zhao S., Jiang T., Li X., Zhao C., Liu Y., et al. (2019b). Impact of EGFR-TKIs Combined with PD-L1 Antibody on the Lung Tissue of EGFR-Driven Tumor-Bearing Mice . Lung Cancer 137 , 85–93. 10.1016/j.lungcan.2019.09.016 [ PubMed ] [ CrossRef ] [ Google Scholar ]
Katayama R., Shaw A. T., Khan T. M., Mino-Kenudson M., Solomon B. J., Halmos B., et al. (2012). Mechanisms of Acquired Crizotinib Resistance in ALK-Rearranged Lung Cancers . Sci. Transl. Med. 4 ( 120 ), 120ra17–120ra117. 10.1126/scitranslmed.3003316 [ PMC free article ] [ PubMed ] [ CrossRef ] [ Google Scholar ]
Kato S., Goodman A., Walavalkar V., Barkauskas D. A., Sharabi A., Kurzrock R. (2017). Hyperprogressors after Immunotherapy: Analysis of Genomic Alterations Associated with Accelerated Growth Rate . Clin. Cancer Res. 23 ( 15 ), 4242–4250. 10.1158/1078-0432.CCR-16-3133 [ PMC free article ] [ PubMed ] [ CrossRef ] [ Google Scholar ]
Kim D.-W., Gadgeel S. M., Gettinger S. N., Riely G. J., Oxnard G. R., Mekhail T., et al. (2018). Safety and Clinical Activity Results from a Phase Ib Study of Alectinib Plus Atezolizumab in ALK+ Advanced NSCLC (aNSCLC) . Am. Soc. Clin. Oncol. 36 ( 15_Suppl. l ), 9009. 10.1200/jco.2018.36.15_suppl.9009 [ CrossRef ] [ Google Scholar ]
Kim S., Kim T. M., Kim D. W., Go H., Keam B., Lee S. H., et al. (2013). Heterogeneity of Genetic Changes Associated with Acquired Crizotinib Resistance in ALK-Rearranged Lung Cancer . J. Thorac. Oncol. 8 ( 4 ), 415–422. 10.1097/JTO.0b013e318283dcc0 [ PubMed ] [ CrossRef ] [ Google Scholar ]
Kotake M., Murakami H., Kenmotsu H., Naito T., Takahashi T. (2017). High Incidence of Interstitial Lung Disease Following Practical Use of Osimertinib in Patients Who Had Undergone Immediate Prior Nivolumab Therapy . Ann. Oncol. 28 ( 3 ), 669–670. 10.1093/annonc/mdw647 [ PubMed ] [ CrossRef ] [ Google Scholar ]
Ladanyi M., Pao W. (2008). Lung Adenocarcinoma: Guiding EGFR-Targeted Therapy and beyond . Mod. Pathol. 21 ( 2 ), S16–S22. 10.1038/modpathol.3801018 [ PubMed ] [ CrossRef ] [ Google Scholar ]
Lin A., Wei T., Meng H., Luo P., Zhang J. (2019a). Role of the Dynamic Tumor Microenvironment in Controversies Regarding Immune Checkpoint Inhibitors for the Treatment of Non-small Cell Lung Cancer (NSCLC) with EGFR Mutations . Mol. Cancer 18 ( 1 ), 139–218. 10.1186/s12943-019-1062-7 [ PMC free article ] [ PubMed ] [ CrossRef ] [ Google Scholar ]
Lin J. J., Chin E., Yeap B. Y., Ferris L. A., Kamesan V., Lennes I. T., et al. (2019b). Increased Hepatotoxicity Associated with Sequential Immune Checkpoint Inhibitor and Crizotinib Therapy in Patients with Non-small Cell Lung Cancer . J. Thorac. Oncol. 14 ( 1 ), 135–140. 10.1016/j.jtho.2018.09.001 [ PMC free article ] [ PubMed ] [ CrossRef ] [ Google Scholar ]
Lu S., Wang J., Yu Y., Yu X., Hu Y., Ai X., et al. (2021). Tislelizumab Plus Chemotherapy as First-Line Treatment for Locally Advanced or Metastatic Nonsquamous NSCLC (RATIONALE 304): a Randomized Phase 3 Trial . J. Thorac. Oncol. 16 ( 9 ), 1512–1522. 10.1016/j.jtho.2021.05.005 [ PubMed ] [ CrossRef ] [ Google Scholar ]
Lynch T. J., Bell D. W., Sordella R., Gurubhagavatula S., Okimoto R. A., Brannigan B. W., et al. (2004). Activating Mutations in the Epidermal Growth Factor Receptor Underlying Responsiveness of Non-small-cell Lung Cancer to Gefitinib . N. Engl. J. Med. 350 ( 21 ), 2129–2139. 10.1056/NEJMoa040938 [ PubMed ] [ CrossRef ] [ Google Scholar ]
Ma B. B. Y., Rudin C. M., Cervantes A., Dowlati A., Costa D., Schmid P., et al. (2016a). 441O Preliminary Safety and Clinical Activity of Erlotinib Plus Atezolizumab from a Phase Ib Study in Advanced NSCLC . Ann. Oncol. 27 , ix141. 10.1016/s0923-7534(21)00599-8 [ CrossRef ] [ Google Scholar ]
Ma B. B. Y., Rudin C. M., Cervantes A., Dowlati A., Costa D., Schmid P., et al. (2016b). 441O Preliminary Safety and Clinical Activity of Erlotinib Plus Atezolizumab from a Phase Ib Study in Advanced NSCLC . Ann. Oncol. 27 , ix141. 10.1016/s0923-7534(21)00599-8 [ CrossRef ] [ Google Scholar ]
Maemondo M., Inoue A., Kobayashi K., Sugawara S., Oizumi S., Isobe H., et al. (2010). Gefitinib or Chemotherapy for Non-small-cell Lung Cancer with Mutated EGFR . N. Engl. J. Med. 362 ( 25 ), 2380–2388. 10.1056/NEJMoa0909530 [ PubMed ] [ CrossRef ] [ Google Scholar ]
Mamesaya N., Kenmotsu H., Katsumata M., Nakajima T., Endo M., Takahashi T. (2017). Osimertinib-induced Interstitial Lung Disease after Treatment with Anti-PD1 Antibody . Invest. New Drugs 35 ( 1 ), 105–107. 10.1007/s10637-016-0389-9 [ PMC free article ] [ PubMed ] [ CrossRef ] [ Google Scholar ]
Mascia F., Schloemann D. T., Cataisson C., McKinnon K. M., Krymskaya L., Wolcott K. M., et al. (2016). Cell Autonomous or Systemic EGFR Blockade Alters the Immune-Environment in Squamous Cell Carcinomas . Int. J. Cancer 139 ( 11 ), 2593–2597. 10.1002/ijc.30376 [ PMC free article ] [ PubMed ] [ CrossRef ] [ Google Scholar ]
Mazzaschi G., Madeddu D., Falco A., Bocchialini G., Goldoni M., Sogni F., et al. (2018). Low PD-1 Expression in Cytotoxic CD8+ Tumor-Infiltrating Lymphocytes Confers an Immune-Privileged Tissue Microenvironment in NSCLC with a Prognostic and Predictive Value . Clin. Cancer Res. 24 ( 2 ), 407–419. 10.1158/1078-0432.CCR-17-2156 [ PubMed ] [ CrossRef ] [ Google Scholar ]
Mitsudomi T., Morita S., Yatabe Y., Negoro S., Okamoto I., Tsurutani J., et al. (2010). Gefitinib versus Cisplatin Plus Docetaxel in Patients with Non-small-cell Lung Cancer Harbouring Mutations of the Epidermal Growth Factor Receptor (WJTOG3405): an Open Label, Randomised Phase 3 Trial . Lancet Oncol. 11 ( 2 ), 121–128. 10.1016/S1470-2045(09)70364-X [ PubMed ] [ CrossRef ] [ Google Scholar ]
Mok T., Camidge D. R., Gadgeel S. M., Rosell R., Dziadziuszko R., Kim D. W., et al. (2020). Updated Overall Survival and Final Progression-free Survival Data for Patients with Treatment-Naive Advanced ALK-Positive Non-small-cell Lung Cancer in the ALEX Study . Ann. Oncol. 31 ( 8 ), 1056–1064. 10.1016/j.annonc.2020.04.478 [ PubMed ] [ CrossRef ] [ Google Scholar ]
Mok T. S., Wu Y. L., Thongprasert S., Yang C. H., Chu D. T., Saijo N., et al. (2009). Gefitinib or Carboplatin-Paclitaxel in Pulmonary Adenocarcinoma . N. Engl. J. Med. 361 ( 10 ), 947–957. 10.1056/NEJMoa0810699 [ PubMed ] [ CrossRef ] [ Google Scholar ]
Mok T. S., Wu Y.-L., Ahn M.-J., Garassino M. C., Kim H. R., Ramalingam S. S., et al. (2017). Osimertinib or Platinum-Pemetrexed in EGFR T790M-Positive Lung Cancer . N. Engl. J. Med. 376 ( 7 ), 629–640. 10.1056/nejmoa1612674 [ PMC free article ] [ PubMed ] [ CrossRef ] [ Google Scholar ]
Oberndorfer F., Müllauer L. (2018). Molecular Pathology of Lung Cancer: Current Status and Perspectives . Curr. Opin. Oncol. 30 ( 2 ), 69–76. 10.1097/CCO.0000000000000429 [ PubMed ] [ CrossRef ] [ Google Scholar ]
Ohashi K., Maruvka Y. E., Michor F., Pao W. (2013). Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor-Resistant Disease . J. Clin. Oncol. 31 ( 8 ), 1070–1080. 10.1200/JCO.2012.43.3912 [ PMC free article ] [ PubMed ] [ CrossRef ] [ Google Scholar ]
Ohe Y., Ohashi Y., Kubota K., Tamura T., Nakagawa K., Negoro S., et al. (2007). Randomized Phase III Study of Cisplatin Plus Irinotecan versus Carboplatin Plus Paclitaxel, Cisplatin Plus Gemcitabine, and Cisplatin Plus Vinorelbine for Advanced Non-small-cell Lung Cancer: Four-Arm Cooperative Study in Japan . Ann. Oncol. 18 ( 2 ), 317–323. 10.1093/annonc/mdl377 [ PubMed ] [ CrossRef ] [ Google Scholar ]
Oshima Y., Tanimoto T., Yuji K., Tojo A. (2018). EGFR-TKI-Associated Interstitial Pneumonitis in Nivolumab-Treated Patients with Non-small Cell Lung Cancer . JAMA Oncol. 4 ( 8 ), 1112–1115. 10.1001/jamaoncol.2017.4526 [ PMC free article ] [ PubMed ] [ CrossRef ] [ Google Scholar ]
Ota K., Azuma K., Kawahara A., Hattori S., Iwama E., Tanizaki J., et al. (2015). Induction of PD-L1 Expression by the EML4-ALK Oncoprotein and Downstream Signaling Pathways in Non-small Cell Lung Cancer . Clin. Cancer Res. 21 ( 17 ), 4014–4021. 10.1158/1078-0432.CCR-15-0016 [ PubMed ] [ CrossRef ] [ Google Scholar ]
Paez J. G., Jänne P. A., Lee J. C., Tracy S., Greulich H., Gabriel S., et al. (2004). EGFR Mutations in Lung Cancer: Correlation with Clinical Response to Gefitinib Therapy . Science 304 ( 5676 ), 1497–1500. 10.1126/science.1099314 [ PubMed ] [ CrossRef ] [ Google Scholar ]
Pardoll D. M. (2012). The Blockade of Immune Checkpoints in Cancer Immunotherapy . Nat. Rev. Cancer 12 ( 4 ), 252–264. 10.1038/nrc3239 [ PMC free article ] [ PubMed ] [ CrossRef ] [ Google Scholar ]
Park L. C., Rhee K., Kim W. B., Cho A., Song J., Anker J. F., et al. (2018). Immunologic and Clinical Implications of CD73 Expression in Non-small Cell Lung Cancer (NSCLC) . Am. Soc. Clin. Oncol. 36 ( 15_Suppl. l ), 12050. 10.1200/jco.2018.36.15_suppl.12050 [ CrossRef ] [ Google Scholar ]
Pauken K. E., Wherry E. J. (2015). Overcoming T Cell Exhaustion in Infection and Cancer . Trends Immunol. 36 ( 4 ), 265–276. 10.1016/j.it.2015.02.008 [ PMC free article ] [ PubMed ] [ CrossRef ] [ Google Scholar ]
Paz-Ares L., Dvorkin M., Chen Y., Reinmuth N., Hotta K., Trukhin D., et al. (2019). Durvalumab Plus Platinum-Etoposide versus Platinum-Etoposide in First-Line Treatment of Extensive-Stage Small-Cell Lung Cancer (CASPIAN): a Randomised, Controlled, Open-Label, Phase 3 Trial . Lancet 394 ( 10212 ), 1929–1939. 10.1016/S0140-6736(19)32222-6 [ PubMed ] [ CrossRef ] [ Google Scholar ]
Paz-Ares L., Tan E. H., O'Byrne K., Zhang L., Hirsh V., Boyer M., et al. (2017). Afatinib versus Gefitinib in Patients with EGFR Mutation-Positive Advanced Non-small-cell Lung Cancer: Overall Survival Data from the Phase IIb LUX-Lung 7 Trial . Ann. Oncol. 28 ( 2 ), 270–277. 10.1093/annonc/mdw611 [ PMC free article ] [ PubMed ] [ CrossRef ] [ Google Scholar ]
Peters S., Zimmermann S. (2018). Management of Resistance to First-Line Anaplastic Lymphoma Kinase Tyrosine Kinase Inhibitor Therapy . Curr. Treat. Options Oncol. 19 ( 7 ), 37–14. 10.1007/s11864-018-0553-x [ PubMed ] [ CrossRef ] [ Google Scholar ]
Piotrowska Z., Isozaki H., Lennerz J. K., Gainor J. F., Lennes I. T., Zhu V. W., et al. (2018). Landscape of Acquired Resistance to Osimertinib in EGFR-Mutant NSCLC and Clinical Validation of Combined EGFR and RET Inhibition with Osimertinib and BLU-667 for Acquired RET Fusion . Cancer Discov. 8 ( 12 ), 1529–1539. 10.1158/2159-8290.CD-18-1022 [ PMC free article ] [ PubMed ] [ CrossRef ] [ Google Scholar ]
Poggio M., Hu T., Pai C. C., Chu B., Belair C. D., Chang A., et al. (2019). Suppression of Exosomal PD-L1 Induces Systemic Anti-tumor Immunity and Memory . Cell 177 ( 2 ), 414–e13. e413. 10.1016/j.cell.2019.02.016 [ PMC free article ] [ PubMed ] [ CrossRef ] [ Google Scholar ]
Rapp E., Pater J. L., Willan A., Cormier Y., Murray N., Evans W. K., et al. (1988). Chemotherapy Can Prolong Survival in Patients with Advanced Non-small-cell Lung Cancer-Rreport of a Canadian Multicenter Randomized Trial . J. Clin. Oncol. 6 ( 4 ), 633–641. 10.1200/JCO.1988.6.4.633 [ PubMed ] [ CrossRef ] [ Google Scholar ]
Reck M., Mok T. S. K., Nishio M., Jotte R. M., Cappuzzo F., Orlandi F., et al. (2019). Atezolizumab Plus Bevacizumab and Chemotherapy in Non-small-cell Lung Cancer (IMpower150): Key Subgroup Analyses of Patients with EGFR Mutations or Baseline Liver Metastases in a Randomised, Open-Label Phase 3 Trial . Lancet Respir. Med. 7 ( 5 ), 387–401. 10.1016/S2213-2600(19)30084-0 [ PubMed ] [ CrossRef ] [ Google Scholar ]
Reck M., Rodríguez-Abreu D., Robinson A. G., Hui R., Csőszi T., Fülöp A., et al. (2016). Pembrolizumab versus Chemotherapy for PD-L1-Positive Non-small-cell Lung Cancer . N. Engl. J. Med. 375 , 1823–1833. 10.1056/NEJMoa1606774 [ PubMed ] [ CrossRef ] [ Google Scholar ]
Rosell R., Carcereny E., Gervais R., Vergnenegre A., Massuti B., Felip E., et al. (2012). Erlotinib versus Standard Chemotherapy as First-Line Treatment for European Patients with Advanced EGFR Mutation-Positive Non-small-cell Lung Cancer (EURTAC): a Multicentre, Open-Label, Randomised Phase 3 Trial . Lancet Oncol. 13 ( 3 ), 239–246. 10.1016/S1470-2045(11)70393-X [ PubMed ] [ CrossRef ] [ Google Scholar ]
Schiller J. H., Harrington D., Belani C. P., Langer C., Sandler A., Krook J., et al. (2002). Comparison of Four Chemotherapy Regimens for Advanced Non-small-cell Lung Cancer . N. Engl. J. Med. 346 ( 2 ), 92–98. 10.1056/NEJMoa011954 [ PubMed ] [ CrossRef ] [ Google Scholar ]
Schoenfeld A. J., Arbour K. C., Rizvi H., Iqbal A. N., Gadgeel S. M., Girshman J., et al. (2019). Severe Immune-Related Adverse Events Are Common with Sequential PD-(L)1 Blockade and Osimertinib . Ann. Oncol. 30 ( 5 ), 839–844. 10.1093/annonc/mdz077 [ PMC free article ] [ PubMed ] [ CrossRef ] [ Google Scholar ]
Sequist L. V., Bell D. W., Lynch T. J., Haber D. A. (2007). Molecular Predictors of Response to Epidermal Growth Factor Receptor Antagonists in Non-small-cell Lung Cancer . J. Clin. Oncol. 25 ( 5 ), 587–595. 10.1200/JCO.2006.07.3585 [ PubMed ] [ CrossRef ] [ Google Scholar ]
Sequist L. V., Waltman B. A., Dias-Santagata D., Digumarthy S., Turke A. B., Fidias P., et al. (2011). Genotypic and Histological Evolution of Lung Cancers Acquiring Resistance to EGFR Inhibitors . Sci. Transl. Med. 3 ( 75 ), 75ra26. 75ra26-75ra26. 10.1126/scitranslmed.3002003 [ PMC free article ] [ PubMed ] [ CrossRef ] [ Google Scholar ]
Shi Y., Zhang L., Liu X., Zhou C., Zhang L., Zhang S., et al. (2013). Icotinib versus Gefitinib in Previously Treated Advanced Non-small-cell Lung Cancer (ICOGEN): a Randomised, Double-Blind Phase 3 Non-inferiority Trial . Lancet Oncol. 14 ( 10 ), 953–961. 10.1016/S1470-2045(13)70355-3 [ PubMed ] [ CrossRef ] [ Google Scholar ]
Shi Y. K., Wang L., Han B. H., Li W., Yu P., Liu Y. P., et al. (2017). First-line Icotinib versus Cisplatin/pemetrexed Plus Pemetrexed Maintenance Therapy for Patients with Advanced EGFR Mutation-Positive Lung Adenocarcinoma (CONVINCE): a Phase 3, Open-Label, Randomized Study . Ann. Oncol. 28 ( 10 ), 2443–2450. 10.1093/annonc/mdx359 [ PubMed ] [ CrossRef ] [ Google Scholar ]
Shigematsu H., Lin L., Takahashi T., Nomura M., Suzuki M., Wistuba I. I., et al. (2005). Clinical and Biological Features Associated with Epidermal Growth Factor Receptor Gene Mutations in Lung Cancers . J. Natl. Cancer Inst. 97 ( 5 ), 339–346. 10.1093/jnci/dji055 [ PubMed ] [ CrossRef ] [ Google Scholar ]
Soda M., Choi Y. L., Enomoto M., Takada S., Yamashita Y., Ishikawa S., et al. (2007). Identification of the Transforming EML4-ALK Fusion Gene in Non-small-cell Lung Cancer . Nature 448 ( 7153 ), 561–566. 10.1038/nature05945 [ PubMed ] [ CrossRef ] [ Google Scholar ]
Solomon B. J., Besse B., Bauer T. M., Felip E., Soo R. A., Camidge D. R., et al. (2018a). Lorlatinib in Patients with ALK-Positive Non-small-cell Lung Cancer: Results from a Global Phase 2 Study . Lancet Oncol. 19 ( 12 ), 1654–1667. 10.1016/S1470-2045(18)30649-1 [ PubMed ] [ CrossRef ] [ Google Scholar ]
Solomon B. J., Cappuzzo F., Felip E., Blackhall F. H., Costa D. B., Kim D. W., et al. (2016). Intracranial Efficacy of Crizotinib versus Chemotherapy in Patients with Advanced ALK-Positive Non-small-cell Lung Cancer: Results from PROFILE 1014 . J. Clin. Oncol. 34 ( 24 ), 2858–2865. 10.1200/JCO.2015.63.5888 [ PubMed ] [ CrossRef ] [ Google Scholar ]
Solomon B. J., Kim D. W., Wu Y. L., Nakagawa K., Mekhail T., Felip E., et al. (2018b). Final Overall Survival Analysis from a Study Comparing First-Line Crizotinib versus Chemotherapy in ALK-Mutation-Positive Non-small-cell Lung Cancer . J. Clin. Oncol. 36 ( 22 ), 2251–2258. 10.1200/JCO.2017.77.4794 [ PubMed ] [ CrossRef ] [ Google Scholar ]
Song Y., Wu Y. L., Cao L. J., Chen J. H., Ma Z. Y., Cui J. W., et al. (2019). Efficacy and Safety of Gefitinib as Third-Line Treatment in NSCLC Patients with Activating EGFR Mutations Treated with First-Line Gefitinib Followed by Second-Line Chemotherapy: a Single-Arm, Prospective, Multicenter Phase II Study (RE-CHALLENGE, CTONG1304) . Am. J. Clin. Oncol. 42 ( 5 ), 432–439. 10.1097/COC.0000000000000538 [ PMC free article ] [ PubMed ] [ CrossRef ] [ Google Scholar ]
Spigel D. R., Reynolds C., Waterhouse D., Garon E. B., Chandler J., Babu S., et al. (2018). Phase 1/2 Study of the Safety and Tolerability of Nivolumab Plus Crizotinib for the First-Line Treatment of Anaplastic Lymphoma Kinase Translocation - Positive Advanced Non-small Cell Lung Cancer (CheckMate 370) . J. Thorac. Oncol. 13 ( 5 ), 682–688. 10.1016/j.jtho.2018.02.022 [ PubMed ] [ CrossRef ] [ Google Scholar ]
Su S., Dong Z. Y., Xie Z., Yan L. X., Li Y. F., Su J., et al. (2018). Strong Programmed Death Ligand 1 Expression Predicts Poor Response and De Novo Resistance to EGFR Tyrosine Kinase Inhibitors Among NSCLC Patients with EGFR Mutation . J. Thorac. Oncol. 13 ( 11 ), 1668–1675. 10.1016/j.jtho.2018.07.016 [ PubMed ] [ CrossRef ] [ Google Scholar ]
Sung H., Ferlay J., Siegel R. L., Laversanne M., Soerjomataram I., Jemal A., et al. (2021). Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries . CA A Cancer J. Clin. 71 ( 3 ), 209–249. 10.3322/caac.21660 [ PubMed ] [ CrossRef ] [ Google Scholar ]
Tanizaki J., Okamoto I., Okabe T., Sakai K., Tanaka K., Hayashi H., et al. (2012). Activation of HER Family Signaling as a Mechanism of Acquired Resistance to ALK Inhibitors in EML4-ALK-Positive Non-small Cell Lung Cancer . Clin. Cancer Res. 18 ( 22 ), 6219–6226. 10.1158/1078-0432.CCR-12-0392 [ PubMed ] [ CrossRef ] [ Google Scholar ]
Thress K. S., Paweletz C. P., Felip E., Cho B. C., Stetson D., Dougherty B., et al. (2015). Acquired EGFR C797S Mutation Mediates Resistance to AZD9291 in Non-small Cell Lung Cancer Harboring EGFR T790M . Nat. Med. 21 ( 6 ), 560–562. 10.1038/nm.3854 [ PMC free article ] [ PubMed ] [ CrossRef ] [ Google Scholar ]
Tu L., Guan R., Yang H., Zhou Y., Hong W., Ma L., et al. (2020). Assessment of the Expression of the Immune Checkpoint Molecules PD-1, CTLA4, TIM-3 and LAG-3 across Different Cancers in Relation to Treatment Response, Tumor-Infiltrating Immune Cells and Survival . Int. J. Cancer 147 ( 2 ), 423–439. 10.1002/ijc.32785 [ PubMed ] [ CrossRef ] [ Google Scholar ]
Uchida T., Kaira K., Yamaguchi O., Mouri A., Shiono A., Miura Y., et al. (2019). Different Incidence of Interstitial Lung Disease According to Different Kinds of EGFR-Tyrosine Kinase Inhibitors Administered Immediately before And/or after Anti-PD-1 Antibodies in Lung Cancer . Thorac. Cancer 10 ( 4 ), 975–979. 10.1111/1759-7714.13039 [ PMC free article ] [ PubMed ] [ CrossRef ] [ Google Scholar ]
Wang J., Lu S., Yu X., Hu Y., Sun Y., Wang Z., et al. (2021). Tislelizumab Plus Chemotherapy vs Chemotherapy Alone as First-Line Treatment for Advanced Squamous Non-small-cell Lung Cancer: A Phase 3 Randomized Clinical Trial . JAMA Oncol. 7 ( 5 ), 709–717. 10.1001/jamaoncol.2021.0366 [ PMC free article ] [ PubMed ] [ CrossRef ] [ Google Scholar ]
Wang S., Song Y., Liu D. (2017). EAI045: The Fourth-Generation EGFR Inhibitor Overcoming T790M and C797S Resistance . Cancer Lett. 385 , 51–54. 10.1016/j.canlet.2016.11.008 [ PubMed ] [ CrossRef ] [ Google Scholar ]
Wu Y. L., Cheng Y., Zhou X., Lee K. H., Nakagawa K., Niho S., et al. (2017). Dacomitinib versus Gefitinib as First-Line Treatment for Patients with EGFR-Mutation-Positive Non-small-cell Lung Cancer (ARCHER 1050): a Randomised, Open-Label, Phase 3 Trial . Lancet Oncol. 18 ( 11 ), 1454–1466. 10.1016/S1470-2045(17)30608-3 [ PubMed ] [ CrossRef ] [ Google Scholar ]
Wu Y. L., Zhou C., Liam C. K., Wu G., Liu X., Zhong Z., et al. (2015). First-line Erlotinib versus Gemcitabine/cisplatin in Patients with Advanced EGFR Mutation-Positive Non-small-cell Lung Cancer: Analyses from the Phase III, Randomized, Open-Label, ENSURE Study . Ann. Oncol. 26 ( 9 ), 1883–1889. 10.1093/annonc/mdv270 [ PubMed ] [ CrossRef ] [ Google Scholar ]
Yamada T., Hirai S., Katayama Y., Yoshimura A., Shiotsu S., Watanabe S., et al. (2019). Retrospective Efficacy Analysis of Immune Checkpoint Inhibitors in Patients with EGFR-Mutated Non-small Cell Lung Cancer . Cancer Med. 8 ( 4 ), 1521–1529. 10.1002/cam4.2037 [ PMC free article ] [ PubMed ] [ CrossRef ] [ Google Scholar ]
Yang J. C., Shepherd F. A., Kim D. W., Lee G. W., Lee J. S., Chang G. C., et al. (2019). Osimertinib Plus Durvalumab versus Osimertinib Monotherapy in EGFR T790M-Positive NSCLC Following Previous EGFR TKI Therapy: CAURAL Brief Report . J. Thorac. Oncol. 14 ( 5 ), 933–939. 10.1016/j.jtho.2019.02.001 [ PubMed ] [ CrossRef ] [ Google Scholar ]
Yang J. C., Wu Y. L., Schuler M., Sebastian M., Popat S., Yamamoto N., et al. (2015). Afatinib versus Cisplatin-Based Chemotherapy for EGFR Mutation-Positive Lung Adenocarcinoma (LUX-Lung 3 and LUX-Lung 6): Analysis of Overall Survival Data from Two Randomised, Phase 3 Trials . Lancet Oncol. 16 ( 2 ), 141–151. 10.1016/S1470-2045(14)71173-8 [ PubMed ] [ CrossRef ] [ Google Scholar ]
Yoshida H., Kim Y. H., Ozasa H., Nagai H., Sakamori Y., Tsuji T., et al. (2018). Nivolumab in Non-small-cell Lung Cancer with EGFR Mutation . Ann. Oncol. 29 ( 3 ), 777–778. 10.1093/annonc/mdx745 [ PubMed ] [ CrossRef ] [ Google Scholar ]
Yy A., Zw B., Jian F. C., Qy D., Bh E., Sc F., et al. (2020). Efficacy and Safety of Sintilimab Plus Pemetrexed and Platinum as First-Line Treatment for Locally Advanced or Metastatic Nonsquamous NSCLC: a Randomized, Double-Blind, Phase 3 Study (Oncology pRogram by InnovENT Anti-PD-1-11) - ScienceDirect . J. Thorac. Oncol. 15 ( 10 ), 1636–1646. [ PubMed ] [ Google Scholar ]
Zhang B., Zhang Y., Zhao J., Wang Z., Wu T., Ou W., et al. (2014). M2-polarized Macrophages Contribute to the Decreased Sensitivity of EGFR-TKIs Treatment in Patients with Advanced Lung Adenocarcinoma . Med. Oncol. 31 ( 8 ), 127–128. 10.1007/s12032-014-0127-0 [ PubMed ] [ CrossRef ] [ Google Scholar ]
Zhou C., Chen G., Huang Y., Zhou J., Lin L., Feng J., et al. (2021a). Camrelizumab Plus Carboplatin and Pemetrexed versus Chemotherapy Alone in Chemotherapy-Naive Patients with Advanced Non-squamous Non-small-cell Lung Cancer (CameL): a Randomised, Open-Label, Multicentre, Phase 3 Trial . Lancet Respir. Med. 9 ( 3 ), 305–314. 10.1016/S2213-2600(20)30365-9 [ PubMed ] [ CrossRef ] [ Google Scholar ]
Zhou C., Wu Y. L., Chen G., Feng J., Liu X. Q., Wang C., et al. (2011). Erlotinib versus Chemotherapy as First-Line Treatment for Patients with Advanced EGFR Mutation-Positive Non-small-cell Lung Cancer (OPTIMAL, CTONG-0802): a Multicentre, Open-Label, Randomised, Phase 3 Study . Lancet Oncol. 12 ( 8 ), 735–742. 10.1016/S1470-2045(11)70184-X [ PubMed ] [ CrossRef ] [ Google Scholar ]
Zhou C., Ren S., Chen J., Xu X., Cheng Y., Chen G., et al. (2021b). 96O Camrelizumab or Placebo Plus Carboplatin and Paclitaxel as First-Line Treatment for Advanced Squamous NSCLC (CameL-Sq): A Randomized, Double-Blind, Multicenter, Phase III Trial . J. Thorac. Oncol. 16 ( 4 ), S748. 10.1016/s1556-0864(21)01938-9 [ PubMed ] [ CrossRef ] [ Google Scholar ]
Zhou C., Wu L., Fan Y., Wang Z., Liu L., Chen G., et al. (2020). LBA56 ORIENT-12: Sintilimab Plus Gemcitabine and Platinum (GP) as First-Line (1L) Treatment for Locally Advanced or Metastatic Squamous Non-small-cell Lung Cancer (sqNSCLC) . Ann. Oncol. 31 , S1186. 10.1016/j.annonc.2020.08.2289 [ CrossRef ] [ Google Scholar ]

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