- Email: [email protected]
Symptomatic leptomeningeal metastasis improvement with nivolumab in advanced non-small cell lung cancer patient
Lung Cancer 108 (2017) 72–74
Contents lists available at ScienceDirect
Lung Cancer journal homepage: www.elsevier.com/locate/lungcan
Case reports
Symptomatic leptomeningeal metastasis improvement with nivolumab in advanced non-small cell lung cancer patient Maria Gion a,b , Jordi Remon a , Caroline Caramella c , Jean-Charles Soria a,d , Benjamin Besse a,d,∗ a
Department of Cancer Medicine, Gustave Roussy, Villejuif, France Hospital Ramon y Cajal, Madrid, Spain c Radiology Department, Gustave Roussy Cancer Campus, Villejuif, France d University Paris-Sud, Orsay, France b
a r t i c l e
i n f o
Article history: Received 6 January 2017 Received in revised form 12 February 2017 Accepted 25 February 2017 Keywords: Nivolumab Lung cancer Meningeal carcinomatosis
a b s t r a c t Leptomeningeal metastasis (LM) is reported in 3.8% of non-small-cell lung cancer (NSCLC) patients, more frequently in adenocarcinoma, and it correlates with poor prognosis. Data regarding the activity of immune checkpoint inhibitors in LM is lacking. We present a case report about the efficacy of nivolumab in a patient with advanced NSCLC and symptomatic LM. © 2017 Elsevier B.V. All rights reserved.
1. Clinical report A 54-year-old male, ex-smoker of 35 pack-years with ECOG performance status (PS) 1 was diagnosed in November 2014 with advanced lung adenocarcinoma T2 N2 M1b (brain metastasis and meningeal carcinomatosis, cytologically-confirmed without radiological evidence in a brain MRI Figs. 1 and 2). Neurologic symptoms related to meningeal carcinomatosis included auditory hallucinations, bilateral facial paralysis, and deafness. Molecular profiling revealed a KRAS mutation (G12C) and a polymorphism in exon 20 of the EGFR gene. No other oncogenic driver mutations were detected. Systemic steroids and seven injections of intrathecal methotrexate and intrathecal steroids (twice weekly) were administrated over January and February. Sequential systemic treatment with carboplatin/pemetrexed was prescribed. After four cycles; stable disease was seen by CT-scan and clinical neurologic improvement was observed. Pemetrexed maintenance treatment was initiated in May 2015 along with systemic steroids withdrawn.
∗ Corresponding author at: University Paris-Sud Orsay and Gustave Roussy Cancer Campus, 114 Rue Edouard Vaillant, 94805 Villejuif, France. Tel.: +33 0142114322; fax: +33 0142115219. E-mail addresses: [email protected] (M. Gion), [email protected] (J. Remon), [email protected] (C. Caramella), [email protected] (J.-C. Soria), [email protected] (B. Besse). http://dx.doi.org/10.1016/j.lungcan.2017.02.022 0169-5002/© 2017 Elsevier B.V. All rights reserved.
In July 2015, after three pemetrexed cycles, a CT-scan showed disease progression in the liver and the patient experienced worsening neurologic symptoms (auditory hallucinations) without brain progression in CT-scan or worsening in PS. The patient was taken off steroids. Second-line treatment with nivolumab was initiated in August 2015. No tissue was available to determine PD-L1 status. After two infusions, meaningful improvement of neurologic symptoms was observed, with disappearance of auditory hallucinations. No nivolumab side effects were reported and steroids were not used during nivolumab treatment. In February 2016, after seven months of treatment, the patient experienced worsening of neurologic symptoms with brain progression by MRI (Fig. 2), and liver and lung progression by CT-scan. Third-line treatment with carboplatin/paclitaxel was initiated with a partial response after four cycles and clinical neurologic improvement. No whole brain radiotherapy was administered as no brain progression was observed. Leptomeningeal metastasis (LM) reflects multifocal seeding of the leptomeninges by malignant cells from a solid tumour. They often lead to deteriorate neurologic and neurocognitive function and are associated with significant morbidity. LM is reported in 3.8% of non-small-cell lung cancer (NSCLC) patients, more frequently adenocarcinoma. Incidence reaches up to 5 and 9% in ALK-rearranged and EGFR-mutant NSCLC patients, respectively. Prognosis remains poor with median survival from 3.6 to 11 months [1,2]. Diagnosis of LM is based on three assessments types: clinical, imaging and cerebral-spinal fluid (CSF) cytological examinations. In current trials, diagnosis is based on the identification of malig-
M. Gion et al. / Lung Cancer 108 (2017) 72–74
73
Fig. 1. Brain MRI on November 2014. MRI sequence T1W after injection of contrast sequence T2W FLAIR showing parietal brain metastasis. No evidence of leptomeningeal carcinomatosis was observed.
Fig. 2. Brain MRI in November 2014 (A) and in February 2016 (B).
nant cells in the CSF, or in absence of its identification based on suggestive clinical and imaging findings [3]. A normal MRI does not rule out LM [4], and it can occur in up to 20% of cases [5]. Despite a normal or partial disrupted blood–brain-barrier in leptomeningeal disease, standard systemic or intrathecal
chemotherapy [6] shows limited efficacy. Methotrexate is the most used drug for intrathecal chemotherapy, although its efficacy has not been established in randomized clinical trials [6]. For molecularly-selected NSCLC patients, personalized treatment is an independent predictive factor of extended survival in patients
74
M. Gion et al. / Lung Cancer 108 (2017) 72–74
with LM [2]. Response evaluation in LM is a challenge, with lack of standardization with respect to response criteria (clinical, neuroimaging, and CSF analysis) in clinical trials [4]. Recently, the Response Assessment in Neuro-Oncology (RANO) LM working group critically re-evaluated the endpoints and response criteria across published randomized studies. Based on this preliminary work, the group has proposed three basic elements in assessing response in LM: a standardized neurological examination, CSF cytology or flow cytometry, and radiologic evaluation. However, this instrument will require prospective validation [7]. Four randomized phase III trials [8–11] reported significant improvement in overall survival with immunotherapy agents (nivolumab, pembrolizumab, and atezolizumab) compared to docetaxel as second-line treatment in advanced NSCLC. A recent phase II [12] study reported a cerebral response of 33% with pembrolizumab (anti-PD-1 antibody) in PD-L1-positive NSCLC patients with untreated or progressive asymptomatic brain metastases between 5 and 20 mm in diameter, with a duration of response of more than six months. However, effectiveness of immune checkpoint inhibitors in symptomatic LM is unknown and moreover, its safety is of concern given the potential flare-up effect at treatment initiation [13]. Stabilization of asymptomatic LM for 10 weeks with nivolumab was recently reported in one patient [14]. However, neither CSF fluid concentration of these compounds or its efficacy as intrathecal treatment remains unknown. Moreover, the optimal sequence of treatment combining immune checkpoint inhibitors and radiotherapy in patients with cerebral nervous system (CNS) metastases is a future challenge in cancer patients. Also, differences in intracranial activity of immune checkpoint inhibitors according to molecular alterations would be of interest. This report managing symptomatic leptomeningeal metastasis with nivolumab in an NSCLC patient supports its efficacy and safety in this lung cancer population without previous CNS radiotherapy. This finding should be validated in a prospective trial. Conflicts of interests The authors did not have any conflict of interest. This research did not receive any specific grant from funding agencies in the public commercial, or not-for-profit sectors. References [1] S. Umemura, K. Tsubouchi, H. Yoshioka, K. Hotta, N. Takigawa, K. Fujiwara, N. Horita, Y. Segawa, N. Hamada, I. Takata, H. Yamane, H. Kamei, K. Kiura, M. Tanimoto, Clinical outcome in patients with leptomeningeal metastasis from non-small cell lung cancer: Okayama lung cancer study group, Lung Cancer 77 (2012) 134–139, http://dx.doi.org/10.1016/j.lungcan.2012.03.002. [2] B.-C. Liao, J.-H. Lee, C.-C. Lin, Y.-F. Chen, C.-H. Chang, C.-C. Ho, J.-Y. Shih, C.-J. Yu, J.C.-H. Yang, Epidermal growth factor receptor tyrosine kinase inhibitors for non-small-cell lung cancer patients with leptomeningeal carcinomatosis, J. Thorac. Oncol. 10 (2015) 1754–1761, http://dx.doi.org/10.1097/JTO. 0000000000000669. [3] M.C. Chamberlain, Leptomeningeal metastasis, Curr. Opin. Oncol. 22 (2010) 627–635, http://dx.doi.org/10.1097/CCO.0b013e32833e986.
[4] M. Chamberlain, R. Soffietti, J. Raizer, R. Rudà, D. Brandsma, W. Boogerd, S. Taillibert, M.D. Groves, E. Le Rhun, L. Junck, M. van den Bent, P.Y. Wen, K.A. Jaeckle, Leptomeningeal metastasis: a response assessment in neuro-oncology critical review of endpoints and response criteria of published randomized clinical trials, Neuro-Oncol. 16 (2014) 1176–1185, http://dx.doi.org/10.1093/neuonc/nou089. [5] J.-W. Hyun, I.H. Jeong, A. Joung, H.J. Cho, S.-H. Kim, H.J. Kim, Leptomeningeal metastasis: clinical experience of 519 cases, Eur. J. Cancer 56 (2016) 107–114, http://dx.doi.org/10.1016/j.ejca.2015.12.021. [6] E. Le Rhun, S. Taillibert, M.C. Chamberlain, Carcinomatous meningitis: leptomeningeal metastases in solid tumors, Surg. Neurol. Int. 4 (2013) S265–S288, http://dx.doi.org/10.4103/2152-7806.111304. [7] M. Chamberlain, L. Junck, D. Brandsma, R. Soffietti, R. Rudà, J. Raizer, W. Boogerd, S. Taillibert, M.D. Groves, E.L. Rhun, J. Walker, M. van den Bent, P.Y. Wen, K.A. Jaeckle, Leptomeningeal metastases: a RANO proposal for response criteria, Neuro Oncol. (2016), http://dx.doi.org/10.1093/neuonc/now183. [8] J. Brahmer, K.L. Reckamp, P. Baas, L. Crinò, W.E.E. Eberhardt, E. Poddubskaya, S. Antonia, A. Pluzanski, E.E. Vokes, E. Holgado, D. Waterhouse, N. Ready, J. Gainor, O. Arén Frontera, L. Havel, M. Steins, M.C. Garassino, J.G. Aerts, M. Domine, L. Paz-Ares, M. Reck, C. Baudelet, C.T. Harbison, B. Lestini, D.R. Spigel, Nivolumab versus docetaxel in advanced squamous-cell non-small-cell lung cancer, N. Engl. J. Med. 373 (2015) 123–135, http://dx.doi.org/10.1056/ NEJMoa1504627. [9] H. Borghaei, L. Paz-Ares, L. Horn, D.R. Spigel, M. Steins, N.E. Ready, L.Q. Chow, E.E. Vokes, E. Felip, E. Holgado, F. Barlesi, M. Kohlhäufl, O. Arrieta, M.A. Burgio, J. Fayette, H. Lena, E. Poddubskaya, D.E. Gerber, S.N. Gettinger, C.M. Rudin, N. Rizvi, L. Crinò, G.R. Blumenschein, S.J. Antonia, C. Dorange, C.T. Harbison, F. Graf Finckenstein, J.R. Brahmer, Nivolumab versus docetaxel in advanced nonsquamous non-small-cell lung cancer, N. Engl. J. Med. (2015), http://dx. doi.org/10.1056/NEJMoa1507643. [10] R.S. Herbst, P. Baas, D.-W. Kim, E. Felip, J.L. Pérez-Gracia, J.-Y. Han, J. Molina, J.-H. Kim, C.D. Arvis, M.-J. Ahn, M. Majem, M.J. Fidler, G. de Castro, M. Garrido, G.M. Lubiniecki, Y. Shentu, E. Im, M. Dolled-Filhart, E.B. Garon, Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomised controlled trial, Lancet 387 (2016) 1540–1550, http://dx.doi.org/10.1016/ S0140-6736(15)01281-7. [11] A. Rittmeyer, F. Barlesi, D. Waterkamp, K. Park, F. Ciardiello, J. von Pawel, S.M. Gadgeel, T. Hida, D.M. Kowalski, M.C. Dols, D.L. Cortinovis, J. Leach, J. Polikoff, C. Barrios, F. Kabbinavar, O.A. Frontera, F. De Marinis, H. Turna, J.-S. Lee, M. Ballinger, M. Kowanetz, P. He, D.S. Chen, A. Sandler, D.R. Gandara, OAK Study Group, Atezolizumab versus docetaxel in patients with previously treated non-small-cell lung cancer (OAK): a phase 3, open-label, multicentre randomised controlled trial, Lancet (2016), http://dx.doi.org/10.1016/S01406736(16)32517-X. [12] S.B. Goldberg, S.N. Gettinger, A. Mahajan, A.C. Chiang, R.S. Herbst, M. Sznol, A.J. Tsiouris, J. Cohen, A. Vortmeyer, L. Jilaveanu, J. Yu, U. Hegde, S. Speaker, M. Madura, A. Ralabate, A. Rivera, E. Rowen, H. Gerrish, X. Yao, V. Chiang, H.M. Kluger, Pembrolizumab for patients with melanoma or non-small-cell lung cancer and untreated brain metastases: early analysis of a non-randomised, open-label, phase 2 trial, Lancet Oncol. 17 (2016) 976–983, http://dx.doi.org/ 10.1016/S1470-2045(16)30053-5. [13] M.K. Doherty, K. Jao, F.A. Shepherd, L.-N. Hazrati, N.B. Leighl, Central nervous system pseudoprogression in a patient treated with PD-1 checkpoint inhibitor, J. Thorac. Oncol. 10 (2015) e100–e101, http://dx.doi.org/10.1097/ JTO.0000000000000587. [14] E. Dudnik, S. Yust-Katz, H. Nechushtan, D.A. Goldstein, A. Zer, D. Flex, T. Siegal, N. Peled, Intracranial response to nivolumab in NSCLC patients with untreated or progressing CNS metastases, Lung Cancer 98 (2016) 114–117, http://dx.doi. org/10.1016/j.lungcan.2016.05.031.
Contents lists available at ScienceDirect
Lung Cancer journal homepage: www.elsevier.com/locate/lungcan
Case reports
Symptomatic leptomeningeal metastasis improvement with nivolumab in advanced non-small cell lung cancer patient Maria Gion a,b , Jordi Remon a , Caroline Caramella c , Jean-Charles Soria a,d , Benjamin Besse a,d,∗ a
Department of Cancer Medicine, Gustave Roussy, Villejuif, France Hospital Ramon y Cajal, Madrid, Spain c Radiology Department, Gustave Roussy Cancer Campus, Villejuif, France d University Paris-Sud, Orsay, France b
a r t i c l e
i n f o
Article history: Received 6 January 2017 Received in revised form 12 February 2017 Accepted 25 February 2017 Keywords: Nivolumab Lung cancer Meningeal carcinomatosis
a b s t r a c t Leptomeningeal metastasis (LM) is reported in 3.8% of non-small-cell lung cancer (NSCLC) patients, more frequently in adenocarcinoma, and it correlates with poor prognosis. Data regarding the activity of immune checkpoint inhibitors in LM is lacking. We present a case report about the efficacy of nivolumab in a patient with advanced NSCLC and symptomatic LM. © 2017 Elsevier B.V. All rights reserved.
1. Clinical report A 54-year-old male, ex-smoker of 35 pack-years with ECOG performance status (PS) 1 was diagnosed in November 2014 with advanced lung adenocarcinoma T2 N2 M1b (brain metastasis and meningeal carcinomatosis, cytologically-confirmed without radiological evidence in a brain MRI Figs. 1 and 2). Neurologic symptoms related to meningeal carcinomatosis included auditory hallucinations, bilateral facial paralysis, and deafness. Molecular profiling revealed a KRAS mutation (G12C) and a polymorphism in exon 20 of the EGFR gene. No other oncogenic driver mutations were detected. Systemic steroids and seven injections of intrathecal methotrexate and intrathecal steroids (twice weekly) were administrated over January and February. Sequential systemic treatment with carboplatin/pemetrexed was prescribed. After four cycles; stable disease was seen by CT-scan and clinical neurologic improvement was observed. Pemetrexed maintenance treatment was initiated in May 2015 along with systemic steroids withdrawn.
∗ Corresponding author at: University Paris-Sud Orsay and Gustave Roussy Cancer Campus, 114 Rue Edouard Vaillant, 94805 Villejuif, France. Tel.: +33 0142114322; fax: +33 0142115219. E-mail addresses: [email protected] (M. Gion), [email protected] (J. Remon), [email protected] (C. Caramella), [email protected] (J.-C. Soria), [email protected] (B. Besse). http://dx.doi.org/10.1016/j.lungcan.2017.02.022 0169-5002/© 2017 Elsevier B.V. All rights reserved.
In July 2015, after three pemetrexed cycles, a CT-scan showed disease progression in the liver and the patient experienced worsening neurologic symptoms (auditory hallucinations) without brain progression in CT-scan or worsening in PS. The patient was taken off steroids. Second-line treatment with nivolumab was initiated in August 2015. No tissue was available to determine PD-L1 status. After two infusions, meaningful improvement of neurologic symptoms was observed, with disappearance of auditory hallucinations. No nivolumab side effects were reported and steroids were not used during nivolumab treatment. In February 2016, after seven months of treatment, the patient experienced worsening of neurologic symptoms with brain progression by MRI (Fig. 2), and liver and lung progression by CT-scan. Third-line treatment with carboplatin/paclitaxel was initiated with a partial response after four cycles and clinical neurologic improvement. No whole brain radiotherapy was administered as no brain progression was observed. Leptomeningeal metastasis (LM) reflects multifocal seeding of the leptomeninges by malignant cells from a solid tumour. They often lead to deteriorate neurologic and neurocognitive function and are associated with significant morbidity. LM is reported in 3.8% of non-small-cell lung cancer (NSCLC) patients, more frequently adenocarcinoma. Incidence reaches up to 5 and 9% in ALK-rearranged and EGFR-mutant NSCLC patients, respectively. Prognosis remains poor with median survival from 3.6 to 11 months [1,2]. Diagnosis of LM is based on three assessments types: clinical, imaging and cerebral-spinal fluid (CSF) cytological examinations. In current trials, diagnosis is based on the identification of malig-
M. Gion et al. / Lung Cancer 108 (2017) 72–74
73
Fig. 1. Brain MRI on November 2014. MRI sequence T1W after injection of contrast sequence T2W FLAIR showing parietal brain metastasis. No evidence of leptomeningeal carcinomatosis was observed.
Fig. 2. Brain MRI in November 2014 (A) and in February 2016 (B).
nant cells in the CSF, or in absence of its identification based on suggestive clinical and imaging findings [3]. A normal MRI does not rule out LM [4], and it can occur in up to 20% of cases [5]. Despite a normal or partial disrupted blood–brain-barrier in leptomeningeal disease, standard systemic or intrathecal
chemotherapy [6] shows limited efficacy. Methotrexate is the most used drug for intrathecal chemotherapy, although its efficacy has not been established in randomized clinical trials [6]. For molecularly-selected NSCLC patients, personalized treatment is an independent predictive factor of extended survival in patients
74
M. Gion et al. / Lung Cancer 108 (2017) 72–74
with LM [2]. Response evaluation in LM is a challenge, with lack of standardization with respect to response criteria (clinical, neuroimaging, and CSF analysis) in clinical trials [4]. Recently, the Response Assessment in Neuro-Oncology (RANO) LM working group critically re-evaluated the endpoints and response criteria across published randomized studies. Based on this preliminary work, the group has proposed three basic elements in assessing response in LM: a standardized neurological examination, CSF cytology or flow cytometry, and radiologic evaluation. However, this instrument will require prospective validation [7]. Four randomized phase III trials [8–11] reported significant improvement in overall survival with immunotherapy agents (nivolumab, pembrolizumab, and atezolizumab) compared to docetaxel as second-line treatment in advanced NSCLC. A recent phase II [12] study reported a cerebral response of 33% with pembrolizumab (anti-PD-1 antibody) in PD-L1-positive NSCLC patients with untreated or progressive asymptomatic brain metastases between 5 and 20 mm in diameter, with a duration of response of more than six months. However, effectiveness of immune checkpoint inhibitors in symptomatic LM is unknown and moreover, its safety is of concern given the potential flare-up effect at treatment initiation [13]. Stabilization of asymptomatic LM for 10 weeks with nivolumab was recently reported in one patient [14]. However, neither CSF fluid concentration of these compounds or its efficacy as intrathecal treatment remains unknown. Moreover, the optimal sequence of treatment combining immune checkpoint inhibitors and radiotherapy in patients with cerebral nervous system (CNS) metastases is a future challenge in cancer patients. Also, differences in intracranial activity of immune checkpoint inhibitors according to molecular alterations would be of interest. This report managing symptomatic leptomeningeal metastasis with nivolumab in an NSCLC patient supports its efficacy and safety in this lung cancer population without previous CNS radiotherapy. This finding should be validated in a prospective trial. Conflicts of interests The authors did not have any conflict of interest. This research did not receive any specific grant from funding agencies in the public commercial, or not-for-profit sectors. References [1] S. Umemura, K. Tsubouchi, H. Yoshioka, K. Hotta, N. Takigawa, K. Fujiwara, N. Horita, Y. Segawa, N. Hamada, I. Takata, H. Yamane, H. Kamei, K. Kiura, M. Tanimoto, Clinical outcome in patients with leptomeningeal metastasis from non-small cell lung cancer: Okayama lung cancer study group, Lung Cancer 77 (2012) 134–139, http://dx.doi.org/10.1016/j.lungcan.2012.03.002. [2] B.-C. Liao, J.-H. Lee, C.-C. Lin, Y.-F. Chen, C.-H. Chang, C.-C. Ho, J.-Y. Shih, C.-J. Yu, J.C.-H. Yang, Epidermal growth factor receptor tyrosine kinase inhibitors for non-small-cell lung cancer patients with leptomeningeal carcinomatosis, J. Thorac. Oncol. 10 (2015) 1754–1761, http://dx.doi.org/10.1097/JTO. 0000000000000669. [3] M.C. Chamberlain, Leptomeningeal metastasis, Curr. Opin. Oncol. 22 (2010) 627–635, http://dx.doi.org/10.1097/CCO.0b013e32833e986.
[4] M. Chamberlain, R. Soffietti, J. Raizer, R. Rudà, D. Brandsma, W. Boogerd, S. Taillibert, M.D. Groves, E. Le Rhun, L. Junck, M. van den Bent, P.Y. Wen, K.A. Jaeckle, Leptomeningeal metastasis: a response assessment in neuro-oncology critical review of endpoints and response criteria of published randomized clinical trials, Neuro-Oncol. 16 (2014) 1176–1185, http://dx.doi.org/10.1093/neuonc/nou089. [5] J.-W. Hyun, I.H. Jeong, A. Joung, H.J. Cho, S.-H. Kim, H.J. Kim, Leptomeningeal metastasis: clinical experience of 519 cases, Eur. J. Cancer 56 (2016) 107–114, http://dx.doi.org/10.1016/j.ejca.2015.12.021. [6] E. Le Rhun, S. Taillibert, M.C. Chamberlain, Carcinomatous meningitis: leptomeningeal metastases in solid tumors, Surg. Neurol. Int. 4 (2013) S265–S288, http://dx.doi.org/10.4103/2152-7806.111304. [7] M. Chamberlain, L. Junck, D. Brandsma, R. Soffietti, R. Rudà, J. Raizer, W. Boogerd, S. Taillibert, M.D. Groves, E.L. Rhun, J. Walker, M. van den Bent, P.Y. Wen, K.A. Jaeckle, Leptomeningeal metastases: a RANO proposal for response criteria, Neuro Oncol. (2016), http://dx.doi.org/10.1093/neuonc/now183. [8] J. Brahmer, K.L. Reckamp, P. Baas, L. Crinò, W.E.E. Eberhardt, E. Poddubskaya, S. Antonia, A. Pluzanski, E.E. Vokes, E. Holgado, D. Waterhouse, N. Ready, J. Gainor, O. Arén Frontera, L. Havel, M. Steins, M.C. Garassino, J.G. Aerts, M. Domine, L. Paz-Ares, M. Reck, C. Baudelet, C.T. Harbison, B. Lestini, D.R. Spigel, Nivolumab versus docetaxel in advanced squamous-cell non-small-cell lung cancer, N. Engl. J. Med. 373 (2015) 123–135, http://dx.doi.org/10.1056/ NEJMoa1504627. [9] H. Borghaei, L. Paz-Ares, L. Horn, D.R. Spigel, M. Steins, N.E. Ready, L.Q. Chow, E.E. Vokes, E. Felip, E. Holgado, F. Barlesi, M. Kohlhäufl, O. Arrieta, M.A. Burgio, J. Fayette, H. Lena, E. Poddubskaya, D.E. Gerber, S.N. Gettinger, C.M. Rudin, N. Rizvi, L. Crinò, G.R. Blumenschein, S.J. Antonia, C. Dorange, C.T. Harbison, F. Graf Finckenstein, J.R. Brahmer, Nivolumab versus docetaxel in advanced nonsquamous non-small-cell lung cancer, N. Engl. J. Med. (2015), http://dx. doi.org/10.1056/NEJMoa1507643. [10] R.S. Herbst, P. Baas, D.-W. Kim, E. Felip, J.L. Pérez-Gracia, J.-Y. Han, J. Molina, J.-H. Kim, C.D. Arvis, M.-J. Ahn, M. Majem, M.J. Fidler, G. de Castro, M. Garrido, G.M. Lubiniecki, Y. Shentu, E. Im, M. Dolled-Filhart, E.B. Garon, Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomised controlled trial, Lancet 387 (2016) 1540–1550, http://dx.doi.org/10.1016/ S0140-6736(15)01281-7. [11] A. Rittmeyer, F. Barlesi, D. Waterkamp, K. Park, F. Ciardiello, J. von Pawel, S.M. Gadgeel, T. Hida, D.M. Kowalski, M.C. Dols, D.L. Cortinovis, J. Leach, J. Polikoff, C. Barrios, F. Kabbinavar, O.A. Frontera, F. De Marinis, H. Turna, J.-S. Lee, M. Ballinger, M. Kowanetz, P. He, D.S. Chen, A. Sandler, D.R. Gandara, OAK Study Group, Atezolizumab versus docetaxel in patients with previously treated non-small-cell lung cancer (OAK): a phase 3, open-label, multicentre randomised controlled trial, Lancet (2016), http://dx.doi.org/10.1016/S01406736(16)32517-X. [12] S.B. Goldberg, S.N. Gettinger, A. Mahajan, A.C. Chiang, R.S. Herbst, M. Sznol, A.J. Tsiouris, J. Cohen, A. Vortmeyer, L. Jilaveanu, J. Yu, U. Hegde, S. Speaker, M. Madura, A. Ralabate, A. Rivera, E. Rowen, H. Gerrish, X. Yao, V. Chiang, H.M. Kluger, Pembrolizumab for patients with melanoma or non-small-cell lung cancer and untreated brain metastases: early analysis of a non-randomised, open-label, phase 2 trial, Lancet Oncol. 17 (2016) 976–983, http://dx.doi.org/ 10.1016/S1470-2045(16)30053-5. [13] M.K. Doherty, K. Jao, F.A. Shepherd, L.-N. Hazrati, N.B. Leighl, Central nervous system pseudoprogression in a patient treated with PD-1 checkpoint inhibitor, J. Thorac. Oncol. 10 (2015) e100–e101, http://dx.doi.org/10.1097/ JTO.0000000000000587. [14] E. Dudnik, S. Yust-Katz, H. Nechushtan, D.A. Goldstein, A. Zer, D. Flex, T. Siegal, N. Peled, Intracranial response to nivolumab in NSCLC patients with untreated or progressing CNS metastases, Lung Cancer 98 (2016) 114–117, http://dx.doi. org/10.1016/j.lungcan.2016.05.031.