Figures
- FIGURE 1
PRISMA flow diagram.
- FIGURE 2
Numbers representing European Medicines Agency approved drugs within their substance class in lung oncology. Blue: chemotherapy (CT); green: targeted agents (tyrosine kinase inhibitors); red: VEGF-inhibitors; yellow: immune checkpoint inhibitors. VEGF: vascular endothelial growth factor.
- FIGURE 3
Correlation of sample size and date of publication regarding approved combinations (blue line and squares), TKIs (orange line and triangles) and single drugs except TKIs (green line and dots). The black line shows the correlation of sample size and date for all approved drugs and combinations. TKI trimmed (red line): shows data without the two first trials for erlotinib and gefitinib [18, 20]. TKI: tyrosine kinase inhibitor.
- FIGURE 4
Time intervals between the publications of linked phase I and phase III trials. Correlation coefficient r= −0.82303; p=0.00001. Estimated rate over time shown along with a 95% credible region.
Tables
- TABLE 1
Approved drugs in lung oncology, 2000–2020
Chemical name Line of therapy Phase I trial
(first author [ref.])Trial leading to approval (first author [ref.]) Sample size EMA approval date Approval trial phase Histology Class Monoclonal antibody Route of administration Primary end-point trial leading to approval Docetaxel Second Extra [13] Shepherd [14] n=103 6 February 2000 III NSCLC Chemotherapy No i.v. MOS Pemetrexed Second McDonald [15] Hanna [16] n=571 22 September 2004 III nsNSCLC# Chemotherapy No i.v. MOS Erlotinib Second Hidalgo [17] Shepherd [18] n=731 27 June 2005 III NSCLC Targeted agent¶ No Oral MOS Gefitinib Any Baselga [19] Mok [20] n=1217 1 July 2009 III nsNSCLC Targeted agent No Oral PFS Erlotinib First Hidalgo [17] Rosell [21] n=174 1 November 2011 III nsNSCLC Targeted agent No Oral PFS Crizotinib Second Kwak [22] Shaw [11] n=347 24 October 2012 III ROS1/ALK+NSCLC+ Targeted agent No Oral PFS Afatinib First Yap [23] Sequist [24] n=345 25 September 2013 III EGFR+nsNSCLC Targeted agent No Oral PFS Ceritinib Second Shaw [25] Shaw [26] n=231 8 May 2015 III ALK+NSCLC Targeted agent No Oral PFS Nivolumab Second Brahmer [27] Brahmer [28] n=272 20 July 2015 III SqNSCLC Immune checkpoint Yes i.v. MOS Crizotinib First Kwak [22] Solomon [29] n=343 24 November 2015 III ROS1/ALK+NSCLC+ Targeted agent No Oral PFS Osimertinib Second Cross [30] Mok [31] n=419 3 February 2016 III EGFR M+NSCLC Targeted agent No Oral PFS Nivolumab Second Brahmer [27] Borghaei [32] n=582 6 April 2016 III nsNSCLC Immune checkpoint Yes i.v. MOS Afatinib Second Yap [23] Thongprasert [33] n=60 7 April 2016 III EGFR+NSCLC Targeted agent No Oral ORR Pembrolizumab Second Garon [34] Herbst [35] n=1034 2 August 2016 III PD-L1 >1%+NSCLC Immune checkpoint Yes i.v. MOS PFS§ Pembrolizumab First Garon [34] Reck [36] n=305 31 January 2017 III PD-L1 >50% NSCLC Immune checkpoint Yes i.v. PFS Alectinib Second Seto [37] Shaw [38] n=87 21 February 2017 II ALK+NSCLC Targeted agent No Oral ORR Dabrafenib/trametinib Any Falchook [39] Planchard [40] n=36 3 April 2017 II BRAf V600E+NSCLC Targeted agent No Oral ORR Atezolizumab Second Herbst [41] Rittmeyer [42] n=1125 22 September 2017 III NSCLC Immune checkpoint Yes i.v. MOSƒ Alectinib First Seto [37] Peters [43] n=303 21 December 2017 III ALK+NSCLC Targeted agent No Oral PFS Osimertinib First Cross [30] Soria [44] n=556 8 June 2018 III EGFR M+NSCLC Targeted agent No Oral PFS Durvalumab Consolidation Antonia [45] Antonia [46] n=709 27 July 2018 III NSCLC Immune checkpoint Yes i.v. MOS PFS§ Brigatinib Second Gettinger [47] Camidge [48] n=275 27 November 2018 III ALK+ NSCLC Targeted agent No Oral PFS Dacomitinib First Takahashi [49] Wu [50] n=452 3 April 2019 III EGFR M+NSCLC Targeted agent No Oral PFS Lorlatinib Second Shaw [51] Solomon [52] n=276 7 May 2019 II ALK+NSCLC Targeted agent No Oral ORRƒ Larotrectinib Any Drilon [53] Drilon [53] n=55 23 September 2019 II NTRK+NSCLC Targeted agent No Oral ORR Brigatinib First Gettinger [47] Hubert [54] n=222 6 April 2020 III ALK+ NSCLC Targeted agent No Oral ORR #: first approval was granted for any NSCLC but after subgroup analyses of three trials employing pemetrexed the approval was restricted to nsNSCLC for lack of efficiency in squamous NSCLC [62]. ¶: although later approved as a targeted agent, the drug was first approved for any NSCLC without any mandatory companion diagnostic to detect a targetable mutation.
+: Pfizer [55].
§: for details please refer to full publication as alpha was split applying different statistical plans. ƒ: and intracranial tumour response. EMA: European Medicines Agency; NSCLC: nonsmall cell lung cancer; MOS: median overall survival; nsNSCLC: nonsquamous nonsmall cell lung cancer; PFS: progression free survival; ALK: anaplastic lymphoma kinase; EGFR: epidermal growth factor receptor; SqNSCLC: squamous nonsmall cell lung cancer; EGFR M+NSCLC: EGFR mutation positive NSCLC; ORR: objective response rate according to RECIST 1.1
- TABLE 2
Approved drug combinations in lung oncology, 2000–2020
Chemical name Line of therapy Phase I Trial leading to approval Sample size EMA approval date Approval trial phase Histology Class Monoclonal antibody Route of administration Primary end-point trial leading to approval Bevacizumab/paclitaxel/carboplatin First Willett (Phase I) [56]; Johnson (Phase II) [57] Sandler [58] n=878 23 August 2007 III nsNSCLC Targeted agent Yes i.v. MOS Pemetrexed/cisplatin First Thödtmann [59] Scagliotti [60] n=1725 28 October 2011 III nsNSCLC CT/CT No i.v. MOS Nintedanib/docetaxel Second Mross [61] Reck [62] n=1324 27 November 2014 III nsNSCLC Targeted agent No Oral PFS nabPaclitaxel/carboplatin First Rizvi [63] Socinski [64] n=1052 2 March 2015 III SqNSCLC Chemotherapy No i.v. ORR Docetaxel/ramucirumab Second Spratlin [65] Garon [66] n=1825 28 January 2016 III nsNSCLC Targeted agent Yes i.v. MOS Gemcitabine/cisplatin/necitumumab First Kuenen [67] Thatcher [68] n=1093 24 February 2016 III SqNSCLC Targeted agent Yes i.v. MOS Pembrolizumab/(nab)Paclitaxel/carboplatin First Gadgeel [69] Paz-Ares [70] n=559 14 March 2019 III SqNSCLC ICP/CT/CT Yes i.v. MOS PFS Pembrolizumab/pemetrexed/platin First Gadgeel [69] Gandhi [71] n=616 15 March 2019 III nsNSCLC ICP/CT/CT Yes i.v. MOS PFS Atezolizumab/carboplatin/etoposide First Horn [72] Horn [72] n=403 6 September 2019 III SCLC ICP/CT/CT Yes i.v. MOS PFS Atezolizumab/nab-Paclitaxel/carboplatin First Liu [73] West [74] n=723 6 September 2019 III nsNSCLC ICP/CT/CT Yes i.v. MOS PFS Atezolizumab/paclitaxel/carboplatin/bevacizumab First Liu [73] Socinski [75] n=692 6 September 2019 III nsNSCLC ICP/CT/CT/TA Yes i.v. MOS PFS EMA: European Medicines Agency; nsNSCLC: nonsquamous nonsmall cell lung cancer; MOS: median overall survival; CT: chemotherapy; PFS: progression free survival; SqNSCLC: squamous nonsmall cell lung cancer; ORR: objective response rate; ICP: immune checkpoint; SCLC: small cell lung cancer; TA: targeted agent
Supplementary Material
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Supplementary_tables ERR-0300-2020_supplementary_tables
