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.	MOS^ƒ
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	ORR^ƒ
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