Table 1 Representative clinical trials for targeted therapies in NSCLC

FLAURA

Treatment-naïve EGFR-mutant advanced NSCLC

Osimertinib

80

18.9

0.46 [0.37–0.57]

38.6

0.80 [0.64–1.00]

34

[11,12,13]

SoC (erlotnib or gefitinib)

76

10.2

31.8

45

FLAURA2

Treatment-naïve EGFR-mutant advanced NSCLC

Osimertinib + CT

83

29.4

0.62 [0.48–0.80]

^$79%

0.90 [0.65–1.24]

54

[22]

Osimertinib

76

19.9

^$73%

11

MARIPOSA

Treatment-naïve EGFR-mutant advanced NSCLC

Lazertinib + amivantamab

86

23.7

0.70 [0.58–0.85]

^$74%

0.80 [0.61–1.05]

75

[17]

Osimertinib

85

16.6

^$69%

43

INSIGHT2

Osimertinib-resistant EGFR-mutant NSCLC

Osimertinib + tepotinib

50

5.6

17.8

[15]

CHRYSALIS

Osimertinib-resistant EGFR-mutant NSCLC (combinational cohort)

Lazertinib + amivantamab

36

4.9

4

[137]

CHRYSALIS-2

NSCLC with uncommon EGFR mutations

[141]

 Total population

Lazertinib + amivantamab

52

11

 Treatment-naïve

Lazertinib + amivantamab

57

19.5

 TKI-pretreated

Lazertinib + amivantamab

48

7.8

PALMOMA-3

Osimertinib- and chemotherapy-pretreated EGFR-mutant advanced NSCLC

Lazertinib + amivantamab (s.c.)

Lazertinib + amivantamab (i.v.)

27

27

6.1

4.3

0.84 [0.64–1.10]

NR

NR

0.62 [0.42–0.92]

52

56

[142]

HARMONi-A

Osimertinib-resistant EGFR-mutant NSCLC

Ivonescimab + CT

Placebo + CT

50.6

35.4

7.1

4.8

61.5

49.1

[20]

ADAURA

Resectable early-stage EGFR-mutant NSCLC (≥ stage IB)

Osimertinib

Placebo

68.5

21.9

*85%

*73%

[24]

LAURA

Unresectable early-stage EGFR-mutant NSCLC

Osimertinib

Placebo

39.1

5.6

[34]

CodeBreaK100

KRAS^G12C-mutant advanced NSCLC refractory to CT and PD-1/PD-L1 Ab

Sotorasib

37.1

6.8

12.5

19.8

[36]

KRYSTAL-1

KRAS^G12C-mutant advanced NSCLC refractory to CT and PD-1/PD-L1 Ab

Adagrasib

42.9

6.5

12.6

44.8

[37]

CodeBreak200

KRAS^G12C-mutant advanced NSCLC refractory to CT and PD-1/PD-L1 Ab

Sotorasib

Docetaxel

28.1

13.2

5.6

4.5

10.6

11.3

33

40

[41]

KRYSTAL-12

KRAS^G12C-mutant advanced NSCLC refractory to CT and PD-1/PD-L1 Ab

Adagrasib

Docetaxel

31.9

9.2

5.5

3.8

47

45.7

[42]

CodeBreak100/101

KRAS G12C inhibitor-naïve KRAS^G12C-mutant advanced NSCLC

Sotorasib + atezolizumab (lead-in)

20

8.1

30

[43]

Sotorasib + atezolizumab (concurrent)

20

11.5

60

Sotorasib + pembrolizumab (lead-in)

37

NR

53

Sotorasib + pembrolizumab (concurrent)

32

14.1

79

CodeBreak 101

KRAS G12C inhibitor-naïve KRAS^G12C-mutant advanced NSCLC

[46]

 First-line

Sotorasib + CT

65

10.8

49

 Second-line

Sotorasib + CT

54

8.3

57

KRYSTAL-7

Treatment-naïve KRAS^G12C-mutant advanced NSCLC with PD-L1 ≥ 50%

Adagrasib + pembrolizumab

63

NR

5

[45]

GO42144

KRAS^G12C-mutant advanced NSCLC

Divarasib

56.4

13.1

18

[47]

CROWN

Treatment-naïve ALK-rearranged advanced NSCLC

Lorlatinib

Crizotinib

76

58

NR

9.3

0.28 [0.19–0.41]

NR

NR

0.72 [0.41–1.25]

58

47

[56]

ALVOKE-1

Pre-treated ALK-rearranged advanced NSCLC

[55]

 Total population

NVL-655

38

  ≥ 3 prior ALK-TKI

NVL-655

37

 Lorlatinib-naïve

NVL-655

53

 Prior lorlatinib

NVL-655

76

 G1202R mutation

NVL-655

49

 Compound mutation

NVL-655

58

ALINA

Resectable early-stage ALK-rearranged NSCLC

[57]

 Stage II-IIIA

Alectinib

NR

0.24 [0.13–0.45]

29.7

CT

44.4

30.8

 Stage IB-IIIA

Alectinib

NR

0.24 [0.13–0.43]

^$98.4%

0.22 [0.08–0.58]

CT

41.3

^$85.8%

Profile1001

ROS1-rearranged advanced NSCLC

Crizotinib

72

19.2

51.4

36

[60, 61]

Phase 2 study of lorlatinib

ROS1-rearranged advanced NSCLC

[62, 63]

 TKI-naïve

Lorlatinib

81

NR

43

 Crizotinib-pretreated

Lorlatinib

46

13.9

Integrated analysis of ALKA-372–001, STARTRK-1, and STARTRK-2

ROS1-rearranged advanced NSCLC

Entrectinib

77

19.0

34

[64, 65, 72, 73]

NTRK-rearranged advanced NSCLC

Entrectinib

57

11.0

21.0

Integrated analysis of 3 phase1/2 studies

NTRK-rearranged advanced NSCLC

Larotrectinib

79

28.3

44.4

39

[71, 74]

TRIDENT-1

ROS1-rearranged advanced NSCLC

[68, 75]

 TKI-naïve

Repotrectinib (TPX-0005)

79

 Prior ROS1 TKI

Repotrectinib (TPX-0005)

38

35.7

 G2032R mutation

Repotrectinib (TPX-0005)

59

9.0

NTRK-rearranged advanced NSCLC

 TKI-naïve

Repotrectinib (TPX-0005)

58

^#50%

 Prior NTRK TKI

Repotrectinib (TPX-0005)

50

^#22%

 Solvent-front mutation

Repotrectinib (TPX-0005)

60

^#21%

SAF001

ROS1-rearranged advanced NSCLC

[70]

 TKI-naïve

Foritinib

94

 TKI-naïve with CNS mets

Foritinib

100

 Prior ROS1 TKI

Foritinib

40

 Prior ROS1 TKI with CNS mets

Foritinib

40

GEOMETRY mono-1

Advanced NSCLC with MET exon 14 skipping

[77, 79]

 Cohort 4 (previously treated)

Capmatinib

41

5.4

46.4

75

 Cohort 5b (treatment naïve)

Capmatinib

68

12.4

66.9

75

VISION cohort A

Advanced NSCLC with MET exon 14 skipping

[78]

 Tissue-biopsy

Tepotinib

62

11.0

 Liquid-biopsy

Tepotinib

56

8.5

Phase 3b study of savolitinib

Advanced NSCLC with MET exon 14 skipping

Savolitinib

58.6

13.8

[80]

ZENITH-20

HER2-mutant advanced NSCLC

[82, 83]

  Cohort 2 (≥ 2 prior treatment)

Poziotinib

39

5.6

  Cohort 4 (treatment naïve)

Poziotinib

30

5.6

BEAMION Lung-1

HER2-mutant advanced NSCLC

[86, 87]

 Cohort 1a

Zongertinib twice-a-day escalation

Zongertinib once-a-day escalation

13.8

12.3

9.6

 Cohort 1b

Zongertinib 120 mg

Zongertinib 240 mg

72.4

78.2

15.2

SOHO-1

HER2-mutant advanced NSCLC

[88, 89]

 Total population

 YVMA insertions

BAY 2927088

BAY 2927088

72.1

90

7.5

9.9

40.9

Phase 1/1b study of telisotuzumab vedotin

EGFR-mutant advanced NSCLC with acquired resistance to osimertinib

Osimertinib + telisotuzumab vedotin

50

7.4

32

[186]