The Path to Personalized Treatment in KRAS-Mutant Non-Small Cell Lung Cancer: A Review of Targeted Therapies and Immunotherapy

Figures & data

Figure 1 The activation and deactivation process of KRAS.

Abbreviations: KRAS, Kirsten rat sarcoma viral oncogene; GTP, guanosine triphosphate; GDP, guanosine diphosphate; GEF, guanine nucleotide exchange factor; GAP, GTPase activating protein.

Table 1 Preliminary Data from Targeted Therapy

Drugs	Study	Phase	Setting	No. of Patients	Outcome
Sotorasib	CodeBreak 100^Citation15	I/II	≥2 line	174	ORR, 40.7%; DCR, 83.7%; mPFS, 6.3 months; mOS, 12.5 months; 1-year OS rate, 50.8%
	CodeBreak 200^Citation16	III	≥1 line	171	ORR, 28.1%; DCR, 82.5%; mPFS, 6.5 months; 1-year PFS rate, 24.8%
				174	ORR, 13.2%; DCR, 83.7%; mPFS, 4.5 months; 1-year PFS rate, 10.1%
Adagrasib	KRYSTAL-1^Citation18	I/II	≥2 line	116	ORR, 43%; DCR, 80%; mPFS, 6.5 months; mOS, 12.6 months; 1-year OS rate, 51%
	D-1553^Citation19	I	≥2 line	59	ORR, 40.4%; DCR, 90.4%

Abbreviations: ORR, objective response rate; DCR, disease control rate; mPFS, median progression-free survival; mOS, median overall survival; OS, overall survival; No, number.

Table 2 Preliminary Data from Immunotherapy

	Study	Phase	Setting	Arms	No. of Patients with KRAS Mutant	Outcome
ICIs alone	Keynote042^Citation23	III	1 line	Pembromab	69	KRAS mutant vs wild type: ORR, 56.7 vs 29.1%; mOS, HR=0.42 (95% CI: 0.22–0.81)
	IMMUNTRGET^Citation24	–	≥2 line	ICIs	246	ORR, 26%; mPFS, 3.2 months; mOS, 13.5 months
	Checkmate 057^Citation31	III	≥2 line	Nivolumab vs docetaxel	62	mOS, 12.2 vs 9.4 months, HR=0.52 (95% CI: 0.29–0.95)
	OAK study^Citation22	III	≥2 line	Atezolizumab vs docetaxel	59	mOS, 13.8 vs 9.6 months, HR=0.71 (95% CI: 0.38–1.34)
	Meta analysis^Citation1	–	1 line/2 line	ICIs alone	694	KRAS mutant vs wild type: HR=1.51 (95% CI: 1.17–1.96), p=0.002
ICIs combined therapy	Keynote-189^Citation25	III	1 line	Pembromab plus chemotherapy	89	KRAS mutant vs wild type: ORR, 40.7 vs 47.6%; mOS, HR=0.79 (95% CI: 0.45–1.38)
	IMPOWER 150^Citation26	III	1 line	Atezolizumab plus chemotherapy	226	KRAS mutant (ABCP vs BCP): mPFS, HR=0.42 (95% CI: 0.29–0.61); OS, HR=0.50 (95% CI: 0.34–0.72)
	Meta analysis^Citation1	–	1 line/2 line	ICIs plus others	386	ICI plus CT vs CT: OS, 0.59 months (95% CI: 0.49–0.72), p <0.00001; PFS, 0.58 months (95% CI: 0.43–0.78), p=0.0003

Abbreviations: ICIs, immune checkpoint inhibitors; KRAS, Kirsten rat sarcoma viral oncogene; HR, hazard ratio; BCP, bevacizumab plus carboplatin plus paclitaxel; ABCP, atezolizumab plus BCP; 95% CI, 95% confidence interval; ORR, objective response rate; mPFS, median progression-free survival; mOS, median overall survival; OS, overall survival; No, number.

Table 3 Ongoing Drug Development Strategies for KRAS Mutant Populations

Classification	Programs (Company)	Combination Therapies Under Investigation	Phase
KRAS G12C (OFF) inhibitors^Citation32	Adagrasib/MRTX849+ (Mirati)	PD-1, PD-L1, SHP2, MEK	III
	Sotorasib/AMG 510‡ (Amgen)	Pan-ErbB, EGFR, mTOR	III
	D-1553+ (Inventis Bio)	CDK4/6, chemotherapy	I/II
	JDQ443 (Novartis)	PD-L1, EGFR, pan-ErbB, SHP2	I/II
	GDC-6036 (Genentech)	Chemotherapy	I
	JNJ-74699157 (JanssenPharmaceuticals)	PD-1, SHP2	I
	LY3499446 (Eli Lilly and Company)	PD-1, VEGF, EGFR	The study terminated due to toxicity
	BI 1823991 (Boehringer Ingelheim)	SOS1	Ia/Ib
	MK-1084 (Merck)	Pembrolizumab	I
KRAS (ON) inhibitors^Citation27,Citation28	RMC-9805 KRASG12D (Revolution Medicines)	-	Preclinical
	RMC-8839 KRASG13C (Revolution Medicines)	EGFR, CDK4/6	Preclinical
	RMC-6291 KRASG12C (Revolution Medicines)	-	Preclinical
	RMC-6236 KRASMULTI (Revolution Medicines)	-	Preclinical
RAS companion inhibitors^Citation27,Citation28	RMC-4630 SHP2 (Revolution Medicines)	SHP2 or SOS1 inhibitors, ICIs	II
	mTORC1	-	I
	Immune checkpoints	MEK, ERK, KRAS G12C, RTK, ICIs	-
	mRNA vaccine and RNAi	-	I/II

Abbreviations: KRAS, Kirsten rat sarcoma viral oncogene; RAS, rat sarcoma viral oncogene; ICIs, immune checkpoint inhibitors; PD-1, programmed cell death-1; PD-L1, programmed death ligand 1; SHP2, Src homology-2 domain containing protein tyrosine phosphatase-2; MEK, MAPK/ERK kinase; EGFR, epidermal growth factor receptor; mTOR, mammalian target of rapamycin; CDK, cyclin-dependent kinase; VEGF, vascular endothelial growth factor; SOS1, SOS Ras/Rac guanine nucleotide exchange factor 1; ERK, extracellular signals regulated kinases; RTK, receptor tyrosine kinase; mTORC1, mechanistic target of rapamycin complex 1.

Dy GK, Govindan R, Velcheti V, et al. Abstract CT008: long-term outcomes with sotorasib in pretreated KRASp.G12C-mutated NSCLC: 2-year analysis of CodeBreaK100. Cancer Res. 2022;82(12_Supplement):CT008–CT008. doi:10.1158/1538-7445.AM2022-CT008

 Web of Science ®Google Scholar

J ML. Presented at European Society for Medical Oncology (ESMO) 2022 Annual Meeting; September 9–13; 2022; Paris, France.

 Google Scholar

Jänne PA, Riely GJ, Gadgeel SM, et al. Adagrasib in Non–Small-Cell lung cancer harboring a KRAS G12C mutation. N Engl J Med. 2022;387(2):120–131. doi:10.1056/NEJMoa2204619

 PubMed Web of Science ®Google Scholar

Luo J, Ostrem J, Pellini B, et al. Overcoming KRAS-mutant lung cancer. Am Soc Clinl Oncol Educ Book. 2022;41:1–11.

 Google Scholar

Herbst R, Lopes G, Kowalski D, et al. LBA4 Association of KRAS mutational status with response to pembrolizumab monotherapy given as first-line therapy for PD-L1-positive advanced non-squamous NSCLC in Keynote-042. Ann Oncol. 2019;30:xi63–xi64. doi:10.1093/annonc/mdz453.001

 Web of Science ®Google Scholar

Mazieres J, Drilon A, Lusque A, et al. Immune checkpoint inhibitors for patients with advanced lung cancer and oncogenic driver alterations: results from the IMMUNOTARGET registry. Ann Oncol. 2019;30(8):1321–1328. doi:10.1093/annonc/mdz167

 PubMed Web of Science ®Google Scholar

Borghaei H, Paz-Ares L, Horn L, et al. Nivolumab versus docetaxel in advanced nonsquamous non-small-cell lung cancer. N Engl J Med. 2015;373(17):1627–1639. doi:10.1056/NEJMoa1507643

 PubMed Web of Science ®Google Scholar

Rittmeyer A, Barlesi F, Waterkamp D, et al. Atezolizumab versus docetaxel in patients with previously treated non-small-cell lung cancer (OAK): a Phase 3, open-label, multicentre randomised controlled trial. Lancet. 2017;389(10066):255–265. doi:10.1016/S0140-6736(16)32517-X

 PubMed Web of Science ®Google Scholar

Landre T, Justeau G, Assié JB, et al. Anti-PD-(L)1 for KRAS-mutant advanced non-small-cell lung cancers: a meta-analysis of randomized-controlled trials. Cancer Immunol Immunother. 2022;71(3):719–726. doi:10.1007/s00262-021-03031-1

 PubMed Web of Science ®Google Scholar

Gadgeel S, Rodriguez-Abreu D, Felip E, et al. KRAS mutational status and efficacy in KEYNOTE-189: pembrolizumab (pembro) plus chemotherapy (chemo) vs placebo plus chemo as first-line therapy for metastatic non-squamous NSCLC. Ann Oncol. 2019;30:xi64–xi65. doi:10.1093/annonc/mdz453.002

 Google Scholar

West H, Cappuzzo F, Reck M, et al. 1265P IMpower150: a post hoc analysis of efficacy outcomes in patients with KRAS, STK11 and KEAP1 mutations. Ann Oncol. 2020;31:S817–S818. doi:10.1016/j.annonc.2020.08.1579

 Web of Science ®Google Scholar

Ostrem JM, Shokat KM. Targeting KRAS G12C with Covalent inhibitors. Annual Rev Cancer Biol. 2022;6:49–64. doi:10.1146/annurev-cancerbio-041621-012549

 Google Scholar

Nagasaka M, Azmi AS. Clinical progress of KRAS-targeted therapies: what next? Future Med Chem. 2022;14(15):1107–1110. doi:10.4155/fmc-2022-0128

 PubMed Web of Science ®Google Scholar

Désage AL, Léonce C, Swalduz A, Ortiz-Cuaran S. Targeting KRAS mutant in non-small cell lung cancer: novel insights into therapeutic strategies. Front Oncol. 2022;12:796832. doi:10.3389/fonc.2022.796832

 PubMed Web of Science ®Google Scholar