CodeBreaK 200: Sotorasib (AMG510) Has Broken the KRAS G12C+ NSCLC Enigma Code

Figures & data

Table 1 Comparison of Efficacy and Safety of Sotorasib in Phase II and Phase III Trials

	CodeBreaK 100*	CodeBreaK 100 (Post Chemo + IO)	CodebreaK 200**
N (sotorasib treated)	124	100	171
Prior chemotherapy	90%	100%	100%
Prior immunotherapy	91%	100%	100%
Progressive disease on enrollment	81%	NR	NR
BIRC-assessed ORR (%)	36 (95% CI: 28–45)*	31 (95% CI: 22–41)*	28.1 (95% CI: 21.5–35.4)
DOR (months)	10.0 (95% CI: 6.9 – NR)*	10.0 (95% CI: 6.9 – NR)*	10.6 (95% CI: 8.9–14.0)
DOR ≥6 months	58%*	58%*
PFS (months)	6.8 (95% CI: 5.1–8.2)	NR	5.6 (95% CI: 4.3–7.8)
OS (months)	12.5 (95% CI: 10 – NR)	NR	10.6 (95% CI: 8.9–14.0)
Top 5 AEs	Diarrhea (50.8%)	NR	Diarrhea (33.7%)
	Nausea (31.0%)		Nausea (14.2%)
	Fatigue (25.8%)		Appetite decrease (10.7%)
	Arthralgia (21.4%)		AST increase (10.1%)
	AST increase (21.4%)		ALT increase (10.1%)

Note: *Federal Drug Administration (FDA) approval summary.

Abbreviations: AEs, adverse events; ALT, Alanine aminotransferase; AST, Aspartate aminotransferase; BIRC, blind independent central review; CI, confidence interval; DOR, duration of response; NR, not reported; ORR, overall response rate; OS, overall survival; PFS, progression-free survival.

Table 2 Reported Phase II Trial of Covalent KRAS G12C Inhibitors

Drug	Sotorasib	Adagrasib	JDQ443	D-1553	GDC-6036
Trial name	CodeBreaK 100 (KRAS G12C+ NSCLC)	Krystalis-1	KontRASt-01
Dosing (RP2D)	960 mg daily	600 mg twice daily	200 mg twice daily	600 mg twice daily	400 mg daily
Participants	126	116	20	32	32
Median age	63.5 years	64 years	64 years	65 years	67 years
Current/former smoker	93%	96%	Unknown	Unknown	93%
Prior immunotherapy	92.1%	98%	Unknown	Unknown	86%
Prior chemotherapy	91.3%	100%	Unknown	Unknown	90%
Median prior therapies (range)	2	2	2	2	1
Brain metastases	20.6%	21%	Unknown	Unknown	Unknown
ORR	37.1% (95% CI 28.6–46.2)	43% (95% CI 33.5–52.6)	57% (4/7)	40.6% (13/32)	53% (30/57)
DOR	11.1 months (95% CI 6.9-NR)	8.5 months (95% CI 6.2–13.8)	15.9 weeks (range 2.0–27.1)	Pending	Pending
PFS	6.8 months (95% CI 5.1–8.2)	6.5 months (95% CI 4.7–8.4)	Pending	Pending	Pending
OS	12.5 months (95% CI 10.0-NR)	12.6 months (95% CI9.2–10.2)	Pending	Pending	Pending
DCR	80.6% (95% CI 72.6–87)	80% (95% CI 70.8–86.5)	Pending	84.4% (27/32)	Pending
AEs	99.2%	97%	72.7%	78%	88.1%
Common AEs	Diarrhea (50.8%)	Diarrhea (63%)	Nausea (27.3%)	Elevated AST (30.5%), elevated ALT (28.8%), elevated GGT (20.3%)	Nausea (76.3%), diarrhea (61%), vomiting (54.2%)
	Nausea (31%)	Nausea (62%)	Vomiting (27.3%)
	Fatigue (25.4%)	Vomiting (47%)	Fatigue (18.2%)

Abbreviations: AEs, adverse events; CI, confidence interval; DCR, disease control rate; DOR, duration of response; ORR, overall response rate; OS, overall survival; PFS, progression-free survival; RP2D, recommended Phase II dose.

Table 3 On-Going KRASG12C Covalent versus Docetaxel Trial

Drug	Sotorasib	Adagrasib	JDQ443	GDC-6036
Trial	CodebreaK 200 (NCT04303780)	KRYSTAL-12 (NCT04685135)	KontRASt-02 (NCT05132075)	B-FAST cohort G (NCT03178552) (RO7435846)
N	345	340	360	NA
Randomized	1:1	1:1	1:1	NA
Prior chemotherapy required	Yes	Yes	Yes	NA
Prior ICI required	No	No	Yes	NA
Stage IIIB/C allowed	Yes	Yes	Yes	NA
Stratification factors	Prior lines of therapy, race, brain mets		Prior lines of treatment; ECOG PS	NA
Plasma ctDNA alone allowed	Not allowed	No	No	NA
Cross-over allowed	Yes	Yes	Yes, if and after primary endpoint is met	NA
Primary endpoint	BIRC-assessed PFS	BIRC-assessed PFS	BIRC-assessed PFS	NA
Number of clinical sites opened	274	142	NA	NA

Abbreviations: BIRC, Blind Independent Review Committee; ctDNA, circulating tumor deoxyribonucleic acid; ECOG PS, Eastern Cooperative Oncology Group Performance Status; NA, not available; PFS, progression-free survival.