Table 4 Summary of combinational approaches [25, 35, 40, 42, 57, 60, 71, 79, 85, 103, 104, 107, 112,113,114]
From: The current landscape of using direct inhibitors to target KRASG12C-mutated NSCLC
Combinational pathway | Target | Combinations discussed (Ex./KRAS G12Ci) | Results |
|---|---|---|---|
Vertical (upstream) | EGFR | Cetuximab or erlotinib/LY3537982 | Improved tumor regression in H358 xenografts compared to cetuximab monotherapy Clinical Trial: NCT04956640 |
Erlotinib/sotorasib | Strong synergy in H358 xenografts marked by score > 10 (12.4) | ||
HER | Afatinib/sotorasib | Strong synergy in H358 xenografts marked by score > 10 (21.3) Clinical Trial: NCT04185883 | |
SHP2 | RMC-4550/sotorasib | Strong synergy in H358 xenografts marked by score > 10 (22.8) | |
RMC-4550/D-1553 | Reduced tumor volume in H358 xenografts compared to either drug individually after 24Â days of study | ||
TNO155/JDQ443 | Greater tumor efficacy when used together in NCI-H2030 CDX models Clinical Trial: NCT04699188 | ||
SOS1 | BAY-293/ARS-853 | Synergy identified with combination index significantly below 0.8 (according to median-effect model of Chou-Talalay) demonstrating parallel inhibition | |
BI-1701963/adagrasib | KRYSTAL-14: terminated due to toxicity concerns Clinical Trial: NCT04975256 | ||
BI-1701963/BI-1823911 | Tumor regression in 9/9 H2122 NSCLC cell models Clinical Trial: NCT04973163 | ||
(Downstream) | AURKA | LY3295668/ LY3537982 | Improved tumor regression in H358 xenografts compared to LY3295668 monotherapy Clinical Trial: NCT04956640 |
MEK/ERK | Trametinib/sotorasib | Strong synergy in H358 xenografts marked by score > 10 (14.7) CodeBreaK101 phase 1b results demonstrated a DCR of 83.3% in 18 KRASG12C mutant NSCLC patients (3 received prior G12C inhibitors) Clinical Trial: NCT04185883 | |
Trametinib/D-1553 | Reduced tumor volume in H358 xenografts compared to either drug individually after 24Â days of study | ||
Parallel | PI3K | GDC0941/ARS-1620 | Well tolerated combination and reduced tumor growth compared to either therapy alone in patient-derived cell lines with G12C mutated lung cancer |
mTOR/IGF1R | Everolimus/linsitinib/ARS-1620 | Profound inhibition of cell viability using all 3 drugs in combination on H358 cells in both 2D and 3D conditions providing evidence of strong, durable reduction of tumor cell growth H358 xenografts were more sensitive to G12C direct inhibitor when combined with IGF1R and mTOR inhibition and achieved more durable regression whereas ARS-1620 monotherapy was ineffective as resistance developed | |
Chemotherapy | Â | Carboplatin/sotorasib | Significant anti-tumor growth in combination compared to inhibited tumor growth in monotherapy Clinical Trials: NCT04185883 NCT05118854 |
Carboplatin/D-1553 | Reduced tumor volume in H358 xenografts compared to either drug individually after 24Â days of study Clinical Trial: NCT05492045 | ||
Immunotherapy | PD-1 & PD-L1 | Anti-PD-1 (unnamed)/sotorasib | 112Â days of tumor regression in 9/10 mice compared to 1/10 in anit-PD-1 monotherapy |
Pembrolizumab/adagrasib | KRYSTAL-7: ORR = 49% and 9% increase in grade 3+ liver TRAEs Clinical Trials: NCT04613596 NCT03785249 NCT04418661 NCT05609578 | ||
Atezolizumab or pembrolizumab/sotorasib | CodeBreaK 100/101: liver toxicity noted as most common TRAE (49%) Clinical Trials: NCT03600883 NCT04185883 | ||
CDK4/6 | Abemaciclib/LY3537982 | Improved tumor regression in H358 xenografts compared to abemaciclib monotherapy Clinical Trial: NCT04956640 | |
Palbociclib/adagrasib | Near-complete inhibition in H2122 and SW1573 cells when used in combination compared to concentration-dependent partial inhibition with adagrasib alone Clinical Trial: NCT05178888 | ||
Autophagy | ULK1/2 | DCC-3116/sotorasib | Improved tumor inhibition compared to sotorasib monotherapy in KRASG12C NSCLC preclinical models Clinical Trial: NCT04892017 |