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. 2022 Oct 17;38:6–14. doi: 10.1016/j.ctro.2022.10.004

Table 1.

Clinical studies targeting K-Ras and K-Ras-regulated DDR signaling. The studies in combination with RT are marked in bold.

Target Drug Trial Combination Cancer type Major findings Ref.
ATR M6620 phase I GEM advanced NSCLC
  • -

    well tolerated.

 [129]
+/- CB ST including CRC
  • -

    well tolerated.

  • -

    complete response in ATM loss CRC

 [130]
TPT ST including NSCLC and PaCa
  • -

    MTD of combination was well tolerated

  • -

    enhanced DNA DSB in combination

  • -

    partially active in TPT-non-responding NSCLC

 [131]
CHK1 AZD7762 phase I GEM ST including CRC and lung cancer
  • -

    MTD of 21 mg, stable disease

 [132]
phase II GEM PaCa
  • -

    not superior to GEM

 [133]
LY26063618 phase II GEM + CDDP advanced nonsquamous NSCLC
  • -

    improved PFS

  • -

    increased risk of thromboembolism

 [134]
pemetrexed advanced or metastatic NSCLC
  • -

    partial response (9.1 %)

  • -

    stable disease (36.4 %)

  • -

    no association between p53 status and response

 [135]
WEE1 AZD1775 phase II GEM + RT LAPaCa
  • -

    well tolerated

  • -

    improved OS

[110]
– RAS and TP53 mutations mCRC
  • -

    improved PFS

 [109]
FTase tipifarnib phase I – brainstem glioma
  • -

    MTD (125 mg/m2 twice-daily)

 [136]
RT+/-TMZ GBM
  • -

    MTD (300 mg/m2 twice-daily)

[137]
RT GBM
  • -

    MTD (200 mg/m2/day)

[138]
phase II RT brainstem glioma
  • -

    no clinical advantage

[115]
GBM
  • -

    no clinical advantage

[116]
FTase + GGTase-1 L-778,123 phase I RT HNSCC and NSCLC
  • -

    acceptable toxicity

  • -

    partial to complete response

  • -

    radiosensitization of PD cell line

  • -

    accumulated in G2/M after L-778,123

[118]
PaCa
  • -

    acceptable toxicity.

  • -

    radiosensitization of PD cell line

[119]
KRASG12C AMG 510 phase I – KRAS G12C ST
  • -

    encouraging anticancer activity

  • -

    Grade 3 or 4 treatment-related toxic effects occurred in 11.6 %

 [128]
phase II – KRAS G12C NSCLC, previously treated with standard therapies
  • -

    durable clinical benefit

  • -

    partial and complete response in 37.1 %

  • -

    adverse events in 69.8 %

 [139]
KRAS G12C CRC, previously treated with standard therapies
  • -

    9.7 % overall response

 [140]

ATR: ataxia telangiectasia and Rad3 related, CB: carboplatin, CDDP:cis-diammindichloridoplatin, CHK1: checkpoint kinase 1, CRC: colorectal cancer, DSB: double-strand break, FTase: farnesyltransferase, GBM: glioblastoma multiforme, GEM: gemcitabine, GGTase-1: geranylgeranyl transferase type-1, HNSCC: head and neck squamous cell carcinoma, LAPaCa: locally advanced pancreatic cancer, mCRC: metastatic colorectal cancer MTD: maximum tolerated dose, NSCLC: non-small-cell lung cancer, PaCa: pancreatic cancer, PD: patient derived, PFS: progression-free survival, OS: overall survival, RT: radiotherapy, ST: solid tumors, TMZ: temozolomide, TPT: topotecan.