ASCO 2024 - Advances in GI Treatments

‍

Metastatic Colorectal Caner

KRAS G12C-mutated mCRC (PhaseIII CodeBreaK 300 Trial¹)

For KRAS G12C-mutated chemorefractory metastatic colorectal cancer,sotorasib plus panitumumab demonstrated promising outcome. After a medianfollow-up of 13.6 months, the median overall survival (mOS) in sotorasib 960 mg+ panitumumab, sotorasib 240 mg + panitumumab and investigator’s choice were NE(not estimable), 11.9 months and 10.3 months, respectively. The overallresponse rate (ORR) was 30% for the sotorasib 960 mg + panitumumab groupcompared to 2% for the investigator’s choice group. Although the OS did notshow a statistically significant difference, considering the ORR and thenumerical trends, the sotorasib 960 mg + panitumumab combination has thepotential to become a new standard-of-care.

HER2-positive mCRC (PhaseII MOUNTAINEER Trial²)

The results demonstrated the clinically meaningful improvement in survivalfrom tucatinib + trastuzumab in HER2+, RAS wild-type metastatic CRC. With amedian 32.4 months follow-up, tucatinib + trastuzumab showed an objectiveresponse rate (ORR) of 39.3%, 8.1 months in median progression-free survival (mPFS),and 23.9 months in mOS. Clinical efficacy was consistent across HER2 testingmethods, including tissue IHC, tissue-based NGS, and liquid-based NGS,supporting the use of various available tests for patients selection.

Acquired gene alterationpatterns in RASwt mCRC after 1L treatments (Phase III PARADIGM trial³)

In the exploratory biomarker study of PARADIGM trial, acquired alterationsin RTK/RAS pathway after panitumumab and in CIMP pathway after bevacizumab wereassociated with shorter survival after disease progression (PPS) and OS. Thisresult suggests that identifying acquired alterations in the RTK/RAS pathway orCIMP pathway may help guide subsequent treatment strategies.

Biliary Tract Cancer

HER2-positive BTC (Phase2b HERIZON-BTC-01 study⁴)

Zanidatamab is a HER2-targeted bispecific antibody that binds to 2 distinctdomains on HER2. The results of phase 2b HERIZON-BTC-01 trial showed an ORR anddisease control rate (DCR) of 41.3% and 68.8%, respectively, which weremaintained from the primary analysis. The mDoR was 14.9 months, and medianoverall survival was 15.5 months. Of note, the global, randomized phase 3 study(HERIZON-BTC-02) investigating zanidatamab in combination with standard-of-caretherapy in the 1L setting for HER2-positive BTC is ongoing.

Sitravatinib andtislelizumab combination in 2L setting of advanced BTC (Phase II BTC-BGB trial⁵)

The result showed a DCR of 65.1% for sitravatinib and tislelizumabcombination. Interestingly, patients with homologous recombination repairdeficiency (HRD) defined by loss-of-function mutations of HRR genes had bettersurvival outcome compared to patients with HRP (PFS: NR vs 4.87 months; OS:21.13 months vs 8.57 months).

Reference:

1.      Marwan G. Fakih et al. presented at the 2024 ASCO annual meeting. Overallsurvival (OS) of phase 3 CodeBreaK 300 study of sotorasib plus panitumumab(soto + pani) versus investigator’s choice of therapy for KRAS G12C-mutatedmetastatic colorectal cancer (mCRC)

2.      John H Strickler et al. presented at the 2024 ASCO annual meeting. Finalresults of a phase 2 study of tucatinib and trastuzumab for HER2-positive mCRC(MOUNTAINEER)

3.      Hiroyuki Uetake et al. presented at the 2024 ASCO annual meeting. Acquiredgene alteration patterns and post-progression survival: PARADIGM study analysis

4.      Shubham Pant et al. presented at the 2024 ASCO annual meeting. Zanidatamabin previously-treated HER2-positive biliary tract cancer (BTC): Overallsurvival (OS) and longer follow-up from the phase 2b HERIZON-BTC-01 study

5.      Jeesun Yoon et al. presented at the 2024 ASCO annual meeting. PhaseII study of sitravatinib in combination with tislelizumab in patients withadvanced biliary tract cancer who have failed to at least 1 prior systemictreatment

‍