Thread by @Aiims1742

2022 was the year mutant KRAS in #PancreaticCancer truly became actionable.

Direct KRAS targeting & #PancreaticCancer, a 🧵:

In @NEJM by @DavidHongMD & colleagues:
Sotorasib in KRAS p.G12C–Mutated Advanced #PancreaticCancer
nejm.org/doi/full/10.10…
G12C is ~1.6% of KRAS alleles in pancreatic cancer, & monotherapy responses in pre-treated patients are mostly transient stable disease, but a step forward.

In addition to Sotorasib, Adagrasib is the other KRAS G12C inhibitor with demonstrated Phase 1 activity in #PancreaticCancer (2022 data).
The expansion cohort in pancreatic cancer will start accrual at @MDAndersonNews soon.
clinicaltrials.gov/ct2/show/NCT05…
@DrShubhamPant @DanZhaoMD

Multiple other KRAS G12C targeted inhibitors are being evaluated in early phase “all comers” trials that include #PancreaticCancer:
clinicaltrials.gov/ct2/show/NCT05…
clinicaltrials.gov/ct2/show/NCT04…
clinicaltrials.gov/ct2/show/NCT05…
Some are monotherapy, others are combined with additional agents (Eg SHP2i)

The most common allelic variant in #PancreaticCancer is G12D, so this preclinical study in @CD_AACR using @Mirati MRTX1133 was important proof of concept & prelude to clinical trials. Also demonstrated role of the immune system.
aacrjournals.org/cancerdiscover…
@BenStanger01 @sam_kemp20

In addition to allele specific inhibitors, phase 1 #clinicaltrials of pan-RAS (allele agnostic) inhibitors - which include solid tumors beyond #PancreaticCancer - have also started, such as this RevMed trial. Of note, RMC-6236 binds to the RAS(ON) state
clinicaltrials.gov/ct2/show/NCT05…

One of the best reviews this year on pharmacological targeting of KRAS - direct or indirect - is written by @norbertkraut1 @Sandra_Misale @gerlach_d @MarcoHHofmann in @CD_AACR - #OpenAccess & worth reading!
aacrjournals.org/cancerdiscover…

The scope of direct KRAS targeting in #PancreaticCancer in 2022 extended beyond small molecules. Eric Tran @BernardAFox et al @ChilesResearch demonstrated T cell receptor (TCR) engineered autologous T cells targeted against KRASG12D can elicit responses.
nejm.org/doi/10.1056/NE…

Clinical trials of TCR engineered autologous T cells targeting HLA-restricted KRAS neoepitopes (including G12D & G12V) are now ongoing in patients with #PancreaticCancer & other solid cancers. Two examples below:
clinicaltrials.gov/ct2/show/NCT05…
clinicaltrials.gov/ct2/show/NCT03…
(Specific to G12V).

On the lines of leveraging KRAS neoepitopes as a target of immune response, clinical trials are ongoing in the adjuvant (minimal residual space) in #PancreaticCancer, using vaccines against mutant KRAS. Two examples below:
clinicaltrials.gov/ct2/show/NCT04…
clinicaltrials.gov/ct2/show/NCT04…

Another novel mechanism to directly target mutant KRAS G12D that has entered clinical trials is the @AstellasUS degrader ASP-3082, that is undergoing evaluation in Phase 1 studies (including previously treated #PancreaticCancer)
clinicaltrials.gov/ct2/show/NCT05…

Very excited about @MDAndersonNews own homegrown effort of genetically targeting mutant KRAS G12D using systemically delivered exosomes (iExosomes) in metastatic #PancreaticCancer. Science emanating from @KalluriLab, trial led by @drsmags @EJShpallMD
clinicaltrials.gov/ct2/show/NCT03…

Amazing to see how many approaches exist that are targeting /leveraging the previously “undruggable” mutant KRAS. Needless to say, mechanisms of resistance will emerge & the best combination regimens have to be discerned. But so much progress as we step into 2023!