Phase I Clinical Trial NCT04800822 by Pfizer
Study of PF-0828492 in Participants with Advanced Solid Tumors
SHP2 Inhibitor
https://clinicaltrials.gov/ct2/show/NCT04800822?term=%22NCT04800822++++%22&draw=2&rank=1#contacts
A stage 1 dose escalation trial for ALK+ NSCLC patients that fit the following criteria for Part 2 of the trial:
Cohort 1: PF-0828492 + Lorlatinib for patients with prior Lorlatinib and without prior platinum-based chemotherapy
Cohort 2: PF-0828492 + Lorlatinib for patients with prior Lorlatinib and with prior platinum-based chemotherapy
Cohort 3: PF-0828492 + Lorlatinib for patients with no prior Lorlatinib
PF-0828492 is a SHP2 inhibitor that is thought to enhance cancer treatments. After progression on Lorlatinib, only about one third of patients still has ALK-dependent tumors. Two thirds have ALK-independent tumors driven by alternative mutations such as EGFR, MET, HER2 and others. The best way to attack them is not with another ALK inhibitor, but with a combination that allows more blockage to the aberrant cellular growth signals. There are three important downstream tumor growth signal pathways made up of chains of proteins in the cell that communicate a signal to the DNA in the nucleus: the PI3K/AKT pathway, the JAK/STAT pathway, and most importantly the RAS/MEK pathway. All these pathways carry signals that tell the cancer cells to proliferate and survive. The ALK protein activates all three of these pathways, and blocking the ALK protein shuts off the proliferation and survival signals. But once the ALK-independent change occurs, other signals are recruited driven by EGFR, MET, HER2 and other oncogenic mutations. A given tumor may have several of these proteins. If there is a bypass signal or an ALK-independent mechanism, it is not enough to just shut down ALK with an ALK TKI because all the other drivers can activate these downstream pathways even after shutting down ALK. It has been found that the RAS/MEK pathway is one of the most important to shut down, and the entry point to that pathway is a pivotal protein called RAS, which needs other proteins including SHP2 to be turned on and signal. If SHP2 is blocked, then RAS may also be blocked, hopefully shutting down the RAS signal sufficiently for the tumor not to grow, even with the extra signals from the bypass tracks like EGFR, HER2, and others. The rational is to inhibit a protein that is important to all these pathways, and it is hoped that SHP2 is that protein.
Frankson et al., Cancer Res 2017. 1
This trial started March 16, 2021, is intended for 70 patients (some in cohorts with other mutations than ALK), and is currently recruiting at The University of Texas MD Anderson Cancer Center in Houston, and shortly at START Midwest, Grand Rapids Michigan. Pfizer is the sponsor, and is manufacturer of both Lorlatinib and PF-0828492. The most relevant ALK inclusion criteria reads “Histological or cytological diagnosis of ALK-positive advanced NSCLC”, without further detail delineated in the clinicaltrials.gov listing.
Pfizer is a global pharmaceutical company headquartered in New York City and listed on the New York Stock Exchange with dozens of drugs for many different diseases on the market. With revenues of over $70B expected in 2021, and the ongoing success of their Covid vaccine, Pfizer continues to innovate in the ALK NSCLC space with follow-on drugs to Xalkori (crizotinib) and Lorbrena (lorlatinib).
Contact Information can be found here: https://clinicaltrials.gov/ct2/show/NCT04800822?term=%22NCT04800822++++%22&draw=2&rank=1#contacts