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Growing Up Ras: Resistance, Combos & Next Gen Agents

Concept for targeted oncology of our own cells fighting cancer cells.
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The KRAS inhibitor field is unfolding apace. To address resistance and move earlier in treatment, combos are crucial. KOLs favor combos w/SHP2 and MEK (despite lackluster data) and are optimistic about RAS(ON) inhibitors.


The mitogen-activated protein kinase (MAPK) pathway is a key driver of oncogenesis in multiple cancers and interdicting it has been a key focus of numerous drug development programs over many decades. The Rat sarcoma virus (RAS) features prominently in the pathway and is considered a linchpin to shut down uncontrolled tumor growth successfully. We believe that the RAS inhibitors story is just beginning.

The next chapter of this class of drugs will rely on their ability to address and overcome resistance mechanisms via rational combinations and move them into earlier lines of treatment. The field is highly competitive, with 40+ programs in earlier stages of development and myriad combination approaches being studied.


Strategies for moving upstream and accessing a larger segment of the population are critical to making this class of drugs sizable and will vary by tumor type. We remain optimistic that KRAS G12C inhibitors will be able to find prominence as single agents in 1L NSCLC patients who also harbor STK11 (serine/threonine kinase 11) mutations and have a low tumor proportion score (TPS<1%).

This is a sizable population (37% of all 1L NSCLC patients) where the bar is low, given that the current standard of care for 1L NSCLC with checkpoint inhibitors (CPI) has more modest efficacy in this setting. But to capture the TPS≥1% segments, combination with CPI or with inhibitors of MAPK/ERK kinase (MEK), Src homology region 2 (SHP2), and other receptor tyrosine kinase (RTK) inhibitors are needed. However, the early data with SHP2i, MEKi, and epidermal growth factor receptor inhibitor (ErbBi) have been lackluster on efficacy and/or tolerability/combinability thus far.

Data released in the second half of the year will be crucial to understanding if this class of drugs could capture the broader 1L KRAS G12C patient population. That said, in CRC, initial combination data with EGFR antibodies look promising.


Ultimately, we believe that KRAS inhibitors will need to be combined with other agents either up or downstream of RAS in the mitogen-activated protein kinase (MAPK) pathway, with pharmacokinetics/pharmacodynamics (PK/PD) and tolerability key drivers of successful combinations. This allows for optimal dosing and translating into deep and durable responses. Key targets for KRAS combinations include SHP2 and MEK, where differentiated product candidates could allow for a favorable therapeutic window for KRAS combinations.

There is a lot of competition with several KRAS(OFF) inhibitors in development. That beings said, these agents might not be differentiated enough given their 2-3+ years lag to market. KRAS(ON) inhibitors are promising. However, we are more interested in next-generation KRAS(ON) therapies from the likes of Revolution Medicines that might offer higher levels of clinical activity and a longer duration of response by posing a higher threshold for the emergence of resistant clones.

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