Adagrasib

Adagrasib is a long-awaited, targeted treatment of cancers with KRASG12C mutation and will likely be the first such treatment option in patients with colorectal cancer (CRC) with this mutation, who historically have had very few treatment options. Despite being second to market for patients with metastatic non-small-cell lung cancer (NSCLC), the great unmet clinical need for effective therapies for this biomarker-defined population make the clinical success of adagrasib very likely.

About adagrasib

Mirati Therapeutics Inc and Zai Lab Limited
KRAS GTPase inhibitor
Twice-daily, second-line, oral treatment of advanced KRASG12C-positive solid tumors: metastatic NSCLC and CRC
KRASG12C-mutant disease:
• 11-13% of metastatic NSCLC
• 3-4% of metastatic CRC

Why is it a drug to watch?

The common KRAS oncoprotein variants are traditionally considered intractable drug targets. The forecasted entry of a KRAS inhibitor for mutation-positive solid tumors (first entry: CRC; second entry: NSCLC) is monumental.

The KRASG12C mutation is the most common KRAS mutation in patients with NSCLC .
Key opinion leaders (KOLs) are cautiously optimistic that adagrasib will be more efficacious than LUMAKRAS™ (sotorasib).
Phase 2 (KRYSTAL-1) data show promising safety and efficacy for CRC and NSCLC.
Currently active trials include:
KRYSTAL-7: phase 2 of adagrasib and KEYTRUDA® (pembrolizumab) for first-line combination therapy.
KRYSTAL-10: phase 3 of adagrasib plus ERBITUX® (cetuximab; EGFR inhibitor) as second- or third-line treatment of CRC.
KRYSTAL-12: phase 3 for second-line monotherapy of NSCLC.
Mirati Therapeutics Inc.’s focus on targeted therapies against KRAS has enabled the company to move quickly during development.
Anticipated to be available as second-line monotherapy for NSCLC initially, but improved efficacy (better than SOC) as combination first-line therapy is highly anticipated by KOLs.

Review and approval status

NSCLC
June 2021:
For patients with KRASG12C-positive NSCLC following prior systemic therapy

Breakthrough Therapy Designation: U.S. FDA
Orphan Drug Designation: U.S. FDA

November 2021:
An NDA submission with the U.S. FDA began in this patient group based on data from the KRYSTAL-1 study

Expected launch:
2022: United States
2023: Europe and Japan

CRC
Expected launch:
2024: United States, Europe and Japan

Patents estimated to expire beginning in 2038

How will adagrasib impact the market for NSCLC and CRC?

NSCLC

Chemotherapy remains the backbone of the NSCLC treatment algorithm.
KRAS inhibitors are part of an ever-growing arsenal of targeted therapies.
Adagrasib will be in direct competition with Amgen’s LUMAKRAS.
Together, adagrasib and LUMAKRAS represent a new therapeutic option for metastatic NSCLC patients with KRASG12C who progress after prior treatment.
Adagrasib as monotherapy has the potential for greater efficacy and safety than LUMAKRAS based on early data.
Experts view even greater potential with combination therapy.

CRC

Adagrasib has potential to be the first-in-class KRAS inhibitor approved for use in combination with ERBITUX in previously treated KRASG12C-mutation-positive metastatic CRC.
Adagrasib is not in direct competition with other treatments.
However, it will be introduced as second- or third-line therapy following standard of care chemotherapy with or without bevacizumab upon initial approval.

What gaps in treatment does adagrasib fill?

Emerging therapies have struggled to target KRAS-mutant cancers, current therapies are not wholly effective, and there are few options for patients who progress after previous therapy. Not only is adagrasib expected to provide better efficacy than the current standard of care but it is also helping to set the scene for other, similar therapies to become available and provide greater choice for providers and patients.

What hurdles might it need to overcome to reach blockbuster status?

For NSCLC, Amgen’s LUMAKRAS has the advantage of being earlier to market for a relatively small patient population, in addition to its once-daily administration compared with twice-daily for adagrasib. Additional study results will be necessary to determine if the hinted-at superior efficacy and safety of adagrasib will be realized, which could influence its uptake. For CRC, an even smaller patient population could limit its overall sales potential.

$1.23B

Expected sales in 2026

95%

probability of success for
adagrasib in the United States.

Source: Cortellis Competitive Intelligence, Drug Timeline & Success Rates Prediction current as of December 15, 2021

“My KRAS-positive NSCLC patients currently get chemoimmunotherapy. The two KRAS G12C inhibitors, LUMAKRAS and adagrasib, were showing a lot of promise in terms of response. The question is how durable are those responses? It is possible that patients with shorter response have multiple mutations, and so we may benefit from better patient segregation.”