Undruggable KRAS—time to rebrand?

After decades of research into KRAS-mutant cancers, clinical development of drugs targeting this pervasive mutation is finally showing some much-awaited promise. RAS proteins are a family of prototypical oncogenes that are mutated in many human cancers. KRAS is the most frequently mutated isoform of RAS mutations (86%), and is mutated in 90% of pancreatic cancers, 40% of colorectal cancers, and 30% of lung cancers. Cancers with these mutations are associated with poor treatment responses and a poor prognosis. Mutant KRAS has long been referred to as an undruggable target because of its unusual shape. Compared with other proteins, the relatively smooth protein structure meant that designing inhibitors to bind to surface grooves was difficult, stalling progress in drug development for many years. But, in a major breakthrough in 2013, a compound was developed that could bind to a small pocket in the mutant KRAS Gly12Cys protein, reinvigorating efforts to find an active inhibitor. Development of inhibitors that were selective for mutant forms of KRAS also reduced the toxicity that might have been observed with widescale inhibition of a ubiquitous protein. Although recently developed KRAS inhibitors still failed to progress to late-stage clinical trials (eg, AZD4785), the advance in 2013 has led to new drugs reaching further stages of development, with recent data representing the first phase 2 evidence of clinical activity of a KRAS inhibitor. At the World Conference on Lung Cancer held virtually on Jan 28–31, 2021, phase 2 results from the CodeBreak 100 trial were presented. In the single-arm study, 124 patients with previously treated non-small-cell lung cancer (NSCLC) with a centrally confirmed KRAS Gly12Cys mutation were enrolled and given sotorasib, which targets that mutation. 46 (37%) patients had an overall response (including two complete responses), and median progression-free survival was 6·8 months. The clinically meaningful results confirmed preliminary data from the phase 1 part of the study, and a phase 3 study is planned (NCT04303780). In late 2020, another KRAS inhibitor targeting the KRAS Gly12Cys mutation—adagrasib—also showed preliminary antitumour activity in a subset of patients with NSCLC. In the phase 1 KRYSTAL-1 study, presented at the EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics in October, 2020, 79 patients with NSCLC were given adagrasib twice a day, resulting in objective responses in 23 (45%) of 51 evaluable patients—another encouraging result in patients with a high unmet clinical need. In view of previous, unsuccessful attempts to target KRAS mutations in cancer, and the fact that most of the patients included in these trials had already received previous lines of therapy, these results are a sign that barriers to targeting KRAS are surmountable. However, these are still early results. CodeBreak 100 is a registrational trial and, together with results from KRYSTAL-1, the outlook for KRAS inhibition in NSCLC is good, but confirmatory studies in larger patient populations and comparison with the current standard of care are needed. Moreover, although progress is being made in lung cancer, results in colorectal and pancreatic cancer have not been as striking. In the KRYSTAL-1 study, only three (17%) of 18 evaluable patients with colorectal cancer or other solid tumours had a confirmed objective response. An unmet need remains, and different approaches to KRAS inhibition are required. Although the KRAS Gly12Cys mutation is highly prevalent, and potentially targetable, in lung cancers, other KRAS mutations, such as KRAS Gly12Asp, are prevalent in different cancer types. Use of pan-KRAS inhibitors that block KRAS irrespective of mutation type, such as BBP-454 (in the preclinical phase), might open up KRAS inhibition to broader patient populations, but the safety of such an approach will be an important consideration. Another concept being explored is the use of KRAS inhibitors as part of combination therapies. For example, phase 1 studies have been initiated to test combination of KRAS blockade with immune checkpoint inhibitors for KRAS-mutant cancers. With a dismal success rate in the past 30 years, targeting KRAS has been deemed impossible for too long. New drugs are showing encouraging results, and the goal of improving outcomes for patients with these difficult-to-treat tumours seems more like a possibility than a mere pipe dream. Research in this area is finally gaining momentum. On this wave of renewed enthusiasm from this rare story of hope in cancer drug discovery, the label of undruggable now seems unsuitable and unhopeful, and active therapies for some of the most deadly cancers are now potentially within our grasp.