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The undruggable cancer target: KRAS inhibitors move ahead in the clinic

Some of the deadliest cancer mutations occur in a gene called KRAS. Drugs that target this gene to stop cancer cells from growing further are known as KRAS inhibitors, which have been regarded as a step forward in cancer research.

These drugs seem to hold clinical promise as, only recently, a spinout of California-based BridgeBio launched with $200 million to solely focus on the development of KRAS inhibitors. A phase 1 study for bbo-8520 is currently enrolling participants. 

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    Drugging the undruggable

    Over the last three decades, KRAS mutations were considered undruggable. The term undruggable refers to target sites (for a specific disease) lacking the ability to interact with other molecules including drugs. This posed a serious challenge when designing drugs to bind to KRAS mutations.

    Dr. Emiliano Calvo, director of Clinical Research at START Madrid-Centro Integral Oncológico Clara Campal (CIOCC) hospital in Spain, explained that KRAS proteins in particular, had a smooth surface with only few pockets for a drug to bind effectively. They also have a very high affinity for molecules like GTP and GDP – involved in cellular functions – making it difficult for small drug molecules to compete well in binding to KRAS. Moreover, KRAS cycles between its inactive and active states, which challenges the sustained binding of a drug to it.

    Nevertheless, these hurdles have been addressed, Calvo pointed out.   

    “Recent advancements have tackled these challenges by designing small molecules called covalent inhibitors that form a covalent bond with the cysteine residue in the G12C mutant form of KRAS, which locks the protein in an inactive GDP-bound state, and by targeting less conserved regions of the protein that are unique to the mutant form (allosteric inhibitors),” said Calvo.

    How do KRAS inhibitors work?

    As drug design has been adapted to tackle these problems, more and more KRAS inhibitors have been cropping up. BridgeBio’s bbo-8520 works like a typical KRAS inhibitor would. These drugs target the KRAS protein, a small enzyme that is involved in cell signaling pathways that regulate cell growth, differentiation, and survival, Calvo explained. 

    “Mutations in the KRAS gene result in a permanently active protein that drives uncontrolled cell division and tumor growth. KRAS inhibitors specifically bind to the mutated form of KRAS, particularly the G12C mutation, locking it in an inactive state. This inhibits the downstream signaling pathways (like the MAPK/ERK and PI3K/AKT pathways) essential for cancer cell proliferation and survival,” said Calvo.

    bbo-8520 is being evaluated in people with non-small cell lung cancer (NSCLC), the most common type of lung cancer that makes up over 80% of lung cancer diagnoses in the U.S. More than 2 million people were diagnosed with NSCLC across the world in 2020, according to a report by Cancer.Net. 

    KRAS inhibitors battle it out in the clinical arena

    KRAS inhibitors head-to-head: adagrasib versus sotorasib

    Like BridgeBio, other biopharmas are ushering their candidates towards the clinic. American cancer therapy company Mirati Therapeutics’ adagrasib, which was recently bought by pharma giant Bristol Myers Squibb in a multi-billion dollar deal, is also being investigated for NSCLC. Known by its brand name Krazati, it bagged accelerated approval from the U.S. Food and Drug Administration (FDA) for patients with NSCLC who have received at least one prior therapy, two years ago. It has also been cleared by the European Commission (EC) and the U.K. Medicines and Healthcare products Regulatory Agency (MHRA). 

    Its phase 3 study is on course to beat Amgen’s sotorasib as well. Results of a confirmatory trial were encouraging as the trial met its primary endpoint of progression-free survival, which is the time during and after a therapy where a patient’s condition does not get worse. The drug was also more effective than chemotherapy, which is the standard of care for NSCLC, according to the press release.  

    The battle between adagrasib and sotorasib is getting closer than ever. Sotorasib, which goes under the name Lumakras, was the first-ever KRAS inhibitor to secure the FDA’s seal of approval back in 2021. While it is regarded as a major player in the KRAS inhibitor space, it has been a bumpy ride for the drug in recent times. 

    Sotorasib’s approval was based on a trial with 124 patients with KRAS G12C mutation-positive NSCLC who had disease progression after receiving an immunotherapy or chemotherapy. A 36% objective response rate (ORR) – the percentage of people who respond to a treatment within a certain period of time – was observed, and the median response duration was 10 months.

    But the drug failed to grab full approval after a regulatory panel found its phase 3 study unreliable in October. Besides, adagrasib and Swiss multinational Roche’s divarasib have threatened Amgen’s stronghold. 

    Could divarasib work better than sotorasib and adagrasib?

    Roche’s data suggests that the drug could work better than sotorasib and adagrasib. Study authors stated that “divarasib appears to show numerically more responses and longer progression-free survival among patients with either NSCLC or colorectal cancer than those observed with existing single-agent KRAS G12C inhibitors,” in a research paper published in The New England Journal of Medicine. 

    In both NSCLC and colorectal cancer, divarasib towered over other KRAS inhibitors. It had a 53.4% response rate in 60 patients in NSCLC, and 29.1% in colorectal cancer. Although colorectal cancer results are not as high as NSCLC, divarasib fared better than sotorasib and adagrasib in treating the cancer.

    “The efficiency of KRAS inhibitors can vary but has shown promising results in different settings, including a demonstrated significant efficacy in NSCLC patients with KRAS G12C mutations, with overall response rates around 40% and disease control rate about 80%, and with a manageable safety profile, leading to FDA approval in this indication,” said Calvo. “In other tumor types, like colorectal cancer or pancreatic ductal adenocarcinoma (PDAC) – the most common type of pancreatic cancer – some antitumor activity has been observed as well, but not to that degree so far yet.”

    Another emerging contender is Swiss multinational Novartis’ JDQ443. JDQ443 is being tested in a phase 3 study against the chemotherapy drug Docetaxel in patients with NSCLC. A phase 1 study is also recruiting patients who have KRAS mutant-positive advanced solid tumors.

    Promising early-stage KRAS inhibitor candidates enter the clinic

    Meanwhile, Mirati’s other KRAS inhibitor MRTX1133 has shown robust results in preclinical studies. Its ability to bind to the KRAS protein, both in its active and inactive states, was exhibited in studies where it inhibited the KRAS pathway and shrunk tumor models.

    More and more preclinical candidates are sprouting up to target this protein that was once considered undruggable. Massachusetts-based Verastem Oncology presented a poster for its KRAS drug VS-7375, which showed efficacy against pancreatic cancer and colorectal cancer in mice. Verastem’s partnership with Chinese biotech GenFleet Therapeutics paves the way for VS-7375’s phase 1 study to be held in China. 

    American biotech Frontier Medicines FMC-376 is similar to VS-7375, as they both bind to KRAS in its active and inactive states. The candidate reduced tumor sizes in mice models of NSCLC and colorectal cancer. And, in combination with an immune checkpoint inhibitor – a drug that blocks proteins called checkpoints – the efficacy improved. A phase 1 study is ongoing.

    American cancer drug companies Quanta Therapeutics and Revolution Medicines are also invested in bringing their candidates through the clinic. Quanta’s QTX3544 showed anti-tumor activity in preclinical models and so did Revolution’s RMC-9805. The latter is in phase 1 trials for KRAS-driven cancers – mainly NSCLC, pancreatic cancers and colorectal cancers. Quanta has a pipeline devoted to KRAS inhibitors. Its most advanced drug is in the phase 1 stage.

    Managing KRAS inhibitors side effects and drug resistance

    Like many cancer drugs, KRAS inhibitors have been found to cause side effects like diarrhea, nausea, and vomiting, liver toxicity – as the elevation of liver enzymes can cause liver damage – and fatigue. A less seen side effect is neutropenia, which is a condition where you have a low number of white blood cells called neutrophils in the blood.

    “Managing these side effects often requires dose adjustments, supportive care, or temporary discontinuation of the therapy,” said Calvo. 

    Additionally, patients are also faced with the challenge of drug resistance. In cases of acquired resistance in cancer, the cells alter their form to evade being a cancer drug target. KRAS inhibitors like adagrasib and sotorasib are privy to this. A better understanding of drug resistance and a combined treatment strategy are key to tackling this issue, according to a study published in Nature. 

    Nevertheless, these drugs fulfill the therapeutic unmet needs of cancer patients with a KRAS mutation. These mutations make up 90% of people with PDAC, 40% with colorectal cancer, and 30% with NSCLC. So, it makes “these inhibitors relevant for a significant patient population,” according to Calvo.

    Calvo concluded: “Patients with KRAS-mutant cancers often have limited treatment options, especially after the failure of conventional therapies, so, these inhibitors provide new treatment options to these oncology patients where, in specific indications, early clinical data suggest these inhibitors might improve their outcomes.”

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