When Kronos Bio committed $120 million for Gilead’s portfolio of Syk inhibitors in July, it was as clear a sign as any that tyrosine kinase blockers are still hot properties in oncology research, despite the rise of flashy new cell therapies.
Syk, or “spleen tyrosine kinase,” is just one of several emerging tyrosine kinases targeted by the biopharma industry. More than 50 kinase-inhibiting meds have been approved in the U.S. so far, and many more are queuing up for FDA review.
Plus, at least 20 are next-generation versions of kinase pathways that have already been validated, including VEGFR and BTK. But the race is on to develop novel kinase inhibitors, too.
Among the hottest targets is KRAS, a gene that in its mutated form is a well-known cancer driver. Amgen is widely considered the leader in the KRAS field with its contender AMG 510, which turned heads in September 2019 with early data showing responses in all of 10 patients with non-small cell lung cancer (NSCLC) in a trial of the highest dose.
More recently, the company reported data from trials of the drug in several other tumor types at the virtual meeting of American Society for Clinical Oncology. But responses were modest, leading some analysts to declare NSCLC as the best prospect for AMG 510—and, now, all eyes are on the European Society for Medical Oncology virtual meeting this weekend, where new KRAS data are set for debut.
RELATED: Mirati clears first clinical hurdle in KRAS race against Amgen
Meanwhile, Amgen is facing competition from Mirati, which has turned in partial responses for its drug, MRTX849, in colon and lung cancers. Now, Boehringer Ingelheim, Revolution Medicines and Merck all want in on the action, with the latter putting down $2.5 billion to gain access to a pipeline from Taiho Pharma and Astex that includes a KRAS inhibitor.
But targeting KRAS carries certain risks. As these inhibitors progress through clinical trials, investors will no doubt be focused on safety: In July, Eli Lilly dropped a KRAS effort from its pipeline after a phase 1 trial uncovered “unexpected toxicity,” the company said at the time.
Confronting challenges in tyrosine kinase inhibition
Another new target in tyrosine kinase development is protein kinase B (Akt), which is involved in regulating the estrogen receptor. AstraZeneca, for one, is testing its Akt inhibitor, capivasertib, with Faslodex in ER-positive breast cancer. In the summer of 2019, the British drugmaker presented phase 2 data showing the combo doubled the time to disease progression over Faslodex alone and extended patients' lives by six months.
Roche and its Akt inhibitor, ipatasertib, have faced some challenges—the company abandoned its plan to develop the drug for triple-negative breast cancer patients to use ahead of surgery.
But, clearly, Roche is still optimistic about Akt inhibition. It’s recruiting patients for new ipatasertib trials in breast, ovarian and prostate cancers, as well as the tough-to-treat brain cancer glioblastoma. And, in June, it released data showing the drug combined with Zytiga improved progression-free survival in prostate cancer patients with an abnormality called PTEN loss.
RELATED: Roche phase 3 hits goal in subgroup of prostate cancer patients
MET is another emerging target—and one that has seen its share of challenges. MET, also called cMET, is a tyrosine kinase that is either over-expressed or mutated in several cancer types, helping drive the survival and replication of tumor cells. In October 2019, AstraZeneca dumped the development of its MET inhibitor, savolitinib, in papillary renal cell carcinoma after the drug failed to best Pfizer’s Sutent in a phase 3 trial.
Still, according to the company's latest pipeline update, AstraZeneca's testing savolitinib solo in a cross-section of lung cancer patients. And it's running trials of the MET inhibitor paired with AZ's blockbuster EGFR inhibitor, Tagrisso, for NSCLC patients whose cancer advanced after Tagrisso therapy or developed resistance to tyrosine kinase inhibitors more broadly.
Novartis and Merck KGaA have stayed in the MET game, too. Persistence paid off first for Novartis, which nabbed FDA approval in May for Tabrecta (capmatinib) to treat NSCLC patients with MET exon 14 skipping mutations. The approval was based on a trial showing the drug produced a 68% response rate in treatment-naïve patients.
Meanwhile, Merck KGaA’s tepotinib has produced an overall response rate of 45% to 50% in the same subset of NSCLC patients and has been fast-tracked by the FDA.
New approaches to old kinase targets
Much of today's work in kinase inhibition targets cancer pathways that are already well known—but aims to do it better. Seattle Genetics, for example, is leading the charge to improve HER2 breast cancer treatment. In January 2018, it laid out a remarkable 69% premium to pick up Cascadian Therapeutics and its HER2-targeted tyrosine kinase inhibitor tucatinib, which it developed for breast cancer patients who've stopped responding to Roche’s Herceptin, Perjeta or Kadcyla.
The company wowed investors with data showing that adding its drug to Herceptin and capecitabine slashed the risk of disease progression or death by 46% over Herceptin and capecitabine alone. In April of this year, tucatinib won an FDA green light under the brand name Tukysa.
BTK and EGFR are also popular targets. BTK inhibition has already been validated in blood cancers with blockbusters like AbbVie’s and Johnson & Johnson’s Imbruvica. Now, Eli Lilly and Bristol Myers Squibb are chasing the same target.
RELATED: ASH: Eli Lilly plots 'ambitious' cancer program after sharing early BTK data
As for EGFR, it’s the target for such well-known drugs as Roche’s Tarceva and AstraZeneca’s Iressa. More than a half-dozen successors are in the pipeline, including Taiho Pharma and Cullinan Oncology, which teamed up in February to develop the EGFR inhibitor TAS6417 in lung cancer.
As investment in tyrosine kinase inhibition continues to accelerate, the targets are getting more and more precise. Take Kronos’ acquisition of Gilead’s Syk inhibitors, for example. The drugs are being developed for patients with acute myelogenous leukemia (AML) that overexpresses two transcription factors, HOXA9 and MEIS1.
Combating resistance
One of the biggest challenges oncologists face in prescribing targeted drugs is that their patients often become resistant to the treatments. That’s why the next frontier in this field is identifying gene mutations that confer resistance and finding new drugs to target those wayward genes.
Among the most common mutations in patients taking tyrosine kinase inhibitors is called a “solvent front” mutation. The solvent front is the area on the kinase surface that many inhibitors attach themselves to—a mechanism disrupted by resistance mutations.
Turning Point Therapeutics has instead designed drugs that bind to an area inside of cancer cells called the ATP pocket, bypassing any solvent-front mutations that develop. Co-founded by the Pfizer scientist who was key in developing the tyrosine kinase inhibitor Xalkori, Turning Point raised $166 million in an IPO in April 2019.
Turning Point’s lead compound, repotrectinib, posted an objective response rate of 86% in an interim analysis of a phase 2 trial in NSCLC, leading the company to suggest it may have an accelerated path to market.
RELATED: Roche to pay Blueprint $775M for pralsetinib rights, setting up showdown with Lilly
Another culprit in drug resistance is RET fusion, a genetic abnormality that some EGFR-positive tumors develop over time. In May, Eli Lilly won early FDA approval for its RET inhibitor selpercatinib, one of the assets picked up last year in its $8 billion Loxo Oncology buyout. The drug was approved to treat thyroid cancers with RET fusion.
Lilly is neck and neck in the RET market with Roche, which in July laid out $775 million for the rights to Blueprint Medicines’ pralsetinib. The RET inhibitor has scored response rates of 65% in NSCLC and 91% in thyroid cancer. Blueprint won approval for pralsetinib, now called Gavreto, in RET-fusion-positive NSCLC in September.
This article is the second in a series.
Part 1: Biopharma rides a new wave of targeted treatments for cancer
Part 3: Biopharma nurtures the next generation of immuno-oncology targets