NEW YORK – Theseus Pharmaceuticals is developing targeted pan-variant treatment programs that it envisions can help patients who have relapsed on multiple lines of therapy and be used as pre-emptive strategies in earlier lines to stave off resistance.
Now that it's well known, and even expected, that cancer patients will eventually develop resistance to targeted therapy, Theseus is among a crop of new firms exploring next-generation drugs that address resistance before it even occurs. The Cambridge, Massachusetts-based drugmaker has three pan-variant targeted therapy programs, for which it is ramping up its clinical development this year with the first clinical trial starting in January and earlier-stage programs inching toward investigational new drug submissions in 2023.
Treating patients with resistance is like playing "whack-a-mole," said Theseus CEO Tim Clackson. Resistance can be driven by "on-target" mutations that appear in the same pathway that the drug is targeting, or by off-target mutations in a completely different genetic pathway.
"The more often you treat a patient with different therapies, the more time the patient's tumors have a chance to mutate and create resistance," Clackson explained. Some patients can develop more than one resistance mutation, he continued, which can make it even more difficult to treat because the tumor has two ways to escape targeted therapies.
"That's why you need a pan-variant inhibitor. You need a molecule that could hit all of those resistance mutations, otherwise you're just going to have a very short [duration of] benefit for the patient, and then the other mutations are going to grow up," Clackson said.
Theseus' lead program is THE-630, a pan-variant KIT inhibitor, which is in a Phase I/II trial for patients with unresectable or metastatic gastrointestinal stromal tumors (GIST) who have developed resistance to prior KIT-targeted therapies. The company's other two pan-variant programs are in the preclinical phase. Within Theseus' EGFR program in non-small cell lung cancer, the firm will pick a candidate to advance clinically in the third quarter of this year. Theseus hasn't disclosed the third program and target yet.
In the ongoing Phase I/II trial of THE-630, investigators are enrolling GIST patients who have progressed on or are intolerant to other tyrosine kinase inhibitors such as Novartis' Gleevec (imatinib), Pfizer's Sutent (sunitinib), Bayer's Stivarga (regorafenib), Blueprint Medicines' Ayvakit (avapritinib), or Deciphera Pharmaceuticals' Qinlock (ripretinib).
"Gastrointestinal stromal tumors were one of the earliest solid tumor types that were targetable with precision oncology medicines, and there are now several different molecules available to patients to treat that initial disease," Clackson said. "Unfortunately, they all suffer from this Achilles' heel of targeted therapies in general, which is resistance."
While KIT mutations occur in about 80 percent of GIST cases, early-generation drugs usually targeted only one or two types of KIT variants. For example, Gleevec has shown the greatest efficacy in patients with KIT exon 11 or exon 9 mutations. When patients develop on-target resistance to these drugs, however, it is through the emergence of KIT variants that can't be blocked by currently available drugs, such as variants in exons 13 and 14, which are associated with the ATP binding pocket, or variants in exons 17 and 18, which occur in the activation loop.
However, THE-630 has shown in preclinical models to have activity across all of these variants. In preclinical data presented last year, THE-630 demonstrated activity not only against activating mutations in KIT exon 9/11, like other drugs in the space, but it also showed efficacy in tumor models with resistance mutations in KIT exon 13/14 and exon 17/18.
"THE-630 is trying to break that cycle [of resistance] once and for all by representing a molecule that is almost immune to on-target resistance," he explained. "The aim is to look at each of the different on-target mutations in KIT that cause resistance to those prior agents and create a molecule that can inhibit any of them from the get-go. By doing that, we should be able to help patients who have gone through all those molecules and have very resistant diseases."
Theseus expects to report safety, tolerability, and initial efficacy data from the THE-630 trial in the first half of 2023. The researchers will also analyze biomarkers in the study and are collecting blood samples to analyze circulating tumor DNA (ctDNA) at different points of the treatment cycle and determine which mutations are being affected by the drug, Clackson said.
The company is approaching its EGFR program similarly. There are several generations of EGFR inhibitors available on the market for the treatment of EGFR-mutant non-small cell lung cancer, including Genentech's Tarceva (erlotinib), Boehringer Ingelheim's Gilotrif (afatinib), and AstraZeneca's Tagrisso (osimertinib).
However, first-generation EGFR inhibitors available on the market are typically more effective for EGFR L858R and exon 19 deletions. Next-generation drugs tackled these mutations as well as common on-target resistance mutations, such as EGFR T790M and C797S variants.
"The standard set of outcomes that you often see with targeted therapy has played out [with EGFR inhibitors]. A particular mutation emerged with first-generation erlotinib that causes resistance, and then other drugs, the second- and now third-generation EGFR inhibitors, have been developed to try and tackle that," Clackson said.
Tagrisso was developed to home in on EGFR T790M. Even then, the other variant, C797S, provided a route of escape and allowed tumors to continue growing. Clackson noted that patients with the C797S variant have an unmet need for treatment, which is something Theseus is trying to address within its EGFR program.
"We're developing a pan-variant, fourth-generation EGFR inhibitor to solve that problem," Clackson said. "The design of that molecule is very important because you need to be able to hit not only that C797S mutation but all the other mutations that might still be present in that patient from his or her prior therapy; otherwise, those mutations will grow up. You can't have a drug that just hits that one flavor."
Theseus presented data for two of its potential pan-variant EGFR compounds at the American Association for Cancer Research annual meeting last month. Both compounds demonstrated anti-tumor activity in tumor models harboring activating EGFR mutations, L858R and exon 19 deletions, as well as T790M and C797S resistance mutations.
Theseus is conducting further studies on the two compounds and plans to pick the best one to advance to the clinic in Q3.
Clackson believes these pan-variant drugs can have utility in different settings where there is unmet need. Theseus is looking to advance THE-630 first as a fifth-line treatment for patients who are heavily pretreated and have developed several resistance mutations.
But there's also an opportunity in earlier lines of treatment. The Theseus team hopes to explore THE-630 and the EGFR candidate, when identified, as second-line treatments to try to block in advance the resistance pathways that tumor cells are expected to exploit. "You can really have an outsized patient benefit if you use pan-variant inhibitors in that earlier setting," he said.
The Theseus team includes veterans of another company also focused on targeted therapy resistance, Ariad Pharmaceuticals, which was acquired by Takeda in 2017. Clackson, who was part of the Ariad team, noted that the drugs developed by Ariad, the ALK inhibitor Alunbrig (brigatinib), the EGFR exon 20 inhibitor Exkivity (mobocertinib), and the chronic myeloid leukemia treatment Iclusig (ponatinib), took a similar approach to resistance and have all been approved in the US.
"We had a deep motivation to come together and do it again at Theseus," Clackson said.