NEW YORK – Oncologists and patient advocacy groups are eagerly tracking the trajectory of promising drugs that target KRAS, while taking a look at the tumor testing changes that will be needed if such compounds do live up to the hype.
Both Amgen and Mirati Therapeutics recently published or presented preliminary data from early-stage trials of their respective KRAS inhibitors, which target the same G12C mutation in KRAS. Meanwhile, other firms such as Johnson & Johnson and Boehringer Ingelheim are pursuing compounds that target one or more mutations in this oft-altered, but historically difficult-to-target gene.
There are still efficacy and safety data to be gathered, and regulatory hurdles to clear before the drugs make their way into clinics in the US and other parts of the world. Still, findings so far have prompted optimism about the long-term prospects for treating patients with KRAS-mutated tumors. That is particularly true in lung cancer and colorectal cancer, where KRAS mutations are relatively common, and in pancreatic cancer, a difficult-to-treat tumor type rife with KRAS mutations.
Still, at least one drugmaker is planning to submit for FDA approval of its KRAS inhibitor based on data from Phase I/II, single-arm trial in heavily pretreated lung cancer patients.
"It's such a huge unmet need for the patient community," explained Upal Basu Roy, VP Research at the lung cancer-focused non-profit LUNGevity, who said he is cautiously optimistic about new compounds being developed, in light of early efficacy and toxicity data coming out from Amgen and Mirati.
Despite being among the first recurrently mutated genes identified in cancer, the KRAS gene has been notoriously difficult to target, in part due to its central role in a signaling pathway that boosts cell growth and proliferation when the KRAS protein is in its GTP-bound, or "on," form.
Even before they had much of a chance to work — if they were ever going to — the early compounds lobbed at KRAS were simply too toxic for patients to withstand, Roy explained, leading to gastrointestinal issues, hematological problems such as plummeting blood cell counts, and other serious side effects.
The structure of KRAS only deepened the complexity associated with targeting it: the protein has such a strong affinity for GTP that competing with that binding pocket is pretty much out of the question, leaving few options for sites to target with small molecule inhibitors.
"For 40 years, the field has tried to develop direct inhibitors to KRAS," Russell Lipford, director of inflammation and oncology research at Amgen, noted. "Based on the structure of the protein, it's proven really challenging to develop direct small molecule inhibitors."
Drug developers started exploiting one potential wedge in this structure when the University of California at San Francisco's Kevan Shokat and his team characterized the crystal structure of an inactive, GDP-bound form of G12C-mutated KRAS for a paper published in Nature in 2013, confirming that there was a small pocket neighboring the mutant cysteine residue at that site that might be amenable to covalent binding.
With the covalent inhibitor approach, Lipford explained, "if you can get a specific-enough binding event and a specific-enough reaction with the target protein, you can lock the small molecule onto the protein and you don't need to have a great deal of affinity."
Both Amgen and Mirati exploited the covalent binding potential at the cysteine site to develop inhibitors — known as AMG 510 and MRTX849, respectively — that target a KRAS mutation called G12C, which shows up in roughly 13 percent of lung adenocarcinoma cases, 3 to 5 percent of CRCs, and 1 to 2 percent of pancreatic cancers and other solid tumors.
Such drugs are "very specific to the G12C version of the KRAS mutated protein, and these drugs lock the KRAS protein in that inactive state, essentially blocking any signaling that can go on," Roy noted.
While other KRAS inhibitors are under development or evaluation, the two drugs are current front-runners in the field based on early-stage clinical and pre-clinical data reported this fall.
In a paper published in Nature in late October, Lipford and his colleagues reported on the anti-tumor activity of AMG 510 in cell lines, tumor xenograft models in mice, and in four non-small cell lung carcinoma (NSCLC) patients treated through a Phase I clinical trial, demonstrating that the G12C inhibitor prompted an objective partial responses — with tumors shrinking 34 percent and 67 percent within six weeks — in two patients who had progressed on several prior treatments.
The study also highlighted the enhanced immune activity and pro-inflammatory tumor microenvironment features found in mouse models of CRC treated with AMG 510 treatment, along with apparent synergy between AMG 510 treatment and other treatments, including those targeting specific mutations.
For its part, Mirati has outlined the pre-clinical and clinical features of the MRTX849 KRAS G12C inhibitor in an October Cancer Discovery paper and in a scientific presentation at a conference.
Along with apparent immune effects for that KRAS inhibitor, including a rise in HLA antigen expression and the expression of certain cytokines, the team saw a pronounced partial response in two metastatic lung cancer patients and one patient with metastatic CRC who participated in its Phase I/II trial.
One of the lung cancer patients who responded to the treatment appeared to have a deepening response over time — going from 33 percent reduction in tumor size at six weeks to 43 percent at the subsequent scan — despite carrying additional KEAP1 and STK1 gene mutations previously proposed as contributors to KRAS inhibitor resistance, explained Mirati President and CEO Chuck Baum.
Canadian medical oncologist Parneet Cheema called the new drugs "exciting," as they may make it possible to "target what we never thought was targetable."
"I'm thrilled as a scientist, as well as a patient advocate, to see that we are actually turning the tables on the KRAS gene," noted LUNGevity's Roy. "I can actually talk about it on a positive note — that there is something on the horizon for our patient community."
The US Food and Drug Administration (FDA) has granted Amgen's AMG 510 an Orphan Drug Designation in pre-treated, metastatic NSCLC and CRC cases marked by KRAS G12C mutations. It has also secured a Fast Track Designation from the FDA in previously treated, metastatic NSCLC cases involving KRAS G12C mutations.
Lipford noted that Phase I trials of AMG 510 — alone or in combination, with varying dosing and scheduling strategies — are ongoing in lung cancer and other tumor types. The firm is also enrolling patients for a Phase II clinical trial, while pursuing accelerated approval "with a number of regulatory agencies," starting with the FDA. Those trials will initially focus on patients with KRAS G12C mutations who have already failed first-line treatments and lack other treatment options.
"We're very keen to develop this molecule to treat any patient who has a tumor with a KRAS G12C mutation, regardless of the tumor type," he said, noting that many CRC patients already know their KRAS G12C mutation status, since KRAS mutations have been linked to treatment non-response for CRC patients receiving EGFR inhibitors such as cetuximab (Lilly's Erbitux) or panitumumab (Amgen's Vectibix).
Despite the EGFR inhibitor non-response documented for CRC patients with KRAS mutations, Baum noted that the Mirati team has very early data suggesting a combination treatment with MRTX849 and the EGFR inhibitor cetuximab may be more effective than the KRAS inhibitor alone in some CRC patients with the G12C mutation.
Such results may influence the strategy the firm pursues when seeking MRTX849 approval, he explained. Baum noted that the company will likely pursue Phase III clinical trials that include an evaluation of MRTX849 in combination with cetuximab in CRC patients.
For lung cancer, on the other hand, Mirati plans to assess MRTX849 in combination with an anti-PD-L1 or anti-PD1 checkpoint inhibitor in lung cancer, since the KRAS G12C mutation tends to turn up in smokers or former smokers, patients with higher tumor mutational burdens, and cases that may be more prone to PD-L1 positivity. If such a combination pans out in ongoing early-stage trials, the company will conduct a larger randomized clinical trial to test this approach in the first-line setting.
In the meantime, Mirati will likely seek accelerated approval for MRTX849 in lung cancer patients on their second-, third-, or subsequent lines of treatment, Baum said, based on response rates in a single-arm study of the drug in roughly 100 patients enrolled in the Phase I/II clinical trial that's already underway.
"This study could be our initial registration study for single-agent treatment, in particular in lung cancer," he explained. "But the same study also includes [KRAS inhibitor combinations with immunotherapy or cetuximab]."
Experts in the field and patient advocates haven't objected to the fact that Mirati's registrational trial wouldn't randomize patients to chemotherapy and compare their responses against patients receiving MRTX849 — at least in a later line treatment setting.
It should be possible to benchmark lung cancer patients' responses to the KRAS inhibitors against known chemotherapy responses in pretreated cancer patients with KRAS mutations, observed LUNGevity's Roy, who is not directly involved in developing any of the drugs, but routinely speaks with drug companies about burgeoning treatments that may benefit lung cancer patients and helps recruit patients for promising clinical trials.
"We know very clearly how patients with a KRAS mutation fare on chemotherapy, or some of these older agents. We know the natural history of the disease, for lack of a better word," Roy said, suggesting Phase III clinical trials may not be needed in certain patient populations.
To tease out the potential benefit of the new KRAS inhibitors in the first-line setting in lung cancer, though, Cheema noted that randomized Phase III trials will be needed to see how the drugs stack up against chemotherapy and immunotherapy, and to work out the most beneficial treatment sequences or combinations.
Moreover, in many parts of the world, access to such drugs will ultimately hinge on results from such Phase III trials, Cheema added — a consideration echoed by LUNGevity's Roy.
"A lot of the [regulatory bodies] in Europe, as well as in Canada, require Phase III studies for a particular drug to be approved," Roy noted, adding that "from a purely business perspective," companies will ultimately reach a much wider patient population if they can demonstrate the effectiveness of their drugs in large, randomized controlled trials.
In the meantime, such clinical trials may offer opportunities for eligible patients to access the KRAS G12C inhibitors in the not-too-distant future — provided patients actually know their KRAS mutation status.
"A lot of patients do not know about the KRAS target, which has been an impediment in enrolling some of these trials," Roy said, noting that LUNGevity is part of an initiative called Take Aim to increase biomarker testing among lung cancer patients so they can have access to personalized targeted treatment and immunotherapy options and enroll in therapeutic studies.
Work done by the Take Aim group so far suggests that KRAS testing is not all that common in lung cancer patients, Roy noted, since there have not been effective drugs targeting these mutations that might spur such testing.
Those results track with what Cheema is seeing in Canada, where broad panel sequencing on tumors is not routinely done. While some centers do panel sequencing, others rely on sequential single gene tests, she explained. Those single gene tests can use up precious tissue samples, and become increasingly expensive as more genes are analyzed. In addition, KRAS testing is far from guaranteed, depending on patients' cancer type and insurers' coverage policies.
Consequently, Cheema and Roy speculated that it will be necessary to reach out to not only doctors — from oncologists to pulmonologists, but also payors, insurers, patients, and policy-makers to expand KRAS testing access, especially if G12C and other KRAS-targeting drugs pan out in ongoing and upcoming clinical trials.
"Over the past year, we've seen an increase in the use of comprehensive genomic profiling, which automatically means KRAS is included in the panel," Roy said. "But we still have a long way to go."