Since the early 1980s, cancer researchers have chased a gene called KRAS that's frequently mutated in many lung, colon and pancreatic tumors. Their efforts to target it repeatedly came up short, earning the elusive gene a reputation as "undruggable."
That label no longer applies. On Friday, the Food and Drug Administration approved the first cancer medicine that can block KRAS, clearing Amgen's Lumakras on a conditional basis for previously treated, locally advanced or metastatic non-small cell lung cancer. The drug, also known as sotorasib, is the result of recent breakthroughs in chemistry that have allowed scientists to target a hidden groove on the mutant KRAS protein.
"KRAS mutations have long been considered resistant to drug therapy, representing a true unmet need for patients with certain types of cancer," said Richard Pazdur, the FDA's top official for cancer drug reviews, in a statement.
Lumakras' approval is the latest advance from a cancer research field that's delivered many new targeted therapies over the past several years. Powerful drugs that block mutated cancer-linked genes like EGFR, ALK and RET are now available, broadening options for patients beyond chemotherapy and radiation. As a result, cancer treatment for certain types of tumors, like those of the lung, has become much more personalized and based on genetics.
In clinical testing, treatment with Lumakras shrank tumors in a little over a third of patients with advanced lung cancer who had previously been treated with other drugs. Responses lasted a median of ten months and median progression-free survival, a measure of how long cancer is held in check, was nearly seven months.
Most study participants experienced side effects to treatment, typically diarrhea, nausea and elevations in liver enzymes. In 20% of patients, side effects were more severe, and 9% discontinued treatment.
While Lumakras' benefit is relatively modest, the results mark a significant advance for the treatment of KRAS-mutated lung cancer, for which there are no good options after initial treatment with either chemotherapy or immunotherapy. The response rate and progression-free survival reported by Amgen for Lumakras are roughly double what would be expected from a second round of chemotherapy, for example.
The drug is aimed at a specific type of KRAS mutation known as G12C that Amgen estimates is present in about 13% of patients with non-small cell lung cancer. Approximately 25,000 people are newly diagnosed with lung tumors harboring that mutation each year, according to the company.
G12C mutations are also found in other cancers, like colorectal, but much less frequently. Amgen is studying Lumakras in colorectal cancer, but results to date appear less promising.
Amgen will charge $17,900 per month for Lumakras at list price, which doesn't account for rebates or discounts that may be offered to insurers.
The biotech company sped Lumakras through development, with just two years between when the first patient was treated and the company's submission to the Food and Drug Administration for an approval. Emboldened by the drug's promise, Amgen has launched a clinical trial program testing Lumakras across 13 different tumor types and in combination with 10 other kinds of cancer drugs.
A Phase 3 trial that compares Lumakras to chemotherapy recently finished enrolling volunteers. Results are "event-driven," meaning their timing depends on how quickly participants' cancers progress. Amgen expects to be able to provide a more specific timeline as the study continues, according to Greg Friberg, a therapeutic area head for Amgen.
Combinations with other drugs, meanwhile, will likely be important to expand on the benefit of Lumakras alone, and to prolong treatment responses.
"Monotherapy is showing therapeutic results. That's why it was approved, but we also know that resistance can develop, so we have to overcome resistance," said Ravi Salgia, chair of City of Hope's medical oncology and therapeutics research, referring to how tumors can evade targeted treatment over time.
Approval for Lumakras came well ahead of the FDA's review deadline of Aug. 16, likely the result of the designations granted by the agency to Amgen that allow for enhanced collaboration and communication. Amgen must confirm the drug's benefits through further testing to maintain the approval, with that Phase 3 study a likely path to do so.
Many new cancer drugs are cleared through this accelerated pathway, on the basis of interim measures like response rates. Critics argue the speed comes at the cost of putting high-priced drugs on the market without knowing whether treatment can actually extend survival.
Confirmatory testing can also take years to complete and sometimes fails to prove out early benefits, leaving regulators in a difficult position.
In addition to submitting to the FDA, Amgen has also filed Lumakras for approval in the U.K., European Union, Australia, Brazil and Canada.
Treatment with Lumakras will require testing for the KRAS G12C mutation the drug targets. Amgen estimates about 55% of patients with non-small cell lung cancer in the U.S. currently know their mutation status, Friberg said in an email. The company expects uptake will be rapid among those patients.
Salgia, from City of Hope, also predicted fast adoption, noting testing for KRAS mutations is already being done in clinical practice.
The FDA also approved two companion diagnostics for Lumakras on Friday, one from Qiagen and one from Guardant Health. Qiagen’s test will analyze tumor tissues, while Guardant’s will analyze plasma specimens to determine if Lumakras is appropriate for patients. According to the FDA, a patient’s tumor should be tested if no mutation is detected in the plasma specimen
Other companies are following close behind Amgen and Lumakras. Mirati Therapeutics, a smaller biotech based in San Diego, has been developing a drug similar to Lumakras that targets KRAS G12C mutations. Updated study results in lung cancer are due in the second half of the year and the company expects to ask for approval later this year. Two Phase 3 trials of the drug are ongoing.
Pharmaceutical firms like Johnson & Johnson, Eli Lilly, Boehringer Ingelheim and Roche are also advancing KRAS-blocking drug candidates.
Note: This story has been updated to include details from Amgen and additional comment.