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Sotorasib, a cancer drug developed by Amgen aimed at blocking the KRAS G12C mutation, reduced tumors in 37% of patients with advanced lung cancer and delayed tumor progression by about seven months, according to new clinical data—findings that, according to some experts, represent a significant breakthrough for oncology care, STAT News' Adam Feuerstein reports.
About the KRAS G12C mutation
According to Feuerstein, the KRAS protein has long been known to cause cancer, but scientists have struggled to develop drugs to block it because the protein has virtually no features and is spherical, meaning that there are few points where drugs can attach to the protein. Bob Li, an oncologist and lung cancer expert at Memorial Sloan Kettering Cancer Center and the principal investigator on Amgen's clinical trial, told Feuerstein that "KRAS is the most frequent genetic driver of human cancer," and "[d]espite 40 years of hard research, we have not been able to crack it."
Although there are some approved cancer drugs that target the KRAS protein, there currently is no approved treatment that directly targets the G12C mutation of the KRAS protein, Feuerstein reports. According to Amgen, the G12C mutation of the KRAS protein is found in about 14% of non-small cell lung cancer adenocarcinomas, as well as 4% of colorectal cancers and 2% of pancreatic cancers.
Amgen touts clinical trial data on sotorasib as promising
But Amgen on Thursday announced the new results from its Phase 2 trial on sotorasib, which showed promise against the G12C mutation, the company said.
For the trial, Amgen enrolled 126 patients who had advanced non-small cell lung cancer with the genetic mutation KRAS G12C. All of the patients previously had been treated with a median of two other anti-cancer medicines that were no longer working. There was no control group in the trial, so all of the participants received sotorasib.
In total, 37% of the 124 evaluable patients in the trial saw a reduction in tumor size that was clinically meaningful after their treatment with sotorasib, Amgen said. Further, Amgen said that three patients' tumors were completely eliminated. The median amount of time for tumor response was 10 months, according to Amgen.
Further, the data showed that the median time of progression-free survival, or the amount of time patients lived before their tumors worsened, was 6.8 months among all 126 patients enrolled in the trial, Amgen said.
About 20% of patients reported side effects during the trial, and nine patients stopped their treatment with sotorasib during the trial because of side effects. One patient experienced severe toxicity of lung inflammation and difficulty breathing, Amgen said. No deaths occurred as a result of side effects related to sotorasib, however.
'This is a clear winner'
Li said the clinical trial results represent "a milestone in oncology," given the difficulties researchers have had in targeting the KRAS protein. Further, Li said the nearly seven-month-long delay in tumor progression observed in the trial was double what physicians typically see with standard chemotherapy treatments.
"This is to me a significant step forward for these patients," he said.
Separately, Narjust Duma, an oncologist and lung cancer expert at the University of Wisconsin School of Medicine and Public Health, called the results "a big deal … because KRAS is a holy grail of lung cancer."
According to Duma, sotorasib could make it possible for physicians to treat a large number of lung cancer patients whose prognosis is poor otherwise.
Similarly, Stephen Liu, director of the lung cancer program at Georgetown Lombardi Comprehensive Cancer Center, said, "This is a clear winner for second-line lung cancer"—meaning the treatment could be useful for treating patients for whom first-line cancer treatments stop working, Feuerstein reports.
However, Liu said he's not as confident about using sotorasib as a first-line treatment for patients recently diagnosed with lung cancer. "For a targeted drug, you want to see a majority of patients have a response, so a 37% response rate doesn't cut it," he said.
Still, Liu added that providers could use sotorasib in combination with another treatment, such as a checkpoint inhibitor, to be more effective for first-line lung cancer patients (Feuerstein, STAT+, 1/28 [subscription required]).
4 immediate takeaways for cancer administrators and providers
By Deirdre Saulet, Expert Partner
Lung cancer's reputation as the deadliest form of cancer is well deserved, as it accounts for about 25% of all cancer deaths. However, advances in treatment for non-small cell lung cancer (NSCLC) have led to marked improvements in lung cancer survival, which has spurred record single-year declines in cancer mortality over the past two years.
Sotorasib has the potential to add to these gains, especially for patients whose tumors have progressed on traditional chemotherapy and/or PD1/L1 inhibitors. And although I still hope that lung cancer screening adoption will eventually pick up and lead to more early-stage diagnoses, the reality is that even more patients are going to be diagnosed with late-stage lung cancer in the coming years due to Covid-19. Furthermore, we will continue to see a growing proportion of "never-smokers" diagnosed with late-stage lung cancer unless lung screening guidelines are expanded to include them. This new targeted treatment, if approved by the FDA, could extend survival for a number of these patients.
In light of this good news, there are four immediate takeaways for cancer administrators and providers:
- Find ways to measure and ensure that providers are following recommendations for comprehensive biomarker testing. KRAS-positive lung cancers make up about 15% to 25% of all NSCLC diagnoses. The good news is that standard of care recommends testing for a panel of biomarkers, including KRAS, upon a lung cancer diagnosis. The bad news is that claims data analyses and conversations with experts reveal that there is wide variability when it comes to adhering to these recommendations. As more targeted treatments like sotorasib come on the market, it is critical that providers have the decision support needed to order the right biomarker tests for the right patients at the right time.
- Prepare for patient questions—and manage their expectations. Cancer patients don't just learn about new treatments from their care team; media coverage, TV and social media advertising, and online patient communities all spread information, often without adequate coverage of potential risks and limitations. Providers need to make sure they're prepared to respond to patient inquiries and requests for specific medications. Furthermore, not all patients will benefit from targeted treatments such as sotorasib, even when they meet the criteria. Providers must be prepared to ground patient expectations and distinguish between remarkable treatment advances and the promise of a cure for their individual case.
- Ensure robust support for patients on oral therapy. In the Phase 2 study, sotorasib was delivered orally every day. As with all patients on oral therapy, cancer providers need to make sure they have the infrastructure necessary to ensure adherence, education, and access. In particular, if and when this drug comes to market, it will likely be for a very acute population of patients whose tumors did not respond to previous treatments, so symptom management and psychosocial support, as well as ensuring smooth coordination and communication with their care team, will be critical.
- Get ready to understand the cost implications—for your organization and for patients. Last, but certainly least surprising, is the issue of cost. We have no idea what the price tag will be if sotorasib is approved by the FDA, nor the channels through which it will be distributed, but recent history suggests this drug won't be cheap. Make sure you know how your payers are thinking about reimbursement. Importantly, we know that the costs of a cancer diagnosis can be devastating for patients. Providers will need to continue educating patients on their financial responsibility and tap into all available assistance from drug manufacturers.
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