4 important clinical studies worth your attention

Every year, a plethora of clinical trials are registered at ClinicalTrials.gov, with more being added. As of August 12, more than 386,000 studies were on the list, with 32% set in the United States and 5% occurring in both the United States and abroad. Of note, more than three-quarters of these trials are interventional and nearly one-quarter are observational.

With hundreds of thousands of trials in existence, it would be impossible for any individual to keep track of even a small fraction. Of course, some clinical trials grab headlines because of their disastrous nature. But many of these trials bear mentioning for their important or ground-breaking nature. 

Here are four recent trials that are worthy of consideration. 

monarchE

Fortunately, for most people with breast cancer, the prognosis is good. Overall, 90% of people are diagnosed with early-stage disease, with most cases HR-positive and HER2-negative. A minority of these patients, however, are at high risk of relapse. According to the results of the monarchE trial, the CD4/6 inhibitor abemaciclib (Verzenio) may be effective in reducing chances of recurrence.

Abemaciclib is one of three CD4/6 inhibitors approved by the FDA that block the CD4 and CD6 proteins on cancer cells. The others are palbociclib (Ibrance) and ribociclib (Kisqali). Currently, these drugs are indicated only for advanced or metastatic breast cancer, and they drastically enhance survival in patients who take them.

In this phase 3, open-label study, researchers examined the administration of abemaciclib plus endocrine therapy (ET) vs ET alone in 5,637 patients with node-positive, HR+, HER2-, high-risk early breast cancer. The investigators found that those who received the experimental agent plus ET were 30% less likely to have their cancer return in an invasive form.

The big question is whether abemaciclib is indicated for the treatment of early-stage breast cancer in those at high risk. After all, it’s possible that the cancer could come back after 5 or 10 years. At this point, longer-term studies are needed.

“One unanswered question is whether the treatment is actually preventing recurrences or just delaying them,” said Larissa Korde, MD, MPH, head of Breast Cancer and Melanoma Therapeutics in NCI’s Division of Cancer Treatment and Diagnosis, per the NIH.

Read more about breakthroughs in breast cancer research at MDLinx.

Aducanumab trials (and tribulations)

Some trials are important not for their evidenced benefits, but rather for the notoriety they generate. Aducanumab (Aduhelm) is an example.

In 2021, the FDA granted accelerated approval to this drug, which is a novel agent that targets the pathophysiologic underpinnings of Alzheimer disease. This anti-amyloid, disease-modifying agent is the first new agent approved for Alzheimer since 2003.

In three separate double-blind, randomized, placebo-controlled, dose-ranging studies involving a cumulative 3,482 patients with the disease, researchers found a dose- and time-dependent decrease in amyloid-beta plaques compared with no reduction in controls.

“These results support the accelerated approval of Aduhelm, which is based on the surrogate endpoint of reduction of amyloid-beta plaque in the brain—a hallmark of Alzheimer’s disease,” wrote the FDA. “Amyloid-beta plaque was quantified using positron emission tomography (PET) imaging to estimate the brain levels of amyloid-beta plaque in a composite of brain regions expected to be widely affected by Alzheimer’s disease pathology compared to a brain region expected to be spared of such pathology.”

Sounds good, right? Not so fast …

The FDA’s accelerated approval of the Alzheimer drug represented a major reversal in light of its own Peripheral and Central Nervous System Drugs Advisory Committee findings months earlier.

According to the minutes: “The Committee recognized inconsistencies in the FDA data analysis from the clinical review and the statistical review, with many members endorsing the statistical review. Therefore, the Committee could not support the primary evidence of effectiveness provided by Study 302 of aducanumab for the treatment of Alzheimer’s disease (AD), independently without regard for Study 301.”

This reversal set off much controversy (and consternation) in the medical community and media. The drug was approved despite previous concerns of the FDA committee.

Click here to read about research that suggests gut health can contribute to diseases such as Alzheimer and others, on MDLinx.

CodeBreak100

In this aptly named trial, researchers had finally discovered a drug that combats the ominous KRAS mutation, which is the etiology for cancer that affects hundreds of thousands of Americans. Specifically, the drug sotorasib (Lumakras) targets KRAS G12C-mutant non-small cell lung cancer (NSCLC). 

In an interview with the NIH, Frank McCormick, PhD, scientific consultant for NCI’s RAS Initiative, remarked that the accelerated approval in May is “really exciting, no question about that. It’s a big breakthrough in the whole field.” For decades, KRAS was thought “undruggable.”

Results of CodeBreak100 demonstrated that sotorasib shrank tumors in 36% of patients, with results lasting a median of 10 months. Current treatment, on the other hand, shrinks tumors in fewer than 20% of previously treated patients, and these results are ephemeral, according to the NIH.

CodeBreak 100 was a single-group, phase 2 trial involving 124 patients who were previously treated for advanced NSCLC. Tumors disappeared completely in four patients, partially shrank in 42, and 54 patients had stable disease (ie, the cancer didn’t get better or worse).

“In this phase 2 trial, sotorasib therapy led to a durable clinical benefit without new safety signals in patients with previously treated KRAS p.G12C-mutated NSCLC,” concluded the study authors.

Learn more about a promising therapy for NSCLC involving oxaliplatin-loaded polycaprolactone nanoparticles, at MDlinx.

STEP 3 

It’s not every day that the FDA approves a new weight-loss agent. Nearly 70% of Americans are overweight or obese. Even losing 5% to 10% of bodyweight via diet and exercise can decrease the odds of heart disease in this population.

In June, the FDA approved the weekly semaglutide (Wegovy) injection (2.4 mg) for use as chronic-weight management in overweight or obese adults with at least one weight-related condition, such as hypertension, hypercholesterolemia, or type 2 diabetes.

“Today’s approval offers adults with obesity or overweight a beneficial new treatment option to incorporate into a weight management program. FDA remains committed to facilitating the development and approval of additional safe and effective therapies for adults with obesity or overweight," said John Sharretts, MD, deputy director of the Division of Diabetes, Lipid Disorders, and Obesity in the FDA’s Center for Drug Evaluation and Research, in an FDA press release.

This agent recapitulates the actions of glucagon-like peptide-1 (GLP-1), thus targeting the area of the brain that mediates appetite and food intake. Doses must be dialed up over 16 to 20 weeks to 2.4 mg once weekly to lower gastrointestinal adverse effects. 

Approval of the drug was based on the results from the STEP 3 Randomized Clinical Trial and three other trials that involved more than 4,000 patients in total. In the STEP 3 trial, published in JAMA, 611 adults who were overweight or obese received treatment for 68 weeks and ended up losing 16.0% of their body weight vs 5.7% in controls. Patients in the trial were also placed on 4 weeks of a low-calorie diet, as well as intensive behavior therapy (ie, counseling) for the duration of the study.