Findings from the phase II DYNAMIC study suggest that circulating tumor DNA analyses could help clinicians decide whether patients with stage II colon cancer require chemotherapy after standard surgery. Liquid biopsies could also shed light on the development of resistance to KRASG12C inhibition, paving the way for better treatment strategies.

Whether patients with stage II colon cancer require chemotherapy after standard surgery, long debated among clinicians, is a decision that could soon be guided by circulating tumor DNA (ctDNA) analyses. Liquid biopsies have also begun illuminating the landscape of acquired resistance to KRASG12C inhibition—a key need, with the advent of drugs such as sotorasib (Lumakras; Amgen) and adagrasib (Mirati Therapeutics).

“We know surgery alone can cure the majority of patients” with stage II colon cancer, observed Jeanne Tie, MD, of Walter and Eliza Hall Institute of Medical Research in Parkville, Australia. Adjuvant chemotherapy's role “is less clear,” however. It's generally recommended “for those with high-risk disease, but how risk features are defined varies between guidelines, and the survival benefit has been modest,” she said.

Prior observational studies “have shown a high recurrence risk if ctDNA is detected following resection and patients receive no further treatment,” Tie noted. As such, she and her fellow investigators designed the phase II DYNAMIC trial “to test our hypothesis that ctDNA analyses could better identify who needs adjuvant chemotherapy and who can be spared.” The data were presented during the 2022 American Society of Clinical Oncology (ASCO) Annual Meeting in Chicago, IL, June 3–7, and concurrently published (N Engl J Med 2022 Jun 4 [Epub ahead of print]).

DYNAMIC enrolled 455 patients who were randomly assigned 2:1 after surgery to receive ctDNA-guided care or standard disease management. Plasma samples from the first group were collected and analyzed at weeks 4 and 7; ctDNA-positive patients received their physician's choice of single-agent fluoropyrimidine or oxaliplatin-based doublet chemotherapy, and ctDNA-negative patients were not treated. In the standard arm, “all adjuvant therapy decisions were based on conventional criteria,” Tie said. The median follow-up was 37 months.

ctDNA guidance resulted in adjuvant chemotherapy being given to fewer patients—15% versus 28% in the control group, Tie reported. Yet the 2-year recurrence-free survival (RFS) rates were similar, 93.5% and 92.4%, “demonstrating the noninferiority of ctDNA-led management,” she said.

Meanwhile, estimated 3-year RFS rates for ctDNA-positive and ctDNA-negative patients were 86.4% and 92.5%, respectively. The former “suggests considerable benefit from adjuvant chemotherapy,” Tie said, because historically, without postsurgery treatment, this rate was less than 20%. The latter “confirms that recurrence isn't very likely in ctDNA-negative patients, so adjuvant treatment shouldn't be considered.”

To discussant Ben Park, MD, PhD, of Vanderbilt University in Nashville, TN, “it's good to know that through ctDNA detection, we could roughly halve the number of patients” getting adjuvant chemotherapy—without compromising recurrence risk. “De-escalation of therapy is an important issue in our business nowadays,” he remarked.

Besides DYNAMIC, several other trials, including COBRA and CIRCULATE, are ongoing and “we keenly await their data,” Tie said, “to help us further optimize ctDNA's role in the adjuvant setting” for colon cancer.

Also at ASCO, Bob Li, MD, PhD, of Memorial Sloan Kettering Cancer Center in New York, NY, highlighted ctDNA analyses of paired plasma samples—obtained at baseline and disease progression—from patients enrolled in CodeBreaK 100, the phase II trial that provided the basis for sotorasib's approval.

“We wanted to identify genomic alterations that weren't present at the start of treatment,” Li explained. “This could help us understand acquired resistance to sotorasib.”

The investigators evaluated 112 patients, 67 with KRASG12C-mutated non–small cell lung cancer (NSCLC) and 45 with KRASG12C-mutated colorectal cancer. “Baseline tumor shedding was high in both populations,” Li observed—93% and 100%, respectively—which “reflects the underlying aggressive biology” of these tumor types.

ctDNA testing revealed that 28% of patients with NSCLC and 71% of patients with colorectal cancer had acquired mutations at disease progression. “These were a heterogeneous set” of alterations, Li said—predominantly in receptor tyrosine kinases (RTK) such as EGFR and MET, as well as along the PI3K/AKT/mTOR pathway for NSCLC and, for colorectal cancer, in cell cycle, DNA damage response, and Wnt/β-catenin pathway genes.

“We also saw a higher incidence of secondary RAS variants in colorectal cancer patients,” Li noted. As well, the investigators pinpointed “fast versus slow progressors”—defined as after less than 3 months or more than 6 months of sotorasib. In both disease cohorts, more than half (52% and 57%, respectively) of all acquired mutations occurred in fast progressors.

“Do these alterations we've identified reflect actual drug resistance mechanisms or clonal evolution of progressing tumors?” Li mused. “We'll need additional studies to figure this out.”

“Some might look at the data pessimistically, saying, ‘Well, how do we make sense of it all?’,” Park said. “But we do have targeted therapies for many of these acquired mutations, so combination and sequential strategies may start coming into play.”

Li agreed, noting that EGFR and SHP2 inhibitors, for instance, could be aimed at mutant RTKs, and a SOS1 inhibitor at secondary RAS alterations. To explore these and other actionable possibilities, the phase I CodeBreaK 101 trial is now enrolling patients, he added.

ctDNA “has been validated as a prognostic, even predictive, marker,” Park concluded, “but the next challenge, demonstrating clinical utility—that test results can actually change outcomes and influence patient care—is still in its infancy. I think these are two studies that will help move the utility needle.” –Alissa Poh