Presentation by David Hsu, MD, PhD, Duke University Medical Center
Despite ongoing improvements in screening, diagnosis, and treatment, colorectal cancer (CRC) continues to be one of the most commonly occurring cancers in both men and women, and a leading cause of cancer-related death. At the 2022 OneOncology Conference in held in Nashville, Tennessee, Dr David Hsu from Duke University Medical Center highlighted some recent developments on three key topics in CRC: colon cancer biology, targeted treatment, and monitoring for disease recurrence after surgery.
What Does it Mean to Have Right-Sided or Left-Sided CRC: PARADIGM
It has been recognized that CRCs developing on the right or the left side of the colon are biologically different, and this has important implications for treatment. The differences in biology are believed to relate to a distinct embryonic origin of structures on the right colon, which are derived from the midgut (i.e., cecum, ascending, and 2/3 of the transverse colon), versus structures on the left colon (1/3 of the transverse, the splenic flexure, descending, and sigmoid colon) and the rectum, which are derived from the hindgut, during early embryonic development. These differences are also reflected in the types of mutations commonly observed in cancers of the right or left side of the colon. Cancers of the right side, for example tend to show more BRAF, slightly more KRAS, and a lower incidence of HER2 gene alterations, as well as a higher incidence of microsatellite instability (i.e., MSI-high status) as compared to cancers of the left side.
In terms of CRC treatments, there are two general types of targeted therapies, anti-EGFR, and anti-VEGF, which have been used in combination with chemotherapy in major clinical trials. Results of these trials (specifically, the FIRE-3, PEAK, and CALGB/SWOG 80405 trials) generally showed no difference between the two targeted therapy types when combined with chemotherapy, however, when comparing outcomes for patients with left-sided versus right-sided tumors across these three trials, there was a much greater benefit of adding anti-EGFR treatments in left-sided tumors versus right, whereas a greater benefit of adding anti-VEGF treatment was observed for patients with right-sided tumors as compared to left. These findings suggested that the two types of targeted therapies differ in efficacy based on which side of the colon the cancer occurs, although direct evidence for these differences had been lacking.
In this regard, Dr Hsu highlighted a phase III study presented at the 2022 ASCO Annual Meeting, PARADIGM, which compared the combination an anti-EGFR treatment (panitumumab) or an anti-VEGF treatment (bevacizumab) with the same chemotherapy regimen (mFOLFOX6) as a first line treatment for patients with newly diagnosed, metastatic, inoperable, CRC that did not have a RAS mutation. The primary endpoint of the trial was overall survival (OS) in the left-sided population, and if a significant difference was observed, also in the overall population. The results showed that, while there was no difference in the more immediate (secondary) endpoint of progression-free survival (PFS), a significant difference in the primary endpoint of OS was observed with the addition of anti-EGFR as compared with anti-VEGF therapy, both in the left-sided population (at 60 months, 32% vs. 21%) and the overall population (at 60 months, 29% vs. 20%). By comparison, there was no significant benefit of either treatment for patients with right-sided tumors. Dr Hsu suggested that, while the results of PARADIGM largely confirmed previous findings, the use of first-line anti-EGFR therapy in combination with chemotherapies such as mFOLFOX6 for patients with left-sided CRC without a RAS mutation was now evidence-supported with data from this phase III clinical trial.
Targeted Therapies: The MOUNTAINEER Study
Targeted therapies also play a role in the treatment of CRC patients who are positive for human epidermal growth factor 2 receptor (HER2+). HER2 gene amplification, or overexpression occurs in 3 to 5% of patients with metastatic CRC (mCRC), and Dr Hsu emphasized that HER2+ patients with mCRC who progress on early lines of chemotherapy have a very limited benefit with the current standard of care treatments. In this regard, Dr Hsu reviewed results from MOUNTAINEER, a phase II study presented at the ESMO 2022 Congress, which examined the combination of tucatinib, a tyrosine kinase inhibitor drug that specifically inhibits HER2, with another HER2-directed therapy, trastuzumab, in patients with HER2+ mCRC that did not have a RAS mutation. Importantly, patients in this trial were highly treatment-refractory, with progression on 2 lines of prior therapy.
The results of the trial showed that 65% of patients had a reduction in their tumor burden, with a median PFS of 8.2 months and a median OS of 24.1 months observed. Dr Hsu noted these results compare very favorably with results from previous studies, which show a PFS of approximately 1.9 months, and an OS of about 5 to 6 months with standard of care regimens in this highly refractory patient population. He also emphasized the overall tolerability of the regimen, with only 5.8% of patients having adverse events leading to study treatment discontinuation, mostly low-grade and manageable diarrhea as the most common event, and a low incidence of hepatotoxicity and cardiac toxicity. He suggested that, if appropriate patients can be selected for this regimen based on molecular profiling, the results of MOUNTAINEER show a significant clinical benefit for this patient population, with minimal toxicity. He also noted that the combination of tucatinib and trastuzumab could become a new standard of care for refractory HER2+ mCRC patients, based on the results of an ongoing randomized, phase III trial, MOUNTAINEER-3.
Monitoring for Recurrence: The DYNAMIC Trial
Circulating tumor DNA, or ctDNA, refers to fragmented DNA molecules that are released into the bloodstream as a result of tumor cell turnover. Using advanced technologies that can determine a precise genomic “fingerprint” of a patient’s tumor from their surgical biopsy sample, it is now possible to detect the continued presence of tumor cells in the body after a curative intent surgical resection using a simple blood test (“liquid biopsy”). The presence of residual tumor DNA in the blood could be indicative of an impending cancer recurrence, even before a gross pathologic recurrence can be detected using standard imaging methods such as PET-CT scanning. If such ctDNA is detected in the blood after surgery, the patient is considered ‘positive’ for what is referred to as ‘minimal residual disease’, or MRD. One of the main controversies in colorectal cancer at present is what the role of ctDNA monitoring and MRD status is with regard to the use of adjuvant chemotherapy, particularly for patients with stage II disease, who have an intermediate risk for disease recurrence after surgery. Dr Hsu noted that this can be one of the most difficult conversations to have with stage II patients, relative to patients with stage I disease (who do not require adjuvant therapy) and stage III disease (who would always require adjuvant therapy).
The DYNAMIC trial enrolled patients with stage II colon cancer who received a surgical ‘R0’ resection of their tumor; blood was collected at Weeks 4 and 7 post-op, and the patients were randomized 2:1 to receive ctDNA-directed adjuvant treatment (based on their MRD status), or standard of care adjuvant treatment (based on clinical and pathologic factors). For patients in the ctDNA guided arm, adjuvant chemotherapy was given if ctDNA was positive at Week 4 or 7 post-op, while no treatment was given if ctDNA was negative at these time points. The results confirmed the positive outcomes for patients who were ctDNA negative, and poorer outcomes for patients who were ctDNA positive (recurrence-free survival [RFS], 92.5% vs. 86.4%). In addition, there was no overall difference in RFS between the two adjuvant therapy assessment methods (2-year RFS, 93.5% vs 92.4%), however, there was a significantly lower use of adjuvant therapy for patients using ctDNA guided treatment as compared with standard treatment (28% vs. 15%; P=0.0017). Interestingly, there was a higher use of oxaliplatin-based doublet therapy (which is more effective, but can have significant side effects such as neuropathy) with ctDNA guided treatment (62%) relative to standard management (10%), which suggests that clinicians may be more cognizant of oxaliplatin-related adverse events such as neuropathy when deciding on use of adjuvant therapy in stage II patients. Results also showed there was a limited benefit of ctDNA-guided versus standard clinical/pathologic guided adjuvant therapy for patients with high-risk features like T4 disease.
Overall, based on the DYNAMIC data, Dr Hsu suggested that for stage II patients with high-risk features such as T4 disease, ctDNA would not impact his current treatment decisions in the absence of additional supportive data, and he would still offer adjuvant treatment to such patients regardless of MRD status. For T3 patients who are node negative (N0), however, he suggested that ctDNA status might prove be more useful, as these patients have a recurrence risk of approximately 10 to 15%, with a benefit of adjuvant chemotherapy of only a 1 to 2% relative risk reduction. He also noted that with ongoing trials and expanded use of ctDNA monitoring in clinical practice, additional data will be forthcoming to resolve this issue.
See more from the 2022 OneOncology Conference here.
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