Liquid biopsy can direct use of EGFR rechallenge in metastatic colorectal cancer
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Liquid biopsy-driven rechallenge with panitumumab led to objective responses in about one-third of patients with metastatic colorectal cancer, according to results of the phase 2 CHRONOS study presented at the virtual ASCO Annual Meeting.
Anti-EGFR therapy is the most prevalent targeted therapy for patients with colorectal cancer; however, even with molecular selection of patients who are negative for RAS and BRAF, all patients eventually develop resistance, according to study background.
“We previously described that resistance under therapeutic EGFR blockade with monoclonal antibodies in metastatic colorectal cancer is driven by expansion of RAS and EGFR ectodomain clones, and this can be monitored in the blood through circulating tumor DNA by liquid biopsy, with a decline in resistance-conferring alleles upon therapy withdrawal,” Andrea Sartore-Bianchi, MD, head of the clinical molecular oncology unit in the department of hematology and oncology at Grande Ospedale Metropolitano Niguarda in Milan, and associate professor of oncology at University of Milano, told Healio. “This pulsatile behavior provides the rationale for a rechallenge when clearance of these tumor mutations in blood takes place and thus the tumor regains sensitivity.”
Given that clinical-based rechallenge has shown promising results, Sartore-Bianchi and colleagues evaluated whether using upfront circulating tumor DNA to select patients can enhance results of a rechallenge strategy.
Researchers analyzed data of 52 patients with RAS and BRAF wild-type metastatic colorectal cancer and an ECOG performance status of 0 to 2 who achieved an objective response to an anti-EGFR-containing regimen during any line of therapy, and who subsequently experienced disease progression during an anti-EGFR-free therapeutic line.
Patients underwent circulating tumor DNA molecular screening to determine whether RAS, BRAF and EGFR ectodomain clones had reassumed wild-type status after progression. Researchers found that 36 (69%) of the patients had wild-type RAS, BRAF and EGFR, 27 (median age, 64 years; range, 42-80) of whom enrolled in the study.
Given 31% of patients had mutations in RAS, BRAF or EGFR, this liquid biopsy approach avoided ineffective treatment for these otherwise clinically eligible patients, Sartore-Bianchi said during his presentation.
Enrolled patients received a median of three prior treatments, with most patients having received prior anti-EGFR therapy in the first line (63%), followed by 15% in the second line and 22% in the third line or later.
Patients received 6 mg/kg IV panitumumab (Vectibix, Amgen), an anti-EGFR antibody, every 2 weeks until progression.
Objective response rate by RECIST version 1.1 served as the study’s primary endpoint, with six responses required to meet the study’s threshold for positivity.
Results showed eight patients achieved a partial response, for an ORR of 30% (95% CI, 12-47), indicating the study met its primary endpoint.
“This ORR favorably compares with what is achievable in later lines of treatment for patients with metastatic colorectal cancer,” Sartore-Bianchi said. “Further, the guidance of circulating tumor DNA allows to exclude patients otherwise clinically eligible who harbor resistance-conferring mutations, overall streamlining anti-EGFR rechallenge in the continuum of care.”
Nine patients (33%) achieved stable disease for at least 4 months. An additional two patients achieved stable disease for fewer than 4 months.
These data translated to a disease control rate of 63%.
Median PFS was 16.4 weeks (range, 9-25) and median duration of response, with one ongoing, reached 17 weeks.
No patients experienced grade 4 or grade 5 toxicity. Nineteen percent of patients experienced grade 3 adverse events, most of which were dermatological.
Researchers also conducted an analysis that looked at the time of last anti-EGFR therapy and status of RAS, BRAF and EGFR in circulating tumor DNA. They found that the presence of resistance-conferring mutations and responses appeared independent of time since last therapy, with some patients clearing the mutations and achieving response to rechallenge therapy as early as 4 months after last anti-EGFR treatment, and others displaying resistance mutations 30 months or later.
“These results indicate that actual molecular data can better guide the optimal time for rechallenging patients than theoretical estimation from the literature of anti-EGFR-free treatment intervals that are required to clear resistance clones proposed of approximately two-half lives, or approximately 8 months,” Sartore-Bianchi said during his presentation.
Multidisciplinary molecular tumor boards will be essential to integrate a liquid biopsy-driven rechallenge approach into clinical practice, according to Sartore-Bianchi.
“There are important aspects to consider for the actual integration into the clinical workflow, starting with approval and reimbursement in the specific indication,” he told Healio. “As for technical feasibility, in general, targeted panels can be performed by local pathology labs, even though multigene assays — requiring state-of-the-art next-generation sequencing apparatus, bioinformatic interpretation of data and appropriate storage space — will likely be prominently decentralized in national or international central laboratories.”
Additional research aims to elucidate the dynamics of resistance that may arise after EGFR rechallenge and how to overcome it, Sartore-Bianchi added.
Perspective
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Wafik S. El-Deiry, MD, PhD, FACP
According to our classical view in cancer therapeutics, we stop using a therapy when a tumor shows resistance to it. In colorectal cancer (CRC), we use 5-FU in combination with other agents, such as in the FOLFOX regimen. Then, often patients are treated with FOLFIRI, which also contains 5-FU, even though the patient may have previously progressed on FOLFOX. The approach works for practical purposes although it may not make sense to grant reviewers who can’t understand why a clinician would use a drug after the tumor showed resistance to it in a combination therapy.
With the advent of liquid biopsy that detects circulating tumor DNA (ctDNA) with tumor-associated mutations and resistance mechanisms, it has been realized that when patients with CRC are treated with anti-EGFR therapy and resistance develops, we can see the emergence of resistance mutations, such as KRAS G12D or others, in ctDNA. When patients become resistant to anti-EGFR therapy, such therapy is discontinued. Because ctDNA liquid biopsy tests can be performed sequentially like any tumor marker used to follow disease burden, a body of knowledge started to provide great insights not previously apparent. It was surprising that after patients with advanced CRC with wild-type KRAS/NRAS/BRAF discontinued anti-EGFR therapy when the tumors became resistant, ctDNA analyses showed the resistance mutations that had emerged began to extinguish. This interesting observation raised questions about why such a thing would happen if the resistance mutation led to a more aggressive tumor. Or, maybe it really didn’t, as it is known that the primary effect of a RAS mutation in cells is cellular senescence and that few cells end up transformed. But, in our case, the cells were already cancerous, making us wonder if the RAS mutation that conferred resistance led to some other disadvantage, and so it would become extinguished. Perhaps all resistance mutations extinguish in the absence of selection pressure. This also begs the question as to whether other mechanisms of resistance to anti-EGFR therapy, such as ErbB2, might similarly extinguish.
The question remained as to whether rechallenging with anti-EGFR therapy would lead to patient benefit when resistance mechanisms to such therapy extinguished as documented in ctDNA. The CHRONOS trial showed objective responses in one-third of patients who had extinguished anti-EGFR resistance alleles in their ctDNA. It was previously reported that EGFR ectodomain mutations with cetuximab (Erbitux, Eli Lilly) allow sensitivity to panitumumab quite unrelated to the phenomenon of extinguishing that resistance allele. It will be interesting to learn more about which resistance mutations might be more likely to respond to rechallenge therapy after such alleles extinguish or why some patients’ tumors do not respond when rechallenged after levels of resistance mutation decrease. There may be quantitative aspects to the decline that determine whether responses occur and for how long and undoubtedly this will be investigated further, especially as very sensitive methods of detecting ctDNA mutations are utilized.
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Sartore-Bianchi A, et al. Abstract 3506. Presented at: ASCO Annual Meeting (virtual meeting); June 4-8, 2021.
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