Successful cetuximab rechallenge in metastatic colorectal cancer: A case report

Abstract

BACKGROUND

Metastatic colorectal cancer (mCRC) treatment has been evolving and increasingly driven by tumor biology and gene expression analysis. Rechallenge with epidermal growth factor receptor (EGFR) inhibitors (anti-EGFR) represents a promising strategy for patients with RAS wild-type (RAS-wt) mCRC and circulating tumor DNA has emerged as a potential selection strategy. Herein, we report the case of a RAS-wt mCRC patient who had a successful response to cetuximab rechallenge.

CASE SUMMARY

Our patient was diagnosed with stage IV RAS-wt, microsatellite-stable rectosigmoid junction adenocarcinoma. He was started on first-line treatment with FOLFIRI and cetuximab and achieved partial response, allowing for a left hepatectomy (R0), followed by post-operative chemotherapy and an anterior resection; progression-free survival (PFS) of 16 months was obtained. Due to hepatic and nodal relapse, second-line treatment with FOLFOX and bevacizumab was started with partial response; metastasectomy was performed (R0), achieving a PFS of 11 months. After a 15 months anti-EGFR-free interval, FOLFIRI and cetuximab were reintroduced upon disease progression, again with partial response and a PFS of 16 months. Following extensive hepatic relapse, cetuximab was reintroduced and a marked clinical and analytical improvement was seen, after only one cycle. RAS-wt status was confirmed on circulating tumor DNA. The patient’s overall survival exceeded 5 years.

CONCLUSION

Our case provides real-world data to support cetuximab rechallenge in later lines of RAS-wt mCRC treatment.

Key Words: Metastatic colorectal cancer; RAS mutation; RAS wild type; Anti-epidermal growth factor receptor; Cetuximab; Rechallenge; Case report

Core Tip: In RAS-wild type patients treated with anti-epidermal growth factor receptor inhibitors, the emergence of RAS mutations leads to resistance to further anti-epidermal growth factor receptor treatment. However, resistant clones seem to decay over time upon treatment withdrawal. Liquid biopsy-driven cetuximab rechallenge can be effective in later lines of treatment of metastatic colorectal cancer. Longer anti-epidermal growth factor receptor-free intervals may act as a surrogate for improved responses and survival outcomes.

INTRODUCTION

According to the World Health Organization, colorectal cancer (CRC) is the third most commonly diagnosed cancer[1,2]. Metastatic CRC (mCRC) represents 25% to 30% of all cases of CRC, with 1.2 million estimated new cases every year and a 5-year overall survival below 20%[3-5]. The treatment of mCRC is evolving and has been increasingly driven by tumor biology and gene expression analysis[5-8]. KRAS mutations are found in up to 50% of sporadic mCRC cases and have been independently associated with a worse prognosis[9,10].

The activation of the epidermal growth factor receptor (EGFR) signaling cascade is a well-described pathway leading to colon tumorigenesis[11]. Considering the relevant role of EGFR and its downstream pathways in tumorigenesis and disease progression, it became a promising target for mCRC treatment[12]. Several studies have shown that EGFR and downstream signaling blocking by drugs such as cetuximab or panitumumab, combined with a doublet chemotherapy backbone, leads to tumor cell growth inhibition with clinical improvement[13-16]. Accordingly, in patients with RAS wild-type (RAS-wt) mCRC, EGFR monoclonal antibody plus chemotherapy is the standard option for treatment in the first-line (1 L) setting[17-19]. However, mutations within the RAS and BRAF oncogenes located downstream of EGFR lead to its constitutive activation, even if the EGFR is blocked. As such, patients with RAS-mutated (RAS-mut) mCRC do not benefit from agents targeting the EGFR[17-20]. In RAS-wt patients treated with anti-EGFR inhibitors based therapy, the emergence of RAS mutations, due to either late acquisition of mutations by cellular subclones or to the progressive selection of initially undetectable mutated subclones, can translate into resistance to further anti-EGFR treatment, including cetuximab[11,20,21]. However, evidence suggests that anti-EGFR-resistant clones decay throughout time upon withdrawal of anti-EGFR pressure, showing that clonal evolution continues beyond clinical progression[20]. It has also been shown that while resistant clones decay, resistance to anti-EGFR antibodies decreases, opening the potential for rechallenge or reintroduction of these drugs in later lines of treatment[20,22]. Rechallenge with cetuximab has proved to be a clinically beneficial option for refractory mCRC patients after an anti-EGFR-free interval, allowing for durable responses and improvement of survival rates[22-26]. In this context, circulating tumor DNA can be an extremely sensitive tool to document the complexity of tumor clonal evolution and to potentially select the best treatment sequencing strategies. Evidence shows RAS-wt status maintenance correlates with improved responses to anti-EGFR rechallenge therapy[26,27]. In this article, we describe a case of RAS-wt mCRC who had an optimal response to anti-EGFR rechallenge.

CASE PRESENTATION

Chief complaints

A 52-year-old man presented to the emergency department complaining of abdominal colic pain, rectal bleeding, asthenia and anorexia.

History of present illness

Symptoms started in June 2014, when the patient began having abdominal pain, asthenia and anorexia, with significant weight loss (15% of body weight, corresponding to 15 kg in 6 months), associated with rectal bleeding. Due to progressive symptoms, he was taken to the emergency department. During hospitalization, an abdominal ultrasound revealed two hepatic nodules and a probable sigmoid neoformation.

History of past illness

The patient was obese and had corrective surgery for an inguinal hernia in 2010.

Personal and family history

The patient reported a family case of CRC (maternal uncle, age unknown).

Physical examination

On physical examination, vital parameters were all within the normal range and cardiopulmonary auscultation was normal. The abdomen was a bit distended but painless on palpation and showed no signs of peritoneal irritation. The Eastern Cooperative Oncology Group performance status (ECOG-PS) was 1.

Laboratory examinations

The patient had mild microcytic anemia (hemoglobin 12.1 g/dL) and a carcinoembryonic antigen level of 60 ng/mL. No other alterations were reported.

Imaging examinations

Imaging studies were obtained. Pelvic computed tomography (CT) revealed a 13 cm left hepatic nodule (Figure 1) and sigmoid mural thickening; thoracic CT did not show lung masses. Colonoscopy revealed a neoformative mass located 15 to 22 cm from the anal margin, with reduction of the lumen diameter (Figure 2). Hepatic magnetic resonance imaging revealed the presence of several confluent hepatic lesions in the left lobe, 16 cm wide (Figure 3A).

Figure 1  Computed tomography image of the primary nodular lesion in the left hepatic lobe.

Figure 2  Colonoscopy images of the neoformative lesion at diagnosis.

Figure 3 Hepatic magnetic resonance image. A: Hepatic magnetic resonance image of several confluent hepatic lesions in the left lobe; B: Hepatic magnetic resonance image of one de novo hepatic metastasis of segment VIII and adenopathy next to the caudate lobe.

Anatomopathological analysis

Endoscopic biopsy of the colorectal mass revealed a well-differentiated adenocarcinoma (grade 1); liver nodule biopsy confirmed metastasis of adenocarcinoma, intestinal type. RAS mutational status was wt and mismatch repair deficiency/microsatellite instability was excluded (mismatch repair-proficient/microsatellite-stable).

FINAL DIAGNOSIS

The final diagnosis was cT3N0M1a - stage IV rectosigmoid junction adenocarcinoma, RAS-wt with microsatellite stability.

TREATMENT

The multidisciplinary team discussion decided on conversion treatment and the patient was started on FOLFIRI chemotherapy; 9 cycles were completed. After RAS mutation was excluded, cetuximab was added for the last 6 cycles (from September 2014 to January 2015). An acneiform rash grade 2-3 was reported and managed with doxycycline and topical steroids.

OUTCOME AND FOLLOW-UP

After conversion chemotherapy, the patient achieved partial response. In February 2015, the patient had a left hepatectomy, R0. Systemic treatment with FOLFIRI and cetuximab was resumed, until June 2015. After 5 cycles, carcinoembryonic antigen had decreased to 4 ng/mL. In July 2015, a rectal anterior resection was performed (ypT3N0, G2, with vascular and perineural invasion, R0). FOLFIRI and cetuximab were reintroduced in August; 7 cycles were completed. Due to catheter-related thrombosis, the patient received anticoagulation treatment with low-molecular weight heparin.

In January 2016, the patient had hepatic and nodal relapse, with one de novo hepatic metastasis of segment VIII 23 mm wide and an adenopathy next to the caudate lobe (Figure 3B). ECOG-PS was still 1 and the patient was asymptomatic. Conversion chemotherapy (second-line) with FOLFOX and bevacizumab was started in February 2016, with partial response after 4 cycles. The patient had a metastasectomy and a celiac trunk and hepatic hilum lymphadenectomy (R0) in June 2016, and continued chemotherapy with FOLFOX post-surgery.

After 8 cycles (January 2017), the patient remained asymptomatic (ECOG-PS 1) but showed hepatic and nodal relapse with two de novo hepatic metastases in the right lobe and portal adenopathy (41 mm; Figure 4A). Palliative third-line (3 L) chemotherapy with FOLFIRI and cetuximab was started in February 2017, with partial response after 7 cycles (Figure 4B). In August 2017, the patient had a metastasectomy (segments I and VIII) and portal lymphadenectomy (R0). Complementary chemotherapy with 5-fluorouracil (DeGramont) was started in October 2017; 6 cycles were completed.

Figure 4 Hepatic magnetic resonance before third-line therapy and after seven cycles of treatment with FOLFIRI and cetuximab. A: Hepatic magnetic resonance before third-line therapy; B: Hepatic magnetic resonance after seven cycles of treatment with FOLFIRI and cetuximab.

In June 2018, the patient presented with 1-week evolution of choluria and pruritus; hepatic dysfunction was evidenced by increased bilirubin, lactate dehydrogenase, aspartate aminotransferase, and alanine aminotransferase. Physical examination was normal with an ECOG-PS of 1 and abdominal ultrasound showed no bile duct dilatation. Abdominal CT scan was compatible with extensive hepatic and nodal relapse. The patient was started on fourth-line therapy (4 L) with cetuximab and, after the first cycle, showed rapid clinical and laboratory improvement. On the third cycle, irinotecan was added and 14 cycles were completed; partial response was obtained. The patient suffered from grade 2 diarrhea and grade 3 rash and treatment was suspended at the patient’s request in February 2019.

Disease progression was detected in March 2019; the patient was asymptomatic with an ECOG-PS of 1. Liquid biopsy showed RAS-wt status. In this setting, fifth-line (5 L) treatment with FOLFOX plus cetuximab was started, in June 2019. Treatment was suspended due to disease progression with asthenia and anorexia; TAS-102 was started as sixth-line (6 L) treatment, in September 2019, but was soon interrupted due to clinical deterioration. The patient died in December 2019 with an overall survival of 5 years and 6 months.

DISCUSSION

In this paper, we describe the case of a mCRC RAS-wt patient who was treated with a combination of CT and cetuximab at 1 L, 3 L, 4 L and 5 L of treatment with clear clinical responses and prolonged survival. The patient showed partial response to 1 L treatment with FOLFIRI plus cetuximab with a progression-free survival (PFS) of 16 months after hepatectomy and primary resection. Upon disease progression, in the context of increasing resistance to anti-EGFR treatment, treatment with FOLFOX plus bevacizumab (2 L) followed by liver metastasectomy led to a PFS of 11 months. Overall, the patient had an anti-EGFR-free interval of 15 months between 1 L and 3 L. As described previously in the literature[26], we believe that the suspension of cetuximab enabled the falloff of resistant clones and resistance to anti-EGFR antibodies was decreased. This allowed for the reintroduction of cetuximab in 3 L, in combination with chemotherapy, obtaining a durable response with a PFS of 16 months. In fact, evidence suggests that a longer anti-EGFR-free interval correlates with improved PFS and OS[24].

Compared with the results of the CRICKET study, which showed a median PFS of 4 months after cetuximab rechallenge in RAS-wt and BRAF-wt mCRC, our patient achieved a longer PFS (16 months), confirming again the importance of real-world evidence to validate the overall potential of this strategy[26]. Reintroduction of cetuximab at 4 L translated into important clinical benefit after only one cycle and allowed for a PFS of 9 months. In total, the patient showed an overall survival of 5 years and 6 months, exceeding the expected survival rates[28].

In this case, we also highlight the previously discussed importance of liquid biopsy to guide clinical decisions[8,24,27,29]. The evaluation of RAS mutational status of the patient at different disease stages allowed for a better understanding of tumoral behavior. In this case, the patient was initially RAS-wt and showed to be RAS-wt again after 4 L, in line with data that showed significantly better responses to anti-EGFR rechallenge and longer PFS in RAS-wt patients[27]. Had it been performed earlier (before the first rechallenge), it would also have probably shown RAS-wt status, given the great response to 3 L treatment. Regarding safety, the most relevant adverse events were gastrointestinal and dermatological. Grade 2-3 rash was initially managed with corticosteroid therapy but eventually led to treatment discontinuation after 4 L.

CONCLUSION

Our case confirmed that liquid biopsy-driven cetuximab rechallenge can be effective in later lines of treatment and that longer anti-EGFR free intervals may act as a surrogate for improved outcomes. Our patient achieved exceedingly good PFS and overall survival rates, highlighting the individual variability in mCRC treatment as well as the yet unexplored potential of the rechallenge strategy for these patients.

ACKNOWLEDGEMENTS

The authors thank Paula Pinto, PharmD, PhD (Pharmaceutical Medicine Academy) for providing medical writing and editorial assistance.