First-line immunotherapy plus chemotherapy in unresectable advanced ESCC

Presentation, treatment and response
A 62-year-old male presented with progressive dysphagia of 1 month in March 2023. Initially, he had difficulty swallowing solid food. At the time of pre­sentation, he had begun to struggle with liquids as well. The patient had been a chronic smoker and alcohol drinker for >20 years, but otherwise had an unre­markable past medical history.

At initial consultation, the patient was malnourished (body mass index [BMI], 18 kg/m²) and had impaired renal func­tion (creatinine clearance rate, 53 mL/min). His baseline Eastern Cooperative Oncology Group (ECOG) performance status (PS) was 1. Oesophagogastro-duodenoscopy revealed a circumferen­tial ulceration in the oesophagus mea­suring 25–30 cm. A feeding tube was inserted due to severe dysphagia.

PET-CT scan in March 2023 showed a 4.8 cm oesophageal mass (T1–T4 level). (Figure 1A, Table) Lymph­adenopathies were noted in the right paratracheal, lower cervical, medias­tinal and supraclavicular lymph nodes (LNs), while multiple bilateral lung nod­ules and a suspicious bone metastasis were noted on the anterior left 10^th rib. (Table) Tumour biopsy confirmed squa­mous cell carcinoma histology. Other relevant pathological findings showed microsatellite-stable disease with a PD-L1 combined positive score (CPS) of 40.

The patient was diagnosed with unresectable advanced oesophageal squamous cell carcinoma (ESCC) with high PD-L1 CPS score. In April 2023, he started treatment with nivolumab plus chemotherapy with cisplatin (reduced dose due to impaired renal function) and fluorouracil.

After two treatment cycles, the pa­tient’s condition gradually improved and he started partial oral feeding while still on a feeding tube. After three treatment cycles, a repeat PET-CT scan in June 2023 showed that the oesophageal tu­mour had decreased in size, which re­duced its mass effect, further improving the patient's dysphagia. (Table, Figure 1B) As a result, his feeding tube could be removed and he resumed full oral feeding. His malnutrition gradually re­solved and his renal function also nor­malized. The other metastatic lesions had decreased in size, confirming good partial response to nivolumab plus che­motherapy. (Table) His ECOG PS im­proved to 0.

The patient did not experience any adverse events (AEs) or immunotherapy-related toxicities. Since his renal function normalized and his overall PS improved, he will continue nivolumab plus full-dose chemotherapy for a total of 6 cycles, after which nivolumab will be given as monotherapy until disease progression or unacceptable toxicity.

Discussion
Oesophageal cancer management is especially challenging because many cases are unresectable at diagnosis and often relapse despite treatment.¹ For advanced ESCC, previous standard of care included fluoropyrimidine plus platinum-based chemotherapy, but this was associated with poor survival out­comes (ie, median survival, <1 year).^1-3

More recently, nivolumab, an anti–PD-1 monoclonal antibody, in com­bination with fluoropyrimidine plus platinum-containing chemotherapy, emerged as one of the preferred first-line treatment options for patients with unresectable advanced ESCC, which is reflected in the latest version of Na­tional Comprehensive Cancer Network’s (NCCN) clinical practice guidelines – a recommendation based on survival ben­efits demonstrated in the global, phase III, open-label CheckMate 648 trial.^4,5

In CheckMate 648, 970 adults with previously untreated, unresectable advanced, recurrent or metastatic ESCC were randomized to receive intravenous (IV) nivolumab (240 mg Q2W) plus che­motherapy (4-week cycle of IV fluorouracil [800 mg/m² on days 1–5] and IV cispla­tin [80 mg/m² on day 1]), IV nivolumab (3 mg/kg Q2W) plus IV ipilimumab (1 mg/ kg Q6W), or chemotherapy alone. Pri­mary endpoints were overall survival (OS) and progression-free survival (PFS).⁵

At the preplanned interim analysis (minimum follow-up, 13 months), OS was significantly longer with nivolumab plus chemotherapy than with chemo­therapy alone, reaching a median of 13.2 months vs 10.7 months (hazard ra­tio [HR], 0.74; 99.1 percent confidence interval [CI], 0.58–0.96; p=0.002) in the overall population.⁵ At a minimum fol­low-up of 29 months, first-line nivolum­ab plus chemotherapy showed superior OS benefit in all randomized patients vs chemotherapy alone (median, 12.8 months vs 10.7 months; HR, 0.78; 95 percent CI, 0.65–0.93).⁶ OS benefit was also observed in patients with PD-L1 CPS ≥1 (median, 13.8 months vs 9.8 months; HR, 0.69), who comprised 91 percent of the population across the three study arms. There was no addi­tional OS benefit for higher CPS expres­sion subgroups.⁵

Of note, in our clinical experience, PD-L1 CPS (defined as the number of PD-L1–expressing tumour cells, lym­phocytes, and macrophages divided by the total number of viable tumour cells and multiplied by 100) is preferred over tumour cell–specific PD-L1 expression measurement in upper gastrointestinal tumours, including ESCC. In addition, American Society of Clinical Oncology guidelines state that CPS ≥1 may be used as a threshold when deciding to use nivolumab plus fluoropyrimidine-and platinum-based chemotherapy in first-line treatment of unresectable ad­vanced ESCC.⁷

At the interim analysis, nivolumab plus chemotherapy demonstrated ben­efits vs chemotherapy in terms of com­plete response (13 percent vs 6 percent in the overall population) and objective response rates (47 percent vs 27 per­cent), as well as durability of respons­es (median duration of response, 8.2 months vs 7.1 months).⁵ This is consis­tent with our patient’s achievement of good partial response after only three cycles of treatment.

No new safety issues were reported in CheckMate 648.⁵ However, patient education, proactive monitoring and early management of potentially severe immune-mediated AEs (eg, pneumonitis and colitis) are essential to ensure safe use of nivolumab. Nivolumab has no ab­solute contraindications, but it may not be suitable for patients with autoimmune diseases or organ transplant recipi­ents.⁸

Although health-related quality of life (HRQoL) analysis in CheckMate 648 did not demonstrate clinically meaningful differences between treatment groups, adding nivolumab was associated with a trend towards improved HRQoL vs chemotherapy alone.9 In our patient’s case, nivolumab plus chemotherapy reduced the primary tumour size, help­ing alleviate his dysphagia, which led to improved nutritional status and renal function after just three cycles of treat­ment, allowing him to tolerate full dose of chemotherapy.

Although several immunotherapies are now approved for advanced un-resectable ESCC, nivolumab plus che­motherapy was chosen for our patient since his profile matched the Check­Mate 648 population, consisting pri­marily of Asian patients (70 percent) and PD-L1 expressors.^4-6

In summary, CheckMate 648 and our patient’s case demonstrate that nivolumab plus chemotherapy is an ef­fective and safe first-line treatment op­tion for advanced unresectable ESCC with PD-L1 expression, with established survival benefits and durable responses vs chemotherapy alone.