An older patient with extensive-stage SCLC treated with a PD-L1 inhibitor
Presentation and history
A 65-year-old male, who had enjoyed good past health, presented in February 2019 with a 1-month history of cough. He was a chronic smoker, consuming up to 30 cigarettes per day for the last 40 years. Chest X-ray revealed a right hilar mass and subsequent PET-CT scan showed a right upper lobe mass of 5.5 cm in diameter with involvement of multiple mediastinal and hilar lymph nodes, with the largest lymph node measuring 3.2 cm. Biopsy confirmed small-cell carcinoma of the lung, a limited-stage disease at presentation.
Chemoradiation and subsequent immunotherapy
The patient received six cycles of etoposide and cisplatin along with radiotherapy administered over 4–5 weeks. He completed chemoradiation in June 2019. Repeat PET scan showed complete remission. The patient subsequently received prophylactic cranial irradiation.
The patient remained in remission for 5 months until November 2019, when he presented with an enlarged lymph node near the cervical ascending artery. Biopsy confirmed extensive-stage small-cell carcinoma of the lung. The patient also developed multiple bone metastases and right pleural effusion.
At this time, the patient was given palliative immunotherapy with a PD-L1 inhibitor, durvalumab, and a carboplatin-based chemotherapy regimen, in view of carboplatin’s better tolerability vs cisplatin and the patient’s marginal renal function (creatinine clearance, 50 mL/mon). Four cycles of immuno-chemotherapy achieved partial response with a reduction in lymph node size.
The patient tolerated the treatment well, with thyroid, liver and renal function test results remaining stable. He experienced some diarrhoea, which is likely due to the chemotherapy treatment, and some malaise. He also had self-limiting skin dryness and a rash over the limbs and the trunk, which was alleviated with topical steroid cream. No immune-mediated side effects were observed.
The patient’s general condition remains satisfactory and he remains ambulatory. As of June 2020, he has received seven cycles of durvalumab – four in combination with chemotherapy and three as maintenance, which will be given until disease progression. (Figure)
While the incidence of small-cell lung cancer (SCLC) is declining along with the decreasing prevalence of smoking in Hong Kong, approximately 15 percent of all newly diagnosed lung carcinoma cases are of small-cell histology.1 It is a fast-growing and aggressive tumour, which is often centrally located, leading to multiple symptoms, such as superior vena cava obstruction, obstruction of the airways, dyspnoea, cough, and haemoptysis. It has a high chance of relapse and metastasis causing further symptoms, such as convulsion and weakness. Unlike non-small-cell lung cancer, the choice of treatment for SCLC is limited even within the chemotherapy modality, making it a disease with high unmet need.
In the era of immunotherapy, the standard treatment for extensive-stage SCLC is a PD-L1 inhibitor plus etoposide and a platinum agent. The US National Comprehensive Cancer Network (NCCN) guidelines list durvalumab in combination with carboplatin plus etoposide or cisplatin plus etoposide as one of the preferred primary or adjuvant therapies for extensive-stage SCLC, while the use of another PD-L1 inhibitor, atezolizumab, is only recommended in combination with carboplatin plus etoposide.2
Our patient was commenced on durvalumab in combination with platinum-based chemotherapy on the basis of significantly prolonged overall survival (OS) vs platinum-etoposide reported in the phase III CASPIAN study in patients with extensive-stage SCLC and a WHO performance status of 0 or 1 (hazard ratio [HR], 0.73; 95 percent confidence interval [CI], 0.59 to 0.91; p=0.0047). The median OS was 13.0 months (95 percent CI, 11.5 to 14.8) in the durvalumab plus platinum-etoposide group vs 10.3 months (95 percent CI, 9.3 to 11.2) in the platinum-etoposide group. In the same trial, the 18-month OS rate in the durvalumab group was 34 percent (95 percent CI, 26.9 to 41.0) vs 25 percent (95 percent CI, 18.4 to 31.6) in the platinum-etoposide group. The OS benefit was consistent across all prespecified groups of patients.3
Updated results of the CASPIAN study, recently presented at the American Society of Clinical Oncology (ASCO) 2020 Virtual Meeting after a median follow-up of 25.1 months, demonstrated that durvalumab plus platinum-etoposide maintained significant OS improvement vs platinum-etoposide, with a HR of 0.75 (95 percent CI, 0.62 to 0.91; nominal p=0.0032) and a median OS of 12.9 months vs 10.5 months. The 24-months OS rate was 22.2 percent in the durvalumab group vs 14.4 percent in the platinum-etoposide group.4
Durvalumab’s benefit was observed across all efficacy endpoints of the CASPIAN trial. The 12-month progression-free survival rate was 17.9 percent in the durvalumab plus platinum-etoposide group vs 5.3 percent in the platinum-etoposide group, 13.9 percent vs 3.4 percent at 18 months, and 11.0 percent vs 2.9 percent at 24 months.
Confirmed objective response was achieved by 67.9 percent of patients on durvalumab plus platinum-etoposide vs 58.0 percent of patients on platinum-etoposide (odds ratio, 1.53; 95 percent CI, 1.08 to 2.18). At 12 months, 23.2 percent of patients in the durvalumab plus platinum-etoposide group and 7.3 percent of patients on platinum-etoposide remained in response; at 24 months, proportion of patients in response was 13.5 percent and 3.9 percent, respectively.5
The CASPIAN trial did not reveal any new safety signals, with safety findings being consistent with those for individual agents. Grade 3 or 4 adverse events (AEs) occurred in 62.3 percent of patients in both the durvalumab plus platinum-etoposide group and in the platinum-etoposide group; AEs led to treatment discontinuation in 10.2 percent of patients in the durvalumab plus platinum-etoposide group and in 9.4 percent of patients in the platinum-etoposide group.5 The most common grade 3 or 4 AEs were neutropenia and anaemia.
Treatment-related AEs leading to death occurred in 2.3 percent of patients in the durvalumab plus platinum-etoposide group and in 0.8 percent of patients in the platinum-etoposide group.5 With the exception of an increased incidence of immune-mediated AEs in the durvalumab vs platinum-etoposide group (20 percent vs 3 percent), the addition of durvalumab to chemotherapy did not appear to exacerbate the regimen’s AE profile.3
The CASPIAN trial enrolled a considerable cohort of Asian patients (from Japan, South Korea, Taiwan and China), which constituted approximately 14 percent of the trial’s global population. The safety profile of durvalumab plus platinum-etoposide in the Asian subgroup was generally consistent with that in the global population, with no treatment-related deaths reported in Asian patients.6
In addition to the survival benefit, durvalumab has a positive impact on health-related quality of life (HRQoL), as demonstrated in the CASPIAN trial and as evidenced by our patient case. The pain caused by the enlarged lymph node in extensive-stage disease subsided after our patient received just one cycle of durvalumab. In the CASPIAN trial, time to deterioration in all patient-reported symptoms, functioning and HRQoL favoured durvalumab plus platinum-etoposide compared with platinum-etoposide alone.7
In conclusion, current case demonstrates that durvalumab plus platinum-based chemotherapy is a viable, well-tolerated treatment option for patients with extensive-stage SCLC, who are able to tolerate chemotherapy and have a good performance status.