Lancet 2019 Oct 04
Durvalumab plus platinum-etoposide versus platinum-etoposide in first-line treatment of extensive-stage small-cell lung cancer (CASPIAN): a randomised, controlled, open-label, phase 3 trial.
Abstract
Background
Most patients with small-cell lung cancer (SCLC) have extensive-stage disease at presentation, and prognosis remains poor. Recently, immunotherapy has demonstrated clinical activity in extensive-stage SCLC (ES-SCLC). The CASPIAN trial assessed durvalumab, with or without tremelimumab, in combination with etoposide plus either cisplatin or carboplatin (platinum-etoposide) in treatment-naive patients with ES-SCLC.
Methods
This randomised, open-label, phase 3 trial was done at 209 sites across 23 countries. Eligible patients were adults with untreated ES-SCLC, with WHO performance status 0 or 1 and measurable disease as per Response Evaluation Criteria in Solid Tumors, version 1.1. Patients were randomly assigned (in a 1:1:1 ratio) to durvalumab plus platinum-etoposide; durvalumab plus tremelimumab plus platinum-etoposide; or platinum-etoposide alone. All drugs were administered intravenously. Platinum-etoposide consisted of etoposide 80-100 mg/m2 on days 1-3 of each cycle with investigator's choice of either carboplatin area under the curve 5-6 mg/mL per min or cisplatin 75-80 mg/m2 (administered on day 1 of each cycle). Patients received up to four cycles of platinum-etoposide plus durvalumab 1500 mg with or without tremelimumab 75 mg every 3 weeks followed by maintenance durvalumab 1500 mg every 4 weeks in the immunotherapy groups and up to six cycles of platinum-etoposide every 3 weeks plus prophylactic cranial irradiation (investigator's discretion) in the platinum-etoposide group. The primary endpoint was overall survival in the intention-to-treat population. We report results for the durvalumab plus platinum-etoposide group versus the platinum-etoposide group from a planned interim analysis. Safety was assessed in all patients who received at least one dose of their assigned study treatment. This study is registered at ClinicalTrials.gov, NCT03043872, and is ongoing.
Findings
Patients were enrolled between March 27, 2017, and May 29, 2018. 268 patients were allocated to the durvalumab plus platinum-etoposide group and 269 to the platinum-etoposide group. Durvalumab plus platinum-etoposide was associated with a significant improvement in overall survival, with a hazard ratio of 0·73 (95% CI 0·59-0·91; p=0·0047]); median overall survival was 13·0 months (95% CI 11·5-14·8) in the durvalumab plus platinum-etoposide group versus 10·3 months (9·3-11·2) in the platinum-etoposide group, with 34% (26·9-41·0) versus 25% (18·4-31·6) of patients alive at 18 months. Any-cause adverse events of grade 3 or 4 occurred in 163 (62%) of 265 treated patients in the durvalumab plus platinum-etoposide group and 166 (62%) of 266 in the platinum-etoposide group; adverse events leading to death occurred in 13 (5%) and 15 (6%) patients.
Interpretation
First-line durvalumab plus platinum-etoposide significantly improved overall survival in patients with ES-SCLC versus a clinically relevant control group. Safety findings were consistent with the known safety profiles of all drugs received.
Funding
AstraZeneca.
Related Questions
Would you add immunotherapy to chemotherapy in the adjuvant treatment of resected small cell lung cancer?
In the absence of data in this space, no. The improvements observed in ES-SCLC in IMpower133 and CASPIAN with the addition of ICI were modest at best. Pending results from ADRIATIC and NRG LU005 for benefits in the limited stage population, but this would still require a leap of faith to the adjuvan...
Do you recommend trilaciclib as primary prophylaxis for myelosuppression in certain patients with ES-SCLC treated with first line chemo-immunotherapy?
I do not routinely use growth factor support nor trilaciclib with chemotherapy or chemo-immunotherapy for people with ES-SCLC. My starting doses of chemo are usually carboplatin AUC 5 day 1 + etoposide 100 mg/m2 days 1-3, and the degree of myelosuppression and incidence of neutropenic fever with thi...
Do the results of CheckMate 451 (nivo-ipi or nivo maintenance after chemotherapy in patients with SCLC) raise any questions for you about the role of immunotherapy in SCLC as established by the CASPIAN and IMpower 133 trials?
The results of the Checkmate 451 trial evaluating nivolumab and ipilimumab or nivolumab maintenance versus no maintenance following front line chemotherapy for extensive stage small cell lung cancer help put the CASPIAN and IMpower 133 trials using front line chemotherapy with immune checkpoint inhi...
When would you ever choose cisplatin over carboplatin in extensive stage small cell lung cancer?
I prefer carboplatin over cisplatin in ES SCLC as there does not seem to be proven benefit and there is certainly higher risk for toxicity. There was a recent report at ASCO with similar findings. I reserve cisplatin for limited stage disease with concurrent radiation or as adjuvant therapy in cases...
Would you consider adding atezolizumab to chemotherapy for metastatic esophageal small cell cancer?
I would consider adding atezolizumab (and indeed I have in the past). Of course, this would be based on the SCLC literature from the IMpower133 and CASPIAN trials where atezolizumab and durvalumab respectively improved outcomes when combined with platinum/etoposide chemotherapy. But there is a cavea...
Are there any data to guide choice of immunotherapy agent in first line treatment for extensive stage small cell lung cancer?
Both the addition of durvalumab and atezolizumab to platinum etoposide resulted in a modest improvement in median progression free, overall survival and saw twelve-month overall survival rates just above 50%. The ECOG-ACRIN phase II trial of nivolumab added to platinum etoposide also improved PFS an...
Would you offer hippocampal sparing whole brain radiation for patients with brain metastases due to ES-SCLC?
Until we have built-in auto-segmentation, I find the RTOG contouring atlas very helpful for manual contouring of the hippocampus. I tend to use the lateral ventricle as my main landmark, and look for the circle of gray matter located medial to it. Once I've drawn a hippocampus, I'll look at it in th...
Would you withhold immunotherapy for ES-SCLC during the COVID-19 pandemic?
Risks of COVID-19 infection and severe pneumonia seem to be higher in our patients with lung cancer. This is fairly early data and some of the patients included in those analyses were not receiving any active therapy. This suggests that at least some of the risk is simply frequent visits to the canc...
Are you testing for PD-L1 IHC expression in extensive stage small cell lung cancer who are planned to be treated with chemotherapy plus immunotherapy?
Based on trial approved chemo-immunotherapy for ES-SCLC, it is not a requirement. IMpower33 (Atezo) and Caspian trial (durva).
Is there a role for upfront next generation sequencing in extensive stage small cell lung carcinoma?
The current standard of care is a combination of chemotherapy and immunotherapy (platinum-etoposide with atezolizumab; durvalumab may be an option as well based on the CASPIAN trial). There are no data for targeted therapy, nor is there any evidence to support using any biomarkers to guide immunothe...
Would you offer WBRT to a patient with ES-SCLC with improving brain mets on immunotherapy?
The answer to this question arises more from the domains of personal opinion and anecdotal experience rather than a strong evidence basis. The study establishing the value of atezolizumab in this setting (N Engl J Med 2018) does not provide data specific to informing a management approach.At my own ...
As consolidative thoracic radiation (cTRT) was prohibited on the seminal chemoimmunotherapy trials in ES-SCLC, how do you approach cTRT in practice?
The data supporting consolidation thoracic radiotherapy (cTRT) after chemotherapy response in ES-SCLC are relatively soft. The phase III Jeremic trial (Jeremic et al., PMID 10561263) reported an overall survival (OS) improvement with accelerated hyperfractionated cTRT to 54 Gy + daily carboplatin/et...
Is it acceptable to treat newly diagnosed small cell lung cancer with limited brain metastasis with upfront SRS?
First, to be clear, there's not good evidence regarding the role of radiosurgery in small cell patients who have not had WBRT or PCI. In patients without brain metastases, there's a clearly defined and clinically significant survival benefit, which seems to result from both control of existing metas...