September 09, 2021: “Positive results from the POSEIDON Phase III trial showed AstraZeneca’s Imfinzi (durvalumab) and tremelimumab, when added to platinum-based chemotherapy, demonstrated a statistically significant and clinically meaningful improvement in overall survival (OS) and progression-free survival (PFS) compared to chemotherapy alone in the 1st-line treatment of patients with Stage IV (metastatic) non-small cell lung cancer (NSCLC).
These results were presented today during a Presidential Symposium at the 2021 World Conference on Lung Cancer hosted by the International Association for the Study of Lung Cancer (abstract PL02.01).
Melissa Johnson, MD, Director of the Lung Cancer Research program at Sarah Cannon Research Institute, and medical oncologist with Tennessee Oncology, PLLC in Nashville, Tennessee, said: “New combinations are increasingly important in addressing the remaining unmet needs that impact patients with metastatic non-small cell lung cancer – especially combinations that have the potential to improve efficacy in patients with lower PD-L1 expression and deliver the long-term survival benefits that have been observed with CTLA-4 inhibition.
The results of POSEIDON confirm that tremelimumab added to Imfinzi and chemotherapy is an effective, well-tolerated treatment in this setting.”
Susan Galbraith, Executive Vice President, Oncology R&D, said: “The POSEIDON data offer patients further benefit from Imfinzi and are an important validation of our development strategy to explore novel combinations.
Adding a short course of tremelimumab to Imfinzi for those patients already receiving chemotherapy, reduced the risk of cancer progressing or death by 28% compared to chemotherapy alone.
The results also showed the significant survival improvement did not compromise tolerability in the 1st-line treatment of patients with metastatic non-small cell lung cancer. We look forward to discussing these data with regulatory authorities.”
Patients treated with a short course of five cycles of tremelimumab, an anti-CTLA4 antibody, over 16 weeks in addition to Imfinzi and chemotherapy experienced a 23% reduction in the risk of death versus a range of chemotherapy options (based on a hazard ratio [HR] of 0.77; 95% CI 0.65-0.92; p=0.00304). Median OS was 14.0 months versus 11.7 months for chemotherapy.
An estimated 33% of patients were alive at two years versus 22% for chemotherapy. This treatment combinationalso reduced the risk of disease progression or death by 28% compared to chemotherapy alone (HR 0.72; 95% CI 0.60-0.86; p=0.00031) with a median PFS of 6.2 months versus 4.8 months, respectively.
The combination delivered a broadly similar safety profile to the Imfinzi and chemotherapy combination and did not lead to an increased discontinuation of treatment.
POSEIDON also tested the combination of Imfinzi plus chemotherapy, which demonstrated a statistically significant improvement in PFS (HR=0.74; 95% CI 0.62-0.89; p=0.00093) versus chemotherapy alone. A positive OS trend observed for Imfinzi plus chemotherapy did not achieve statistical significance.
Summary of OS and PFS
|Imfinzi + tremelimumab + chemotherapy(n=338)||Chemotherapy(n=337)|
|Number of patients with event (%)3||251 (74.3)||285 (84.6)|
|Median OS (95% CI) (in months)||14.0 (11.7, 16.1)||11.7 (10.5, 13.1)|
|Hazard ratio (95% CI)||0.77 (0.65-0.92)|
|OS rate at 24 months (95% CI) (%)||32.9 (27.9, 37.9)||22.1 (17.8, 26.8)|
|Number of patients with event (%)5||238 (70.4)||258 (76.6)|
|Median PFS (95% CI) (in months)||6.2 (5.0, 6.5)||4.8 (4.6, 5.8)|
|Hazard ratio (95% CI)||0.72 (0.60-0.86)|
|PFS rate at 12 months (%)||26.6 (21.7, 31.7)||13.1 (9.3, 17.6)|
1 Investigator-assessed. OS data cut-off date was 12 March 2021; PFS data cut-off date was 24 July 2019
2 Median follow-up in censored patients at DCO: 34.9 months (range 0–44.5)
3 Analysis was done at 79% maturity
4 Median follow-up in censored patients at DCO: 10.3 months (range 0–23.1)
5 Analysis was done at 73% maturity
The safety profile of each Imfinzi combination was consistent with the known profiles of the individual medicines, and no new safety signals were identified. Grade 3 or 4 treatment-related adverse events were experienced by 51.8% of patients treated with Imfinzi, tremelimumab and chemotherapy and by 44.6% of patients treated with Imfinzi plus chemotherapy, versus 44.4% for chemotherapy.
Treatment-related adverse events led to treatment discontinuation in 15.5% of patients treated with Imfinzi, tremelimumab and chemotherapy and 14.1% of patients treated with Imfinzi plus chemotherapy, versus 9.9% for chemotherapy.
Imfinzi is the only approved immunotherapy in the curative-intent setting of unresectable, Stage III NSCLC after chemoradiation therapy and is the global standard of care based on the PACIFIC Phase III trial.
Imfinzi is also approved in the US, the EU, Japan and many countries around the world for the treatment of extensive-stage small cell lung cancer (ES-SCLC) based on the CASPIAN Phase III trial.
Imfinzi is being further assessed across all stages of lung cancer as part of an extensive development programme across NSCLC and SCLC, as well as in other tumour types. The combination of Imfinzi and tremelimumab is being tested in lung cancer, bladder cancer and liver cancer settings.
Stage IV NSCLC
Lung cancer is the leading cause of cancer death accounting for about one-fifth of all cancer deaths.
Patients are commonly diagnosed at Stage IV, when the tumour has spread outside of the lung.
Lung cancer is broadly split into NSCLC and SCLC, with 80-85% classified as NSCLC.
Within NSCLC, patients are classified as squamous, representing 25-30% of patients, or non-squamous, the most common type representing approximately 70-75% of NSCLC patients.
Stage IV is the most advanced form of lung cancer and is often referred to as metastatic disease.
The POSEIDON trial was a randomised, open-label, multi-centre, global, Phase III trial of Imfinzi plus platinum-based chemotherapy or Imfinzi, tremelimumab and chemotherapy versus chemotherapy alone in the 1st-line treatment of 1,013 patients with metastatic NSCLC.
The trial population included patients with either non-squamous or squamous disease and the full range of PD-L1 expression levels. POSEIDON excluded patients with certain epidermal growth factor receptor (EGFR) mutations or anaplastic lymphoma kinase (ALK) fusions.
In the experimental arms, patients were treated with a flat dose of 1,500mg of Imfinzi with up to four cycles of chemotherapy once every three weeks or Imfinzi and 75mg of tremelimumab with chemotherapy, followed by maintenance treatment with Imfinzi, or Imfinzi and one dose of tremelimumab on a once-every-four-weeks dosing schedule.
In comparison, the control arm allowed up to six cycles of chemotherapy. Pemetrexed maintenance treatment was allowed in all arms in patients with non-squamous disease if given during the induction phase.
Nearly all patients with non-squamous disease (95.5%) had pemetrexed and platinum, while the majority of patients with squamous disease receiving chemotherapy (88.3%) received gemcitabine and platinum.
Primary endpoints included PFS and OS for the Imfinzi plus chemotherapy arm. Key secondary endpoints included PFS and OS in the Imfinzi plus tremelimumab and chemotherapy arm.
As both PFS endpoints were met for Imfinzi plus chemotherapy and Imfinzi, tremelimumab and chemotherapy, the prespecified statistical analysis plan allowed for testing OS in the Imfinzi plus tremelimumab and chemotherapy arm.
The trial was conducted in more than 150 centres across 18 countries, including the US, Europe, South America, Asia and South Africa.”