Limited course of tremelimumab with durvalumab and chemotherapy showed sustained OS benefit in NSCLC patients
Sep 12, 2022 | DelveInsight
Lung Cancer is broadly divided into two that is NSCLC and small cell lung cancer (SCLC), with around 80-85% of patients falling under NSCLC. Within NSCLC, patients are classified as squamous, representing around 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. Only about 5% of patients with metastatic NSCLC will survive 5 years after diagnosis.
The POSEIDON trial was a randomized, open-label, multicenter, 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 or 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.
The triplet combination induced a median OS of 14.0 months (95% CI, 11.7-16.1), compared with 11.7 months (95% CI, 10.5-13.1) with chemotherapy alone (HR, 0.75; 95% CI, 0.63-0.88), reducing the risk for death by 25%. The 36-month OS rates were 25% vs 13.6%, respectively. Similarly, durvalumab plus chemotherapy showed a median OS of 13.3 months (95% CI, 11.4-14.7), compared with 11.7 months (95% CI, 10.5-13.1) with chemotherapy alone (HR, 0.84; 95% CI, 0.71-0.99). The 36-month OS rates were 20.7% vs 13.6%, respectively.
The OS benefit was greater in patients with nonsquamous mNSCLC, compared with the squamous disease, when they were treated with the triplet regimen (median OS, 17.2 months; 95% CI, 14.9-21.8) vs chemotherapy alone (median OS, 13.1 months; 95% CI, 10.6-15.1), reducing the risk for death by 32% (HR, 0.68; 95% CI, 0.55-0.85). At 3 years, OS rates were 31.4% vs 17.3%, respectively. Without the addition of tremelimumab, patients with nonsquamous histology demonstrated a median OS of 14.8 months (95% CI, 11.8-18.3), with a 3-year OS rate of 25.0%. In those who harbor an STK11 mutation, the triplet reduced the risk for death by 38%, with a median OS of 15.0 months, compared with 10.7 months with chemotherapy alone. At 3 years, the OS rates were 25.8% vs 4.5%, respectively.
Those with a KEAP1 mutation saw a 57% reduction in the risk for death with the triplet regimen, demonstrating a median OS of 13.7 months, vs 8.7 months with chemotherapy alone. The 36-month OS rates were 30.0% vs 0.0%, respectively; however, Johnson noted this was a small sample size.
Lastly, patients with a KRAS mutation experienced a 45% reduction in the risk for death with tremelimumab plus durvalumab and chemotherapy, with a median OS of 25.7 months, compared with 10.4 months, with chemotherapy alone. The 36-month OS rates were 40.0% vs 15.8%, respectively.
Conclusion- It is now a well-known fact that KRAS mutations are the most common tumor growth driver in NSCLC, which occur in almost 25% of the patients. NSCLC tumors with STK11 and KEAP1 mutations are often associated with poor outcomes and are generally classified as “cold.” KRAS-mutated NSCLC can be responsive to immunotherapy but also can have poor outcomes, particularly when associated with STK11 or KEAP1 co-mutations. But, the post-hoc, exploratory analyses continued to show a trend for OS improvement with triplet combination in STK11, KEAP1 and KRAS mutated NSCLC, as well as in patients whose tumors were PD-L1-negative. These results further support the addition of a limited course of tremelimumab to durvalumab plus chemotherapy as a potential new treatment option for patients with these harder-to-treat forms of lung cancer. Also, tremelimumab is under review by global regulatory authorities in combination with Imfinzi and chemotherapy in the 1st-line mNSCLC based on the results from the POSEIDON trial.
Expert Opinion: "These updated POSEIDON results at nearly four years of follow-up show further evidence that the addition of a limited course of tremelimumab to Imfinzi plus chemotherapy improves outcomes for metastatic non-small cell lung cancer patients, including those with specific tumour mutations where a high unmet need for effective, well-tolerated treatments remains. We look forward to bringing this potential new treatment option to patients as quickly as possible."