Limited course of tremelimumab with durvalumab and chemotherapy showed sustained OS benefit in NSCLC patients

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 1^st-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."

For more insights: Small cell lung cancer (SCLC) Market, prostate cancer Market, ovarian cancer Market.