Triple Therapy Continues to Impress in Metastatic NSCLC With High-Risk Mutations

VIENNA -- Patients with non-squamous metastatic non-small cell lung cancer (NSCLC) who had tumor mutations associated with poor prognosis experienced meaningful improvements in survival when treated with a first-line regimen of two immunotherapies plus chemotherapy, a researcher reported.

An exploratory analysis from the POSEIDON trial showed a trend for an overall survival (OS) benefit with a combination of PD-L1 inhibitor durvalumab (Imfinzi), the CTLA-4 inhibitor tremelimumab, and chemotherapy compared with chemotherapy alone in patients with the following mutational status, according to Solange Peters, MD, of Centre Hospitalier Universitaire Vaudois, Lausanne University in Switzerland:

• STK11: HR 0.56 (95% CI 0.30-1.03)
• KEAP1: HR 0.43 (95% CI 0.16-1.25)
• KRAS: HR 0.56 (95% CI 0.36-0.88)

Patients with STK11 mutations had a median OS of 15.0 months with the triple therapy compared with 10.7 months in the chemotherapy arm, with estimated 2-year OS rates of 32.3% versus 4.5%. Those with KEAP1 mutations had a median OS of 13.7 months and 8.7 months in the two arms, with 2-year OS rates of 35.0% and 0%, Peters said in a presentation at the World Conference on Lung Cancer (WCLC).

There was a trend towards improved OS in patients with KRAS mutations, with a median OS of 25.7 months versus 10.4 months in the triple therapy and chemotherapy groups, with estimated 2-year OS rates of 51.7% and 25.6%.

The triple therapy also produced improved progressive-free survival (PFS), and "most interesting to me was the more frequent, and deeper responses, including complete responses, and sustained disease control," Peters observed during a WCLC press briefing. "The data suggest that this may be a strategy to adopt for these specific subgroups in the future and should be further validated."

POSEIDON was a phase III global, randomized, open-label, multicenter study in which 1,013 patients with treatment-naïve, EGFR/ALK wild-type metastatic NSCLC were randomized into three treatment arms: tremelimumab, durvalumab, plus chemotherapy; durvalumab plus chemotherapy; and chemotherapy alone. A previous analysis of POSEIDON demonstrated that patients receiving the triple therapy achieved clinically meaningful improvements in PFS (HR 0.72, 95% CI 0.60-0.86, P=0.0003) and OS (HR 0.77, 95% CI 0.65-0.92, P=0.0030) versus chemotherapy alone.

"While we have growing experience using immunotherapy, we're also starting to identify subgroups of patients who are characterized by poor outcomes," Peters noted. "Basically, STK11- and KEAP1-mutated tumors are associated with strongly poor prognosis. They have also been shown to be immunologically cold and lacking T-cell infiltration. The KRAS-mutated group is slightly more heterogenous and generally has been shown to be responsive to anti-PD-1- or anti-PD-L1-based therapy, unless they are found to be associated with STK11 and KEAP1 mutations."

The mutation-evaluable population for this analysis included 612 patients, 182 (30%) with KRAS mutations, 87 (14%) with STK11 mutations, and 37 (6%) with KEAP1 mutations. There was some overlap resulting in patients with co-mutations, but these subgroups were small and were not evaluable because of the sample size.

Peters and colleagues reported that in patients with STK11 mutations, PFS matched OS data, with a median PFS of 6.4 versus 4.8 months in the two groups (HR 0.47, 95% CI 0.23-0.93), and 1-year PFS rates of 34.6% and 0%, respectively. Also, there was a higher overall response rate (ORR) of 45.2% in the triple-therapy group versus 27.3% in the chemotherapy group, and a greater depth and more durable response (14.6 months vs 3.3 months).

In KEAP1-mutant patients, the median PFS was 5.0 and 5.1 months in the triple therapy and chemotherapy groups, respectively (HR 0.94, 95% CI 0.33-3.36), while 1-year PFS rates were 30.6% and 0%. ORR, depth of response, and durability of response were greater with the triple-therapy arm versus chemotherapy (ORR 45.5% and median duration of response 16.4 months vs ORR 33.3% and median duration of response 4.8 months).

In patients with KRAS mutations, PFS was in line with OS, with a median of 8.5 and 4.7 months in the triple therapy and chemotherapy groups (HR 0.57, 95% CI 0.35-0.92), and 1-year PFS rates of 40.0% and 20.0%. Also, there was a 55.0% ORR in the triple-therapy group, with median duration of response not reached versus ORR 21.2% in the chemotherapy arm, with median duration of response 5.4 months.

WCLC discussant Puey Ling Chia, MBBS, PhD, of Tan Tock Seng Hospital in Singapore, said treatment with durvalumab and chemotherapy appeared to derive no benefit compared with chemotherapy alone in the STK11 and KEAP1 groups. "This was consistent with previous studies that have shown that lung cancer patients with STK11 mutations are associated with reduced PD-L1 expression, and also diminished response with immune checkpoint inhibitors," she said.

However, she observed that the substantial improvement in OS when tremelimumab was added to durvalumab and chemotherapy "suggests that this combination should be studied and can be a potential first-line option."

Chia also noted that the numbers in this study were small and pointed out that co-occurring mutations in KRAS/STK11 and KRAS/KEAP1 were found in just a small percentage of patients and that only 1% had triple co-mutated tumors, "which are the higher risk groups."

"We'll definitely have to wait for larger data sets to draw better conclusions," she said.

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