Mutations of STK11/KRAS Genes and Efficacy of Immunotherapy in NSCLC

SUMMARY: The American Cancer Society estimates that for 2022, about 236,740 new cases of lung cancer will be diagnosed and 135,360 patients will die of the disease. Lung cancer is the leading cause of cancer-related mortality in the United States. Non-Small Cell Lung Cancer (NSCLC) accounts for approximately 85% of all lung cancers and Adenocarcinoma now is the most frequent histologic subtype of lung cancer.

Immune checkpoints are cell surface inhibitory proteins/receptors that are expressed on activated T cells. They harness the immune system and prevent uncontrolled immune reactions by switching off the T cells of the immune system. Immune checkpoint proteins/receptors include CTLA-4 (Cytotoxic T-Lymphocyte Antigen 4, also known as CD152) and PD-1(Programmed cell Death 1). Checkpoint inhibitors unleash the T cells resulting in T cell proliferation, activation, and a therapeutic response.

TECENTRIQ® (Atezolizumab) is an anti-PDL1 monoclonal antibody, designed to directly bind to PD-L1 expressed on tumor cells and tumor-infiltrating immune cells, thereby blocking its interactions with PD-1 and B7.1 receptors and thus enabling the activation of T cells. AVASTIN® (Bevacizumab) is a biologic antiangiogenic antibody, directed against Vascular Endothelial Growth Factor (VEGF), and prevents the interaction of VEGF to its receptors (Flt-1 and KDR) on the surface of endothelial cells. The interaction of VEGF with its receptors has been shown to result in endothelial cell proliferation and new blood vessel formation. Combining TECENTRIQ® and AVASTIN® is supported by the following scientific rationale. AVASTIN® in addition to its established anti-angiogenic effects, may further enhance the ability of TECENTRIQ® to restore anti-cancer immunity, by inhibiting VEGF-related immunosuppression, promoting T-cell tumor infiltration and enabling priming and activation of T-cell responses against tumor antigens.

IMpower150 is a multicenter, open-label, randomized, Phase III study, conducted to evaluate the efficacy and safety of TECENTRIQ® in combination with Carboplatin and Paclitaxel with or without AVASTIN®, in patients with Stage IV, treatment naïve, non-squamous NSCLC. This study enrolled 1,202 patients, who were randomized (1:1:1) to receive either TECENTRIQ® along with Carboplatin and Paclitaxel (ACP-Group A), TECENTRIQ® and AVASTIN® along with Carboplatin and Paclitaxel (ABCP-Group B), or AVASTIN® plus Carboplatin and Paclitaxel (BCP-Group C – control arm). During the treatment-induction phase, patients in Group A received TECENTRIQ® 1200 mg IV along with Carboplatin AUC 6 and Paclitaxel 200mg/m2 IV on Day 1 of a 3-week treatment cycle for 4 or 6 cycles. Following the induction phase, patients received maintenance treatment with TECENTRIQ® on the same dose schedule until disease progression. Patients in Group B received AVASTIN® 15 mg/kg IV, along with TECENTRIQ®, Carboplatin and Paclitaxel IV, Day 1 of a 3-week treatment cycle for 4 or 6 cycles followed by maintenance treatment with the TECENTRIQ® and AVASTIN® until disease progression. Patients in the control Group C received AVASTIN® plus Carboplatin and Paclitaxel every 3 weeks for 4 or 6 cycles followed by AVASTIN® maintenance treatment until disease progression. Among randomized patients with tumors demonstrating no ALK and EGFR mutations, ABCP was associated with significant improvements in Progression Free Survival (PFS) and Overall Survival (OS), compared with BCP, in an updated OS analysis. ABCP also prolonged OS and PFS compared with BCP in an exploratory subgroup analysis of patients with EGFR-sensitizing mutations.

The Serine‐Threonine Kinase 11 (STK11) gene is located on the short arm of chromosome 19 and germline STK11 mutations are often detected in Peutz‐Jeghers syndrome, an Autosomal Dominant disorder resulting in mucocutaneous hyperpigmentation, hamartomas throughout the gastrointestinal tract, and a predisposition for breast, lung, pancreas, and gastrointestinal malignancies including cancers of the colon and small bowel. Both STK11 (also called LKB1) and KEAP1 mutation occur in about 17% of NSCLC (adenocarcinomas), respectively, and correlates with poor outcome with immune checkpoint inhibitors or immune checkpoint inhibitors plus chemotherapy. Although immune checkpoint inhibitors with or without chemotherapy have demonstrated survival benefit in patients with KRAS mutated tumors, it remains unclear how co-occurring STK11, KEAP1, and TP53 mutations affect outcomes following immune checkpoint blockade.

The authors in this publication conducted a retrospective exploratory analysis of the efficacy of ABCP (TECENTRIQ® and AVASTIN® along with Carboplatin and Paclitaxel), in patients with KRAS mutations and co-occuring STK11, KEAP1, or TP53 mutations, from the IMpower150 nonsquamous NSCLC patient population. Mutation status was determined by circulating tumor DNA Next-Generation Sequencing.

Among the KRAS mutated population, there was numerical improvement in median OS with ABCP compared to BCP (19.8 vs 9.9 months; HR=0.50), as well as PFS (8.1 vs 5.8 months; HR=0.42) respectively. The median OS with ACP (TECENTRIQ® along with Carboplatin and Paclitaxel) was 11.7 vs 9.9 months (HR=0.63), and PFS was 4.8 vs 5.8 months (HR=0.80), when compared with BCP (AVASTIN® plus Carboplatin and Paclitaxel). When compared to BCP, the ABCP group showed numerically greater survival than the ACP group among KRAS mutated patients. These results were consistent with reported survival improvements with immune checkpoint inhibitors in KRAS-mutant NSCLC.

In KRAS mutant patients across PD-L1 subgroups, OS and PFS were longer with ABCP when compared with BCP, but in PD-L1-low and PD-L1-negative subgroups, OS with ACP was similar to BCP. Conversely, in KRAS wild type patients, OS was longer with ACP than with ABCP or BCP across PD-L1 subgroups.

KRAS was frequently comutated with STK11, KEAP1, and TP53 and these subgroups conferred different prognostic outcomes. Within the KRAS mutated population, STK11 and/or KEAP1 mutations were associated with inferior OS and PFS across treatments compared with STK11-wild type and/or KEAP1wild type. In KRAS mutated patients with co-occurring STK11 and/or KEAP1 mutations (44.9%) or TP53 mutations (49.3%), survival was longer with ABCP than with ACP or BCP.

It was concluded that this analysis supported previous findings of mutation of STK11 and/or KEAP1 as poor prognostic indicators. Even though the clinical efficacy of ABCP (TECENTRIQ® and AVASTIN® along with Carboplatin and Paclitaxel) and ACP (TECENTRIQ® along with Carboplatin and Paclitaxel) was favorable compared with BCP (AVASTIN® plus Carboplatin and Paclitaxel) in these mutational subgroups, survival benefits were greater in the KRAS mutated and KEAP1 and STK11 wild type population versus KRAS mutated and KEAP1 and STK11 mutated population, suggesting both prognostic and predictive value of mutational analysis. The researchers added that these results suggest that TECENTRIQ® in combination with AVASTIN® and chemotherapy is an efficacious first-line treatment in metastatic NSCLC subgroups with KRAS mutations co-occurring with STK11 and/or KEAP1 or TP53 mutations and/or high PD-L1 expression.

Clinical efficacy of atezolizumab plus bevacizumab and chemotherapy in KRAS- mutated non-small cell lung cancer with STK11, KEAP1, or TP53 comutations: subgroup results from the phase III IMpower150 trial. West JH, McCleland M, Cappuzzo, F, et al. J Immunother Cancer. 2022 Feb;10(2):e003027. doi: 10.1136/jitc-2021-003027.