Decoding KRAS mutation in non-small cell lung cancer patients receiving immunotherapy: A retrospective institutional comparison and literature review.

KRAS mutation the most common molecular alteration in advanced non-small cell lung cancer (NSCLC) and is associated with an unfavourable prognosis, largely due to the lack of targeted therapeutic options for the majority of the KRAS mutated isoforms. The landscape of NSCLC treatment has expanded with the introduction of immune checkpoint inhibitors (ICIs). Nonetheless, data regarding the efficacy of ICI in NSCLC patients harbouring KRAS mutations are conflicting. This study aimed to compare clinical outcomes of ICIs in advanced NSCLC with different isoforms of KRAS mutations. A retrospective study was conducted on 143 patients with advanced NSCLC harbouring different KRAS mutation and treated with immune checkpoint inhibitors (ICI) between December 2020 and July 2022 at "Fondazione IRCCS Istituto Nazionale dei Tumori" in Milan. Log-rank and Cox Hazard methods were used for survival analysis. We evaluated 143 patients with advanced non-small cell lung cancer (NSCLC) harboring KRAS mutations. The most common mutation was G12C (41 %), followed by G12V (23.7 %) and G12D (11.8 %). The G12C mutation was notably associated with a higher incidence of bone metastases (42 %). Immunotherapy was administered as monotherapy in 54.5 % of cases, while 69 % received it as part of a first-line combination with chemotherapy. Co-mutations were detected in 52 % of patients, with Q61 (63 %) and G12C (58 %) being the most prevalent. Among these, 24 % had STK11 co-mutations, and 29 % had TP53 co-mutations. No significant differences in overall survival (OS) or progression-free survival (PFS) were observed across different KRAS subtypes. The longest OS was seen in patients with Q61 (46.5 months), 13X (31.8 months), and G12C (28.7 months). The highest overall response rate (ORR) of 73 % was observed in the G12D group, particularly with the combination of chemoimmunotherapy, where stable disease was the most common outcome at 40 %. The median duration of response (DOR) was 7.4 months across both treatments. The longest DOR was seen in the G12V group at 10.2 months, with no significant difference between treatments. In contrast, the shortest DOR was in the G12A group, with 1.54 months in those treated with combination therapy compared to 2.57 months with single-agent therapy. Regarding co-mutations, patients with STK11 co-mutations had a higher median OS than those without (39.7 vs. 26.1 months), but this was not statistically significant (p = 1). Similarly, TP53 co-mutations were associated with a lower median OS (19.1 vs. 26.1 months, p = 0.7), though this too was not statistically significant. Importantly, bone metastases emerged as a significant adverse prognostic factor, nearly doubling the risk of mortality (HR: 2.81, p < 0.001), regardless of KRAS subtype or co-mutation status. KRAS mutation subtypes demonstrate varying clinical outcomes. Although no statistically significant differences were observed in overall survival (OS) or progression-free survival (PFS), bone metastases were identified as a significant adverse prognostic factor, nearly doubling the risk of mortality (HR: 2.72, p < 0.001) regardless of KRAS subtype or co-mutation status. These findings underscore the importance of personalized treatment approaches tailored to the genetic profiles of patients with advanced NSCLC.

Urtecho SB ，Provenzano L ，Spagnoletti A ，Bottiglieri A ，Pircher C ，Massa G ，Sposetti C ，Proto C ，Brambilla M ，Occhipinti M ，Mazzeo L ，Beninato T ，Leporati R ，Giani C ，Cavalli C ，Serino R ，Prina MM ，Bassetti A ，Nasca V ，di Mauro RM ，Abate A ，Manglaviti S ，Dumitrascu AD ，Liberti GD ，Cassano TS ，Ganzinelli M ，Wu S ，Garassino MC ，de Braud FGM ，Russo GL ，Prelaj A ... -  《-》

Exploration of efficacy of different therapy regimens for advanced NSCLC patients with KRAS mutation in the first-line treatment.

The treatment of the advanced non-small cell lung cancer (NSCLC) with KRAS mutation has been closely paid more attention. The aim of this study is to investigate the efficacy of different first-line regimens in advanced KRAS-mutated non-small cell lung cancer. In our retrospective study, we collected patients with advanced NSCLC with KRAS mutation in Zhejiang Cancer Hospital between January 2015 and May 2023. We analyzed the benefit of different first-line therapy according to theraputic methods and the differential effect of the same treatment method among KRAS-mutated subtypes. We divided the patients into group A (A1, chemotherapy alone; A2, immunotherapy alone) and group B (B1, chemotherapy plus immunotherapy; B2, chemotherapy combined with antiangiogenic therapy; B3, chemotherapy combined with immunotherapy plus antiangiogenic therapy). The Kaplan-Meier survival curve was used to reflect the PFS and OS of different methods. The objective response rate (ORR) and the disease control rate (DCR) were used to evaluated the response. We enrolled 227 patients including eighty-two with KRAS G12C mutation. The ORR and DCR of first-line treatment in the overall population were 32.2% and 80.6% respectively. The median PFS was 6.7 months and the median OS was 17.4 months for the overall population. The PFS of the Group B was significantly better than that of the Group A (7.7 months vs 5.4 months, P = 0.003), while no significant difference in OS was observed (19.4 months vs 15.0 months, P = 0.077). In the Group B, chemotherapy combined immunotherapy with antiangiogenic therapy showed better PFS than chemotherapy plus immunotherapy (14.1 months vs 7.7 months, P = 0.049), and OS also showed that tendency of difference (31.9 months vs 19.3 months, P = 0.158). There was no statistically significant difference between KRAS G12C and non-G12C mutation according to first-line treatment methods, whereas patients with TP53 co-mutation showed a better survival benefit (OS, 23.7 vs 12.5 months, P = 0.023). In the first-line treatment, combination regimen has advantages over single regimen. Among them, chemotherapy combined with immunotherapy plus antiangiogenic therapy can achieve significant efficacy benefits.

Wang K ，Xu M ，Wang Y ，Xu C ，Hao Y ，Song Z ... -  《-》

Efficacy and Safety of KRASG12C Inhibitor IBI351 Monotherapy in Patients With Advanced NSCLC: Results From a Phase 2 Pivotal Study.

KRAS glycine-to-cysteine substitution at codon 12 (G12C) mutation is a well-recognized and increasingly promising therapeutic target with huge unmet clinical needs in NSCLC patients. IBI351 is a potent covalent and irreversible inhibitor of KRAS G12C. Here, we present the efficacy and safety of IBI351 from an open-label, single-arm, phase 2 pivotal study. Eligible patients with NSCLC with KRAS G12C who failed standard therapy were enrolled. IBI351 was orally administered at a dose of 600 mg twice daily. The primary endpoint was confirmed objective response rate assessed by an independent radiological review committee (IRRC) as per Response Evaluation Criteria in Solid Tumors v1.1. Other endpoints were safety, IRRC-confirmed disease control rate, duration of response, progression-free survival (PFS), and overall survival. As of December 13, 2023, 116 patients were enrolled (Eastern Cooperative Oncology Group Performance Status 1: 91.4%; brain metastasis: 30.2%; prior treatments with both anti-PD-1 or anti-PD-L1 inhibitors and platinum-based chemotherapy: 84.5%). As per the IRRC assessment, the confirmed objective response rate was 49.1% (95% confidence interval [CI]: 39.7-58.6), and the disease control rate was 90.5% (95% CI: 83.7-95.2). The median duration of response was not reached whereas disease progression or death events occurred in 22 patients (38.6%), and the median PFS was 9.7 months (95% CI: 5.6-11.0). overall survival data was immature. Treatment-related adverse events (TRAEs) occurred in 107 patients (92.2%) whereas 48 patients (41.4%) had equal to or higher than grade three TRAEs. Common TRAEs were anemia (44.8%), increased alanine aminotransferase (28.4%), increased aspartate aminotransferase (27.6%), asthenia (26.7%) and presence of protein in urine (25.0%). TRAEs leading to treatment discontinuation occurred in nine patients (7.8%). In biomarker evaluable patients (n = 95), all patients had positive KRAS G12C in tissue whereas 72 patients were blood-positive and 23 were blood-negative for KRAS G12C. Patients with KRAS G12C in both blood and tissue had higher tumor burden at baseline (p < 0.05) and worse PFS (p < 0.05). Tumor mutation profiling identified tumor protein p53 (45.3%), serine/threonine kinase 11 (STK11) (30.5%), and kelch-like ECH-associated protein 1 (21.1%) as the most common genes co-mutated with KRAS G12C. Among 13 genes with mutation frequency equal to or higher than 5%, mutations of six genes (STK11, kelch-like ECH-associated protein 1, phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit gamma, DNA polymerase epsilon, SMAD family member 4, and BMP/retinoic acid-inducible neural-specific protein 3) were significantly associated with worse PFS (p < 0.05). Mutation in STK11 was also found to have a significant association with higher tumor burden at baseline and lower response rate (p < 0.05). IBI351 monotherapy demonstrated promising and sustained efficacy with manageable safety, supporting its potential as a new treatment option for KRAS G12C-mutant NSCLC.

Zhou Q ，Meng X ，Sun L ，Huang D ，Yang N ，Yu Y ，Zhao M ，Zhuang W ，Guo R ，Hu Y ，Pan Y ，Shan J ，Sun M ，Yuan Y ，Fan Y ，Huang J ，Liu L ，Chu Q ，Wang X ，Xu C ，Lin J ，Huang J ，Huang M ，Sun J ，Zhang S ，Zhou H ，Wu YL ... -  《-》

Immune checkpoint inhibitors plus platinum-based chemotherapy compared to platinum-based chemotherapy with or without bevacizumab for first-line treatment of older people with advanced non-small cell lung cancer.

Lung cancer is a cancer of the elderly, with a median age at diagnosis of 71. More than one-third of people diagnosed with lung cancer are over 75 years old. Immune checkpoint inhibitors (ICIs) are special antibodies that target a pathway in the immune system called the programmed cell death 1/programmed cell death-ligand 1 (PD-1/PD-L1) pathway. These antibodies help the immune system fight cancer cells by blocking signals that cancer cells use to avoid being attacked by the immune system. ICIs have changed the treatment of people with lung cancer. In particular, for people with previously-untreated advanced non-small cell lung cancer (NSCLC), current first-line treatment now comprises ICIs plus platinum-based chemotherapy, rather than platinum-based chemotherapy alone, regardless of their PD-L1 expression status. However, as people age, their immune system changes, becoming less effective in its T cell responses. This raises questions about how well ICIs work in older adults. To assess the effects of immune checkpoint inhibitors (ICIs) in combination with platinum-based chemotherapy compared to platinum-based chemotherapy (with or without bevacizumab) in treatment-naïve adults aged 65 years and older with advanced NSCLC. We searched the Cochrane Lung Cancer Group Trial Register, CENTRAL, MEDLINE, Embase, two other trial registers, and the websites of drug regulators. The latest search date was 23 August 2023. We also checked references and searched abstracts from the meetings of seven cancer organisations from 2019 to August 2023. We included randomised controlled trials (RCTs) that reported on the efficacy and safety of adding ICIs to platinum-based chemotherapy compared to platinum-based chemotherapy alone for people 65 years and older who had not previously been treated. All data emanated from international multicentre studies involving adults with histologically-confirmed advanced NSCLC who had not received any previous systemic anticancer therapy for their advanced disease. We used standard methodological procedures expected by Cochrane. Our primary outcomes were overall survival and treatment-related adverse events (grade 3 or higher). Our secondary outcomes were progression-free survival, objective response rate, time to response, duration of response, and health-related quality of life (HRQoL). We included 17 primary studies, with a total of 4276 participants, in the review synthesis. We identified nine ongoing studies, and listed one study as 'awaiting classification'. Twelve of the 17 studies included people older than 75 years, accounting for 9% to 13% of their participants. We rated some studies as having 'some concerns' for risk of bias arising from the randomisation process, deviations from the intended interventions, or measurement of the outcome. The overall GRADE rating for the certainty of the evidence ranged from moderate to low because of the risk of bias, imprecision, or inconsistency. People aged 65 years and older The addition of ICIs to platinum-based chemotherapy probably increased overall survival compared to platinum-based chemotherapy alone (hazard ratio (HR) 0.78, 95% confidence interval (CI) 0.70 to 0.88; 8 studies, 2093 participants; moderate-certainty evidence). Only one study reported data for treatment-related adverse events (grade 3 or higher). The frequency of treatment-related adverse events may not differ between the two treatment groups (risk ratio (RR) 1.09, 95% CI 0.89 to 1.32; 1 study, 127 participants; low-certainty evidence). The addition of ICIs to platinum-based chemotherapy probably improves progression-free survival (HR 0.61, 95% CI 0.54 to 0.68; 7 studies, 1885 participants; moderate-certainty evidence). People aged 65 to 75 years, inclusive The addition of ICIs to platinum-based chemotherapy probably improved overall survival compared to platinum-based chemotherapy alone (HR 0.75, 95% CI 0.65 to 0.87; 6 studies, 1406 participants; moderate-certainty evidence). Only one study reported data for treatment-related adverse events (grade 3 or higher). The frequency of treatment-related adverse events probably increased in people treated with ICIs plus platinum-based chemotherapy compared to those treated with platinum-based chemotherapy alone (RR 1.47, 95% CI 1.02 to 2.13; 1 study, 97 participants; moderate-certainty evidence). The addition of ICIs to platinum-based chemotherapy probably improved progression-free survival (HR 0.64, 95% CI 0.57 to 0.73; 8 studies, 1466 participants; moderate-certainty evidence). People aged 75 years and older There may be no difference in overall survival in people treated with ICIs combined with platinum-based chemotherapy compared to platinum-based chemotherapy alone (HR 0.90, 95% CI 0.70 to 1.16; 4 studies, 297 participants; low-certainty evidence). No data on treatment-related adverse events were available in this age group. The effect of combination ICI and platinum-based chemotherapy on progression-free survival is uncertain (HR 0.83, 95% CI 0.51 to 1.36; 3 studies, 226 participants; very low-certainty evidence). Only three studies assessed the objective response rate. For time to response, duration of response, and health-related quality of life, we do not have any evidence yet. Compared to platinum-based chemotherapy alone, adding ICIs to platinum-based chemotherapy probably leads to higher overall survival and progression-free survival, without an increase in treatment-related adverse events (grade 3 or higher), in people 65 years and older with advanced NSCLC. These data are based on results from studies dominated by participants between 65 and 75 years old. However, the analysis also suggests that the improvements reported in overall survival and progression-free survival may not be seen in people older than 75 years.

Orillard E ，Adhikari A ，Malouf RS ，Calais F ，Marchal C ，Westeel V ... -  《Cochrane Database of Systematic Reviews》

STK11 mutations correlate with poor prognosis for advanced NSCLC treated with first-line immunotherapy or chemo-immunotherapy according to KRAS, TP53, KEAP1, and SMARCA4 status.

The upfront treatment of non-oncogene-addicted NSCLC relies on immunotherapy alone (ICI) or in combination with chemotherapy (CT-ICI). Genomic aberrations such as KRAS, TP53, KEAP1, SMARCA4, or STK11 may impact survival outcomes. We performed an observational study of 145 patients treated with first-line IO or CT-ICI for advanced non-squamous (nsq) NSCLC at our institution tested with an extensive lab-developed NGS panel. The primary objective was to assess the clinical outcomes of STK11-mutated patients. Then, we performed an external validation through the public OAK/POPLAR dataset, including nsq NSCLC patients treated with single-agent ICI or CT. Most patients were male (59.7 %), former smokers (61.1 %), with ECOG PS 0-1 (84 %), and received first-line CT-IO (58.6 %). 44.8 % had a mutation in KRAS, 21.4 % in KEAP1, 50.3 % in TP53, 13.1 % in SMARCA4, and 14.4 % in the STK11 gene. The mOS was 8 mo. (95 % CI, 5-16.7) for STK11 mutated pts and 17.3 mo. for STK11 wild-type patients (95 % CI, 8.9-24.4) (p = 0.038). TP53 (8.3 vs 17.3), KRAS (9.2 vs 15.9), and KEAP1 (8.9 vs 15.9) mutated patients evidenced a trend for dismal mOS. SMARCA4 status had no impact on mOS. STK11 mutations were detrimental to OS in the univariate (HR 1.74, p = 0.041) and multivariate model (HR 1.97, p = 0.025) after adjusting for sex, age, ECOG PS, treatment (ICI vs CT-ICI), KRAS, KEAP1, TP53, and SMARCA4 status. Genomic alterations did not impact the mPFS in our cohort. Within the OAK/POPLAR dataset, STK11 mutations (60/818 pts) were significantly associated with increased death risk in the univariate (HR 2.01, p < 0.001) and multivariate model (HR 1.66, p = 0.001) after adjusting for age, sex, treatment (ICI vs CT), KRAS, KEAP1, TP53, and SMARCA4 status. STK11 aberrations hampered the mOS of nsq NSCLC patients treated with first-line ICI or CT-ICI. The negative prognostic impact seems to be unrelated to ICI administration.

De Giglio A ，De Biase D ，Favorito V ，Maloberti T ，Di Federico A ，Zacchini F ，Venturi G ，Parisi C ，Gustavo Dall'Olio F ，Ricciotti I ，Gagliano A ，Melotti B ，Sperandi F ，Altimari A ，Gruppioni E ，Tallini G ，Gelsomino F ，Montanaro L ，Ardizzoni A ... -  《-》