Real‐world retrospective study of KRAS mutations in advanced non–small cell lung cancer in the era of immunotherapy

Abstract

Background KRAS mutation‐positive (KRAS‐positive), advanced nonsmall‐cell lung cancer (NSCLC) is characterized by a poor prognosis. KRAS mutations are extremely heterogeneous from a biologic point of view, and real‐world data by mutation subtype in the era of immunotherapy are still incomplete. Methods The objective of this study was to retrospectively analyze all consecutive patients with advanced/metastatic, KRAS‐positive NSCLC who were diagnosed at a single academic institution since the advent of immunotherapy. The authors report on the natural history of the disease as well as the efficacy of first‐line treatments in the entire cohort and by KRAS mutation subtypes as well as the presence/absence of co‐mutations. Results From March 2016 to December 2021, the authors identified 199 consecutive patients who had KRAS‐positive, advanced or metastatic NSCLC. The median overall survival (OS) was 10.7 months (95% confidence interval [CI], 8.5–12.9 months), and there were no differences by mutation subtype. Among 134 patients who received first‐line treatment, the median OS was 12.2 months (95% CI, 8.3–16.1 months), and the median progression‐free survival was 5.6 months (95% CI, 4.5–6.6 months). At multivariate analysis, only an Eastern Cooperative Oncology Group performance status of 2 was associated with significantly shorter progression‐free survival and OS. Conclusions KRAS‐positive, advanced NSCLC is characterized by a poor prognosis despite the introduction of immunotherapy. Survival was not associated with KRAS mutation subtype. Plain Language Summary This study evaluated the efficacy of systemic therapies for advanced/metastatic nonsmall cell lung cancer harboring KRAS mutations, along with the potential predictive and prognostic role of mutation subtypes. The authors found that advanced/metastatic, KRAS‐positive nonsmall cell lung cancer is characterized by a poor prognosis and that first‐line treatment efficacy is not related to different KRAS mutations, although a numerically shorter median progression‐free survival was observed in patients who had p.G12D and p.G12A mutations. These results underline the need for novel treatment options in this population, such as next‐generation KRAS inhibitors, which are in clinical and preclinical development.

Pulmonary Low Malignant Potential Adenocarcinoma

“…All but one case had genetic alterations, including KRAS (5 cases), EGFR (3 cases), MET exon 14 skipping (1 case), and TP53 (1 case) mutations. Such profiles are similar to those reported in conventional invasive ADCs in Western countries and at our latitudes 3,13,19–21 …”

“…Such profiles are similar to those reported in conventional invasive ADCs in Western countries and at our latitudes. 3,13,[19][20][21] Based on the above findings, the described additional ancillary techniques were helpful to support the assessment of the required parameters and may be used in selected cases where mitotic count and/or definition of the extent of invasion (lepidic growth vs. papillary carcinoma in collapsed parenchyma) are problematic, though not strictly required for an optimal case stratification. As a matter of fact, in our series, the prevalence of selected LMP cases of resected stage I ADCs overlapped with that of the original paper, around 15% and in any case identified a subtype of lung cancers associated with a relatively favorable outcome.…”

“…Eleven out of 34 cases, including one case in which both primary and recurrence tissues were available, were analyzed. Tumor area selection, DNA and RNA extraction, library preparation, and data analyses were performed as previously described 13 . Next-generation sequencing was performed using the Ion Torrent Genexus System (ThermoFisher Scientific) with Oncomine Precision DNA and RNA Assay.…”

The PI3K-AKT-mTOR axis persists as a therapeutic dependency in KRASG12D-driven non-small cell lung cancer

“…Importantly, our established tumor models and patient data reveal that in advanced disease, differences in KRAS mutant isoform-specific potency are no longer evident, mirroring findings from previous large cohort studies which failed to support KRAS-mutant allele-specific differences in outcomes 8,46,47 . KRAS mutant isoforms occur alongside distinct co-mutation patterns which ultimately affect signaling networks, immune surveillance and response to therapy 8,9 .…”

Global research trends in immunotherapy for non-small cell lung cancer patients with KRAS mutations: a bibliometric analysis

“…A real-world retrospective study revealed that the effectiveness of first-line ICIs, either alone or in combination with chemotherapy, did not differ among patients with different isoforms of KRAS mutations. Patients with KRAS-G12D and KRAS-G12A mutations showed a shorter median progression-free survival (mPFS), which did not reach statistical significance ( 40 ). The intermediate mechanism of immunotherapy for various KRAS mutation subtypes merits investigation.…”