Discussion
IMA account for approximately 2–10% of lung adenocarcinomas (4) and 3–10% of invasive adenocarcinomas (1); however, it is sometimes misdiagnosed due to its pneumonia-like features. IMA is characterized by molecular features distinct from those of non-mucinous adenocarcinoma (4), including a high frequency of KRAS mutations (28–87%, particularly G12D and G12V) and NRG1 fusions (7–27%, particularly in those without KRAS mutations), low frequency of EGFR mutations (0–5%), and low expression rates of PD-L1 (0–6.1%) and TTF-1 (11–27.5%).
While the general predictors of ICI effectiveness include PD-L1 expression, tumor mutational burden (TMB), and tumor-infiltrating lymphocytes, their role in IMA requires further investigation. KRAS-mutated NSCLC is generally considered responsive to ICIs, however clinical efficacy varies significantly depending on the specific KRAS subtype and co-mutation profile (5,6). KRAS G12C mutations, which are common in smokers, are often associated with high TMB and PD-L1 expression, making them more sensitive to immunotherapy. In contrast, KRAS G12D mutations, the predominant subtype in IMA, are frequently found in non-smokers and typically exhibit low PD-L1 expression and an immunologically ‘colder’ tumor microenvironment (TME). This TME is less immunogenic, characterized by impeded effective T-cell infiltration and the enhanced recruitment of myeloid-derived suppressor cells (MDSCs), regulatory T cells (Tregs), and cancer-associated fibroblasts (CAFs). Furthermore, the presence of co-mutations is a critical factor: while TP53 co-mutations can prime the tumor for ICI responsiveness by creating a ‘hot’ TME, other loss-of-function co-mutations, such as STK11 and KEAP1, foster a ‘colder’ TME. There are conflicting reports regarding the effectiveness of ICIs in IMA treatment. Jang et al (7) suggested that immunotherapy may lead to better outcomes than chemotherapy for IMA, reporting significantly better overall survival (median OS undefined vs. 17.0 months, P<0.001). Conversely, Kim et al (8) observed no significant difference in overall survival (OS) after immunotherapy (P=0.992). A phase II trial by Chae et al (9) showed promising results for the combination of dual ICIs (ipilimumab and nivolumab) in IMA and non-mucinous lepidic adenocarcinoma, reporting an overall response rate of 25% and a clinical benefit rate of 62.5%. Dual ICIs are commonly used for NSCLC, particularly for those with low PD-L1 expression, and chemotherapy is often administered for early tumor reduction. However, evidence for the efficacy of this combination therapy for IMA remains limited.
This case series included 15 patients with advanced or recurrent IMA. Molecular characteristics, including the frequency of KRAS mutations and TTF-1 positivity, were largely consistent with those reported previously. The rate of positive PD-L1 expression (TPS ≥1%) in this cohort was 13%, which is slightly higher than that reported previously. This may be attributed to the six patients whose PD-L1 status was unknown.
Among the seven patients who received first-line ICI-based therapy, the overall response rate was modest at 14%, but the disease control rate (DCR) was high at 86%. For the two PD-L1-positive patients, a single ICI was administered, one in combination with chemotherapy and the other without. Although one of these patients was lost to follow-up, both demonstrated a longer OS compared to the rest of the cohort. This aligns with previous reports from pembrolizumab studies, indicating that higher PD-L1 expression correlates with longer OS. Notably, three patients treated with a combination of dual ICIs and chemotherapy were PD-L1 negative yet achieved a 100% DCR. The clinical benefit of dual ICIs in IMA may be largely explained by the synergistic effect of anti-PD-1/PD-L1 and anti-CTLA-4 antibodies in modulating the ‘cold’ TME. Anti-CTLA-4 antibodies (such as tremelimumab and ipilimumab) act complementarily to PD-1 inhibition by enhancing T-cell priming in the lymph nodes and potentially reducing the immunosuppressive influence of intratumoral Tregs. For mucin-rich tumors like IMA, where the mucin barrier typically hinders immune cell infiltration, combining chemotherapy might play an important role in enhancing the efficacy of immunotherapy.
Regarding chemotherapy selection, two of the seven ICI-treated patients received nab-paclitaxel as part of a dual ICI regimen. The only patient who achieved a PR harbored a KRAS G12D mutation and was treated with dual ICIs (durvalumab and tremelimumab) plus nab-paclitaxel. The addition of paclitaxel for KRAS-G12D-mutant NSCLC has been reported to induce the secretion of Th1-type chemokines, including CXCL10 and CXCL11, which facilitate the infiltration of CD8+ T cells into the tumor (10). This combination of chemotherapy-induced T-cell recruitment and CTLA-4-mediated TME modulation could be crucial for overcoming the primary resistance of KRAS-G12D-mutated IMA to immunotherapy. However, due to concerns regarding taxane-related adverse effects, Patient 5 in this cohort received pemetrexed. Although pemetrexed generally has limited efficacy in TTF-1-negative cases (11), the disease subsequently stabilized following an initial PD assessment, and SD was achieved after the third maintenance cycle. Evaluating the responses in some IMA cases may be challenging using RECIST version 1.1. The characteristic growth pattern of IMA, involving multifocal lesions and airspace spread, complicates the selection and measurement of target lesions, potentially leading to an inaccurate response assessment. Similar to the development of iRECIST for evaluating atypical responses to ICIs (12), a modified evaluation framework may be required for IMA.
However, this promising effectiveness of ICIs was accompanied by a high incidence of irAEs; five of the seven patients (71%) experienced irAEs, leading to treatment discontinuation. Despite these toxicities, the survival outcomes were highly encouraging. Five of the seven patients (71%) remained alive at the time of analysis, with one patient continuing first-line treatment. While irAEs are a significant concern, these findings suggest that ICI-based regimens, especially the combination of dual ICIs with chemotherapy, may offer clinical benefits and prolong the survival of patients with IMA.
Specific genetic subsets of IMA present unique therapeutic challenges. Patient 4 harbored a KRAS G12C mutation, for which sotorasib was the standard second-line therapy for NSCLC. However, the efficacy of sotorasib in the treatment of the IMA subtype remains unclear. A case report (13) suggested that VEGF-A overexpression could be a mechanism of sotorasib resistance in IMA, indicating the complex biology of this disease.
Previous case reports (14,15) indicated that bevacizumab, a monoclonal antibody against vascular endothelial growth factor, may offer therapeutic benefit for IMA when combined with platinum and pemetrexed. Although bevacizumab is widely used to treat various malignancies, notably NSCLC, it is often administered in combination with chemotherapy and immunotherapy. Since none of the patients in this cohort received bevacizumab, we could not evaluate its potential synergistic effects with other ICIs. This remains an important issue for future clinical investigations.
This study has several limitations. First, the sample size was small (n=15) due to the rarity of IMA, and the study was conducted retrospectively at a single institution. Second, there was heterogeneity in the treatment regimens. Among the four patients treated with dual ICIs, three were administered concurrent platinum-based cytotoxic chemotherapy, while one received dual ICIs alone. Finally, this study did not assess the presence of NRG1 fusions or co-mutations (TP53, STK11 and KEAP1), which might have influenced treatment outcomes. An exception was Patient 7, in whom the absence of these co-mutations was confirmed by FoundationOne® CDx.
Further studies are required to optimize the balance between therapeutic benefits and irAE risk by identifying patients who are most likely to respond to immunotherapy while minimizing severe toxicity. In addition, the development of targeted therapies for specific alterations, including distinct KRAS subtypes and NRG1 fusions, may provide promising alternatives for patients with this challenging lung cancer subtype.