For squamous-cell NSCLC patients at the advanced stage that develop disease progression in or after first-line chemotherapy, there are limited treatment options. PD-1 inhibitors have demonstrated more remarkable survival benefit than chemotherapy in patients who are previously treated for their advanced squamous-cell NSCLC, with the 3-year survival of 17% . Typically, the rationale for combined immunotherapy with chemotherapy depends on the hypothesis that cytotoxic chemotherapy will indiscriminately kill normal and cancer cells, while immunotherapy can “rev up” the immune system against cancer cells. In this study, one case with squamous-cell NSCLC was reported; He had developed co-occurring TP53 and KRAS mutations and was treated by pembrolizumab-combined gemcitabine. Fortunately, the patient had developed substantial responses to the treatment, which could last for over 7 months (until the time of submitting this manuscript).
Biomarkers, such as PD-L1 expression, TMB, MMR deficiency, and CD8+ T-cell infiltrate intensity, are recently proposed to be the predictors of the response to PD-1 blockade immunotherapy . This patient received chemotherapy after relapse, and all markers related to the PD-1 blockade immunotherapy, such as weak PD-L1 expression, MSI and TMB-low, had indicated invalid immunotherapy. However, co-mutations of TP53 (pY220C, MAF = 11.07%) and KRAS (pG12V, MAF = 19.37%) were detected in the tumor. Dong et al.  reported that co-mutations of TP53 and KRAS had exerted evident effects on up-regulating PD-L1 expression, accelerating T-cell infiltration and enhancing tumor immunogenicity. More importantly, lung adenocarcinoma patients with TP53 or KRAS mutation, especially those with co-mutations of TP53 and KRAS, can favorably benefit from the anti–PD-1 treatment. In our case, the patient was resistant to docetaxel, so he was treated with pembrolizumab combined with gemcitabine, achieved significant tumor shrinkage. It seems neither one is the answer since our patient (squamous-cell NSCLC) has weak PD-L1 expression in the tumor and low TMB of 3.2 mutations/Mb. It may be the first case of TMB-L/PD-L1 low expression and TP53 and KRAS mutant lung squamous cell NSCLC patients have a long-term benefit of immunotherapy. Co-mutations of TP53 and KRAS may also be used as the promising biomarkers in immune checkpoint blockade for squamous-cell NSCLC. The patient with co-mutations of TP53 and KRAS had low PD-L1 expression, but the tumors shrank significantly, and the underlying mechanism should be further studied. In addition, there are still many treatment responses apart from the factors mentioned above; therefore, more effective biomarkers are still needed for the PD-1 blockade.
As shown in two phases III trials, for advanced squamous-cell NSCLC patients, the progression-free survival (PFS) and overall survival (OS) were improved, and using PD-1 inhibitors in combination with chemotherapy had displayed favorable safety over chemotherapy [1, 12]. Moreover, a recent report from the three-phase IMpower131 trial suggested that squamous-cell NSCLC patients at the advanced stage could benefit more from the first-line treatment combined with atezolizumab plus chemotherapy than chemotherapy alone. At the landmark of 12-month PFS, the PFS in the group receiving atezolizumab combined with chemotherapy was doubled compared with that in the group undergoing chemotherapy alone (24.7% vs. 12.0%, respectively). Such a benefit could be seen in all patients regardless of the PD-L1 expression status. However, the difference was most significant in the high PD-L1 expression group (48 and 20%, respectively). Typically, it was one of the first phase III trials that suggested that the PFS was markedly improved in squamous-cell NSCLC patients at the advanced stage treated in combination with immunotherapy . Besides, KEYNOTE-407 was presented, showing that pembrolizumab combined with carboplatin and paclitaxel or nanoparticle albumin-bound (nab)-paclitaxel could improve both OS and PFS in metastatic squamous-cell NSCLC patients, compared with those receiving chemotherapy alone, irrespective of the PD-L1 expression status. In addition, the median OS was 15.9 and 11.3 months in pembrolizumab and placebo groups, respectively. The OS benefit was consistent regardless of the PD-L1 expression levels, with the hazard ratios of 0.61 among patients with the PD-L1 expression of < 1% and 0.65 among those with the PD-L1 expression of ≥1% .
Taken together, PD-L1 expression should be assessed in the tissues of all squamous-cell NSCLC patients at the advanced stage, and for patients with the PD-L1 expression of 50% or higher in the tumor, pembrolizumab can be used as the first-line therapy; whereas treatment for those with the PD-L1 expression of less than 50% should be started with pembrolizumab combined with carboplatin and paclitaxel. Besides, to test common driving genes, like EGFR, ALK, ROS1, and BRAF, both P53 and KRAS should also be considered. Nonetheless, the underlying mechanism of the favorable effect of immunotherapy for squamous-cell NSCLC patients with TP53 and KRAS co-mutations should be further studied. Additionally, further studies of first-line and later-line immunotherapy with chemotherapy should be carried out in larger populations.