Efficacy of tyrosine kinase inhibitors in patients with non-small-cell lung cancer with performance status 4: a case series and review of the literature

Lung cancer is the most common type of cancer and the leading cause of cancer-related mortality worldwide [1]. Non-small-cell lung cancer (NSCLC) accounts for > 70% of all lung cancers and is usually diagnosed at an advanced stage [2].

Generally, driver alterations and expression of programmed death ligand-1 are assessed before chemotherapy initiation for advanced or metastatic NSCLC. Important driver alterations for the medical treatment of advanced or metastatic NSCLC include epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK), ROS1 proto-oncogene receptor tyrosine kinase (ROS1), BRAFV600E, MET exon 14 skipping, and RET. Tyrosine kinase inhibitors (TKIs) have a higher tumor response rate and shorter response time than cytotoxic chemotherapy for patients with driver alteration-positive NSCLC [3‐8]. Therefore, TKIs are the standard treatment for such patients having a good performance status (PS).

Additionally, previous studies have reported that several TKIs have shown significant efficacy in patients with extremely poor PS [9‐11]. These studies demonstrated an improved PS score, progression-free survival, and overall response rate in most patients. The Japanese and National Comprehensive Cancer Network (NCCN) and European Society for Medical Oncology (ESMO) guidelines recommend that each TKI be indicated even for diverse mutation-positive patients with poor PS [12‐14]. However, most patients had a PS of 2–3, but only a few had a PS of 4 in previous studies. Therefore, the efficacy of TKIs in patients with NSCLC with a PS of 4 remains unclear. Moreover, limited clinical information is available regarding older patients with poor PS.

This case series describes our experience in treating patients with a PS of 4 with TKIs. Three out of four patients were aged ≥ 80 years, which is classified as “oldest old.” In this article, we discuss whether treatment with TKIs is effective for older patients with a PS of 4.

We present a case series, in which four patients with NSCLC and PS 4 received TKIs for various alterations. To our knowledge, this is the first report to summarize the efficacy of TKIs in patients with PS 4. TKIs showed a significant effect in one patient, and his PS score improved to 0; however, no improvement in the PS scores of the other patients was observed, and they subsequently died in the hospital.

Chemotherapy is the standard treatment for patients with NSCLC with relapsed or advanced disease, as it prolongs survival compared to the best supportive care [15]. First, the patients scheduled to undergo chemotherapy are assessed for their PS by their doctors. The PS scale ranges from 0 to 4, with 0 denoting physical activity without restriction and 4 representing complete disability. Cytotoxic chemotherapy is indicated only for those with a good PS (0–2) before identifying driver alterations. In contrast, patients with a poor PS [3, 4] receive the best supportive care (BSC) [12, 13]. A comprehensive genomic analysis of NSCLC has identified several driver mutations and has guided the development of targeted TKIs in recent decades. Each TKI has shown a more effective response and fewer adverse events than those of the general cytotoxic chemotherapy. Therefore, it is recommended in the Japanese, NCCN and ESMO Clinical Practice Guidelines that tumors with driver alterations (e.g., EGFR, ALK, ROS1, BRAFV600E) be treated with front-line TKIs [12‐14].

Additionally, previous studies have demonstrated that TKI therapy could have a favorable outcome and safety profile, even in patients with advanced NSCLC with a poor PS [9‐11]. A phase-2 study suggested that patients with EGFR T790M mutation-positive advanced NSCLC with poor PS benefited from osimertinib treatment [11]; the PS improvement rate was > 70%, and nearly 90% of the patients improved from ≥ PS 3 at baseline to ≤ PS 2. Based on these results, the Japanese, NCCN and ESMO guidelines have recommended that each TKI be indicated even for diverse mutation-positive patients with a poor PS. Only EGFR and ALK TKIs showed significant improvement in patients with extremely poor PS. In contrast, there are no reports on the efficacy and safety of TKIs in patients with a poor PS harboring driver alterations of EGFR-uncommon, ROS1, BRAFV600E, MET, and RET. It is difficult to demonstrate TKI efficacy for patients with a poor PS and these driver alterations, because patients harboring these driver alterations are very rare. However, TKI treatment for these driver alterations is as effective as EGFR TKIs. Therefore, Japanese, NCCN and ESMO guidelines have recommended that TKIs of EGFR-uncommon, ROS1, BRAFV600E, MET, and RET are indicated for each driver mutation-positive patient with a poor PS.

In this case series, we analyzed driver gene alterations and TKI treatment for patients with NSCLC with a PS of 4 based on the above recommendations. One patient showed significant shrinkage in multiple lesions, and the PS score improved to 0 after TKI treatment. Two others showed slight shrinkage of the tumors but the PS score was not improved. Another patient showed tumor progression but the PS score was not improved. The three patients who could not establish an improvement in PS died in the hospital. All patients had a PS of 0–2 before being hospitalized, but three out of four patients were late-stage older individuals, aged ≥ 80 years. In addition, it took approximately 3 weeks for the patients to obtain the results of driver alteration analysis after hospitalization. They spent the entire time in bed, and their PS gradually worsened.

There are no upper age limits for the administration of TKIs in the guidelines. Furthermore, a previous study, which was conducted for patients with poor PS, did not perform a subgroup analysis of patients’ ages. Therefore, we usually proceed with the analysis of driver gene alterations and indication for TKIs, even for older patients and those with poor PS, in clinical practice.

Table 1 summarizes several reports that described 12 cases of patients with PS 4 after TKI administration, including our cases [11, 16‐21]. Additionally, Fig. 5 shows the change in PS for 12 cases during TKI treatment. Improved PS scores were observed in half of the patients. Almost all patients with improved PS were young or started TKI treatment early, owing to liquid biopsy. These results imply that younger age and early administration may be factors for PS improvement. Conversely, only one case reported that the PS of an older patient was significantly improved by TKI treatment over 3 weeks after hospitalization.

Certainly, several TKIs have the potential to dramatically improve a patient’s condition, even if their PS is very poor, such as the so-called “Lazarus effect” [22]. However, it is imperative that we differentiate between the deterioration of PS owing to advanced age and instigated by malignant tumors. Previous studies have reported that older patients have worsened PS during hospitalization [23, 24], as it easily aggravates muscular strength and cognitive function, even though patients are in good general condition before admission. This hospitalization-associated disability occurs in more than one-third of patients aged > 70 years [25]. Additionally, worse general conditions cannot be reversed in more than half of older patients [26]. In our case series, most patients did not show improvement in PS after TKI administration. Continuous TKI treatment for older patients would be difficult due to aggravation of PS, even if the cancer responds to TKI treatment.

In contrast, patients with NSCLC can select BSC from the start when they do not want to undergo chemotherapy. In this case, they need not undergo invasive examinations or treatments, such as bronchoscopy, central intravenous catheters, or mechanical ventilation. In addition, these patients could spend time with their families at home if they wanted to. It has become available for indications of chemotherapy, especially TKI, even in older patients with a poor PS, because of the development of cancer treatment. A previous study reported that an improvement in the PS of patients with cancer led to an enhancement in their quality of life [27]. Namely, these patients might enjoy the rest of their lives with a good quality of life instead of spending the end of their lives in bed. However, some patients might spend different amounts of time in the terminal phase owing to the potential to receive chemotherapy. Regarding this point, the early involvement of palliative care, especially in older patients with NSCLC with a poor PS, would help guide the appropriateness of the use of TKIs in such patients.

Recently, several trials have evaluated the utility of circulating tumor DNA (ctDNA) genotyping, reporting that the screening duration of ctDNA genotyping is significantly shorter than that of tissue genotyping [28]. This utility may provide an early indication of TKI treatment without aggravation of patient PS. In fact, liquid biopsy was used in the patient’s improved PS with TKI therapy in previous case reports (Table 1).

In this case series, we examined four cases of TKI usage in patients with NSCLC with a poor PS. One patient demonstrated an improvement in his general condition after TKI administration. However, despite receiving TKI treatment, three older patients, did not exhibit any improvement and ultimately passed away. The appropriateness of TKI treatment in patients with a PS of 4, particularly among older individuals, warrants further discussion. The potential for patients to endure an unwanted terminal phase due to invasive treatment cannot be overlooked. However, ctDNA genotyping, such as liquid biopsy, might initiate the treatment without worsening PS in the future. Our findings underscore the necessity for more comprehensive research in larger cohorts to conclusively assess the effectiveness of TKI treatment for patients with NSCLC with a poor PS.