Systems therapies for metastatic NSCLC in poor general health.

Non-small cell lung cancer (NSCLC) is the cancer with the highest mortality worldwide, with two-thirds of cases detected only at locally advanced or metastatic stages. Unfortunately, recommendations for patients with reduced general health are usually not evidence-based. In this vulnerable patient group, treatment decisions should be made individually based on performance status and tumor characteristics.

Non-small cell lung cancer (NSCLC) is the cancer with the highest mortality worldwide [1]. Two-thirds of disease is not detected until the locally advanced or metastatic stage [2]. Since the turn of the millennium, new developments have revolutionized the system therapy of metastatic NSCLC (mNSCLC): First, the development of so-called third-generation cytostatics, then the discovery of driver alterations in a subset of tumors, most notably the mutation in the epidermal growth factor receptor (EGFR) among many others, and most recently the most significant innovation, so-called checkpoint inhibition (“immunotherapy”) [3]. Whereas in the past there were at most 1-2 lines of therapy, today 5-7 lines of therapy are not uncommon.

By improving supportive therapy, the side effects of systemic therapy could be better mitigated. Especially as monotherapy, checkpoint inhibition is again better tolerated than system therapy [4]. An important independent prognostic factor in mNSCLC is the so-called “performance status” (PS) [5], which was divided into 6 groups by the Eastern Cooperative Oncology Group (ECOG) (Table 1) [6].

Treatment of mNSCLC is based on studies conducted almost exclusively in patients at PS 0 or 1. Poorer general health was an exclusion criterion in most phase 3 trials. Thus, it can be said that almost any therapy with modern substances in patients with PS 2 – 4 is not evidence-based in the true sense. If there are at least subgroup analyses or case series for PS 2, the data situation for PS 3 – 4 is extremely thin.

Should we now withhold tumor-directed therapy from patients who are in a reduced general condition? In this article I would like to give some – partly scientifically provable, partly very subjective – decision-making aids.

Forecast estimation

The prognosis of a disease depends primarily on the general condition of the patient and the tumor stage. It should be borne in mind that every effort must of course be made to optimize the patient’s general condition pre-therapeutically. It is also hoped that the therapy will lead to an improvement, if it is successful. Important, treatable comorbidities associated with mNSCLC that can be effectively managed include infections, electrolyte imbalances such as hyponatremia (common in small cell lung carcinoma) or hypercalcemia, and hormonal imbalances such as hyper- or hypothyroidism and cortisol deficiency. These disorders also occur more frequently during immunotherapy. Non-tumor-associated pre-existing conditions such as heart failure, chronic obstructive pulmonary disease (COPD), or metabolic disease can also have a major impact on general health.

Now, when all the above parameters are optimally controlled, it is crucial to adequately estimate the disease prognosis. In addition to the aforementioned factors of general condition and tumor stage, molecular characteristics of the tumor should also be considered here: The presence of a treatable driver alteration or a high expression of programmed death ligand 1 (PD-L1) in the tumor are markers for a good treatment success (Tab. 2).

A simple tool for assessing prognosis is the so-called “Surprise Question”: would I be surprised if the patient died within the next 12 months? If this question is answered with “yes”, 92.1% of the patients were still alive after one year. If the answer is “no”, only 45.2% were still alive at that time. Even more precise is the “Double Surprise Question”: For patients in the group where the first question is answered with “no”, a second question is added: Would I be surprised if the patient is still alive in 12 months? If this question is answered with “yes”, significantly fewer are alive again after one year: 26.5% versus 60% if the answer to the second question is “no” [7]. As a caveat, this study did not include patients with mNSCLC. Moreover, with the generally unfavorable prognosis of mNSCLC, one year is a long time, so these questions are unlikely to help in a treatment decision. Even a gain of 2.5 to 3 months in life expectancy is considered relevant here [8]. So in the end the performance status remains as the most reliable parameter.

In the next section, I have summarized expected outcomes for selected system therapies in relation to general condition.

Effectiveness of systemic therapies depending on general condition

Tumors without driver alterations

In performance status 2, there are still reasonably valid data: In one study, the efficacy of chemotherapy with carboplatin and weekly paclitaxel was compared with monochemotherapy (vinorelbine or gemzitabine). The primary endpoint was median overall survival. This was significantly longer in the carboplatin group, at 10.3 months, than in the monotherapy group, at 6.2 months (hazard ratio 0.64; p<0.0001). Of the 451 patients, 123 were in PS status 2. In this group, a similar result was obtained with a HR of 0.63 in favor of the combination [9]. Data on patients in PS 3 and 4 were not collected to a sufficient extent. Their proportion in studies is too low: in a study of patients with COPD in performance status ≥2, only 8 of 51 patients in this group were [10].

One group with a principally good response to therapy are patients with high PD-L1 expression when treated with immunotherapy. In one study, 153 patients with mNSCLC in a PS 2 and PD-L1 expression of ≥50%in the tumor were treated with first-line pembrolizumab. The median survival in this group was only three months [11]. In general, a median survival of 4.5 months can be expected even with Best Supportive Care alone [12], but across all PS levels. In addition, median survival in patients with PS 0 or 1 with PD-L1 ≥50%in tumor is 26.3 months [13] (Fig. 1). In a further analysis of the named study, the cohort was then divided into those patients whose performance status was caused by comorbidities and those where the tumor was responsible for the poor status. In the former group, me-diane survival was 11.8 months, in the latter 2.8 months (p<0.001) [11].

In another retrospective study, response rates to pembrolizumab in first- or second-line patients with mNSCLC (regardless of PD-L1 expression) were compared with such patients in PS 0 or 1: The response rate was significantly lower in the first group (9.1% vs. 28.1%) than in the second, as was the disease control rate (27.3% vs. 51.8%) [14].

In a study of post-line therapy with the PD-L1 antibody atezolizumab after -PD-1 antibody pre-therapy, the time to treatment failure (TTF) was determined as a function of performance status (Fig. 2). Again, in PS 2 (only one patient was in PS 3), treatment failure occurred on average as early as the first cycle [15]. The significantly worse survival times, especially in patients whose general condition is reduced by the tumor, should lead to a critical view of the use of immunotherapy starting at PS 2. There are virtually no data for patients in PS 3 or 4.

Tumors with driver alterations

A retrospective study identified 52 patients with an activating EGFR mutation who had mNSCLC and were in PS 2 (40.4%), 3 (51.9%), or 4 (7.7%). These were treated with the first-generation tyrosine kinase inhibitor (TKI) gefitinib. The response rate was 65.4%, and the median overall survival was 19.6 months. Unfortunately, the evaluation did not differentiate between the performance stages, only stating that in PS 4 the risk of dying was -10.5 times higher [16].

The third-generation TKI osimertinib was also the subject of a retrospective analysis: 30 pa-tients (24 PS 2 and 6 PS 3) with a resistance mutation (T790M) after prior TKI therapy were analyzed: Response rate was 53%, median progression-free survival was 8.2 months. Median overall survival has not yet been achieved. An important information from this study is also that 63% of patients achieved improvement in PS [10]. A prospective analysis is available for a small cohort of patients with an EML4 ALK translocation.The LOGiK-1401 study included 18 patients with an EML-4 ALK translocation and reduced general status (12 with PS 2, 5 with PS 3, and 1 with PS 4) treated with the third-generation TKI alectinib. Median overall survival reached 30.3 months in this group [17].

Thus, in the case of an activating EGFR mutation or an EML-4-ALK translocation, it seems quite reasonable to attempt therapy at least up to performance status 3. Data are too sparse for the other driver alterations, but for ROS-1 or BRAF alterations one would also treat by analogy.

The principle of hope. Only on what?

The American Cancer Society issued a statement outlining the “TOP 5” measures that will make cancer patient care better and more efficient. This includes the abandonment of systemic therapy in PS 3 and 4 – especially if previous therapies have already been unsuccessful – outside of clinical trials [18].

In contrast, many colleagues have found that patients with high PD-L1 expression or treatable driver alteration, even in poor general health, can experience a dramatic improvement in their condition as a result of treatment (“Lazarus response”). Hope may justify an attempt at therapy, but the data on this is limited to case reports [19 – 21]. On the other hand, improvement in condition can also be achieved by early palliative care (“early palliative care”) [22,23]. This palliative care should be an integral part of the care of mNSCLC [24]. Continuation of systemic therapy should not delay adequate palliative care.

Patients should be taught that improvement in condition can also be achieved by purely supportive therapy and that systemic therapy sometimes only has the opposite effect.

Take-Home Messages

The prognosis of people with mNSCLC is largely determined by their general condition. By treating tumor symptoms or comorbidities, this can sometimes already be improved.
Up to PS 2, systemic therapy is warranted, although at PS 2 purely supportive therapy can already be discussed with the patient as an alternative, especially if there is no high PD-L1 expression or treatable driver alteration.
In PS 3, one should be very critical regarding system therapy. In principle, the data situation here only speaks for the use of TKIs in driver alterations; the results of immunotherapies are disappointing. In PS 4, in principle, there is no indication for system therapy from the author’s point of view. Exceptions in individual cases are also the driver alterations in case of urgent therapy request of the patient.
Hospice therapy should only be provided if it is appropriate to maintain or improve the patient’s quality of life.

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