Limited doses of immunotherapy use in advanced non‐small cell lung cancer elderly patients with ECOG of 2 and high PDL‐1 expression

Immunotherapy is an effective treatment in advanced non‐small cell lung cancer (NSCLC) patients with high PDL‐1 expression. Here, we report three such patients with durable response despite limited doses immunotherapy.


| INTRODUC TI ON
The treatment landscape of lung cancer has evolved over the years; the standard of care has shifted from chemotherapy to the use of targeted therapy or immunotherapy (IO) as first-line treatment in patients with advanced non-small cell lung cancer (NSCLC).
Breakthroughs were seen in 2015 and 2016 when IO demonstrated significant survival benefit compared with platinum-based chemotherapy in previously treated advanced NSCLC. The use of IO as first-line monotherapy in patients with positive PD-L1 expression was subsequently approved by the US Food and Drug Administration. [1][2][3] In randomized clinical trials, treatment with pembrolizumab resulted in significant improvements in progression-free survival (PFS) and overall survival (OS) compared with chemotherapy alone.
An updated analysis of the KEYNOTE-024 study comparing the outcomes of pembrolizumab versus platinum-based chemotherapy in treatment-naïve patients with PD-L1-positive advanced NSCLC (TPS of ≥50%) showed that the median OS was doubled following pembrolizumab treatment compared with chemotherapy (30.0 months vs 14.2 months, respectively). Fifty-four percent of those randomly assigned to chemotherapy crossed over to the pembrolizumab arm and despite that, the improvement in OS from the first analysis was maintained. 2 In the KEYNOTE-042 phase III study in NSCLC patients with positive PD-L1 expression, those assigned to pembrolizumab as first-line treatment had better OS compared with those on chemotherapy. 4 The IMpower 110 trial in treatment-naïve metastatic NSCLC patients with positive PD-L1 expression showed that treatment with atezolizumab resulted in significantly longer median OS and PFS compared with chemotherapy. 5 Despite their significant benefits, IO drugs are, nonetheless, expensive and not funded by the national health in most developing countries. Here, we report on three cases of advanced NSCLC with high PD-L1 expression in the absence of EGFR and ALK alterations. The three patients who were treated with limited doses of IO showed durable partial response for more than 19 months after treatment cessation.
This is an open access article under the terms of the Creat ive Commo ns Attri bution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

| Case 1
In October 2019, an 88-year-old lady who is an ex-smoker of 15 pack-years with underlying left ischaemic stroke with no residual hemiparesis presented with bilateral lower limb weakness secondary to statin-induced myopathy. She was referred for an incidental chest x-ray finding of a left lower lobe mass. She had no shortness of breath, cough, or hemoptysis but appeared lethargic and emaciated. Vital signs were normal. There was dullness on percussion and reduced air entry on the left lower lobe with no palpable supraclavicular lymph nodes. Neurological examination was unremarkable after the statin was discontinued. Blood investigations were normal.
The incidental lung mass was better visualized on a computed tomography (CT) thorax, which showed a heterogenous mass mea-

| Case 2
An 82-year-old gentleman with underlying hypertension and an 80-pack-year smoking history presented with persistent right upper back pain, which he had been experiencing for 2 weeks. He had progressive swelling of the right upper chest wall, associated with loss of appetite and a 3-kg weight loss over a period of 2 months. He denied having shortness of breath, fever, or hemoptysis. Vitals were normal; however, the right supraclavicular lymph node was palpable and a hard, nonerythematous, nontender mass of irregular mar- The patient had persistent good partial response to pembrolizumab with repeated blood tests showing serum CEA levels of 3.0 ng/ml. At the time of writing this report, the patient has remained asymptomatic with no further weight loss for 19 months.

| Case 3
An 87-year-old gentleman, a nonsmoker with underlying hypertension and hyperlipidemia, was referred for an incidental chest x-ray finding of a mediastinal mass during a health screening. The patient reported experiencing some weight loss but had no episodes of fever, cough, hemoptysis, shortness of breath, or loss of appetite. Neither clubbing nor palpable lymph nodes were observed.
However, reduced air entry over the right lower lobe with dullness on percussion was noted. Vital signs and blood investigations were normal. Transthoracic ultrasound-guided trucut biopsy of the mass was performed and it was confirmed to be adenocarcinoma. EGFR mutation and ALK rearrangement were not detected but the patient was PD-L1-positive (TPS 80%). An initial CT scan suggested that the patient had stage 4A lung adenocarcinoma (T4N2M1b) with a mass seen in the left lower lobe measuring 13.3 × 8.8 cm, encasing the descending aorta and extending to the lower oesophagus. Tumor thrombus was seen in the left segmental pulmonary veins extending to the left atrium. Ipsilateral hilar lymph node enlargement and multiple hypodense liver lesions were observed ( Figure 3A). The patient's ECOG status was 2.
In November 2019, the patient was given only two doses of pembrolizumab 100 mg IV Q3W owing to financial constraint. The  Figure 3B). The patient remained in good condition with durable partial response for 19 months.

| DISCUSS ION
The patients described in these case reports are elderly (i.e. above A study was conducted in Oulu University Hospital involving 59 patients with different tumor types including lung cancer, who were treated with IO following the institutional recommended maximum duration of 6 months. All of the lung cancer patients were given IO as second-line therapy or more, and the OS was similar to clinical trial data. 9 The authors observed exceptional durable response in those who had IO for only a short duration, similar to our patients' clinical experience. Our patients could not afford the cost of 35 doses of IO, which would amount between USD75,000 to USD150,000 and is not financed by our institutions. With the average Malaysians' median income of USD1468, many would not be able to afford the expensive cost of IO. 10 A study of real-world data conducted by Youn et al. analyzed the prognosis of 1256 patients with a median age of 75.3 years. Almost half of the cohort had multiple comorbidities and 11.5% had poor ECOG status. Half of the cohort received IO after platinum chemotherapy while only 8.1% were treatment-naïve patients. The median survival after IO treatment was 9.3 months, which could be explained by the shorter survival rate of elderly patients with multiple comorbid conditions. 11 Our patients, on the other hand, who were above 80 years old, with high PD-L1 expression and preexisting comorbidities, survived for more than 19 months since being treated with IO.
Gridelli et al. discussed the use of gemcitabine as single-agent chemotherapy in elderly patients aged more than 70 years with advanced NSCLC. The ORR, based on several phase II trials, was reported as 18% to 38% with a median OS of 6.8-9 months, which were inferior to the outcomes reported in IO clinical trials. A phase II trial of paclitaxel given Q3W in two cohorts of patients below and above 70 years of age showed no difference in the ORR or median OS between the two groups; however, it was noted that the frequency of adverse effects such as neutropenia and toxicity was more prevalent in older patients. 12 Our patients were not keen on chemotherapy given its known side effects. IO was given instead, in short duration, and none of the patients developed any adverse events.
Most phase III clinical trials exclude patients with poor ECOG (≥2) due to preexisting comorbidities, contraindication to ongoing treatment, potentially lower drug metabolism, and less tolerability to treatment. 13 14 These studies suggest that pembrolizumab, with its relatively favorable adverse event profile, is safe to be administered in patients with ECOG 2.

| CON CLUS ION
We have here reported a case series of three advanced NSCLC patients who received only a few doses of IO and experienced durable partial response for over 19 months despite having poor ECOG and being elderly. Limited doses of IO may be beneficial in patients with high PD-L1 expression especially in resource-limited countries.

ACK N OWLED G EM ENTS
We would like to thank Dr KC S., a professional writer and editor for the language editing and proofreading of this manuscript.

CO N FLI C T O F I NTE R E S T
The authors have no conflicts of interest to declare.

AUTH O R CO NTR I B UTI O N S
Pui Yee Wong and Soon Hin How conceptualized the topic, performed literature search, and wrote the case series. Radhiana Hassan analyzed the radiological images as well as reviewed and edited the case series. Muhammad Naimmuddin Abdul Azih reviewed and edited the case series.

E TH I C A L A PPROVA L
The authors have obtained written informed consent for publication of patient information and radiological images. In our local setting, IRB approval is not required for publication of these case reports.