Immunotherapy in stage IV non-small cell lung cancer in a patient with Grave’s disease: safety and biomarkers of response

Abstract

Patients with cancer and pre-existing autoimmune diseases have been excluded from immunotherapy clinical trials. So, studying these patients who received immunotherapy is critical to increasing evidence of the treatment’s safety and efficacy in this population. Furthermore, a complete and durable response to immunotherapy in metastatic non-small cell lung cancer (NSCLC) is rare. Therefore, it is imperative to study patients with a complete response in order to identify potential predictors of response to immunotherapy. In this case report, we highlight a 62-year-old man with a smoking history and Graves’ disease who achieved a complete response with immunotherapy for metastatic NSCLC, with a long-lasting response and no immune-related adverse events. Male gender, high programmed death-ligand 1 expression, current smokers, epidermal growth factor receptor and anaplastic lymphoma kinase wild types could be biomarkers of response to immune checkpoint inhibitors presented at baseline. Caution should be exercised when interpreting this finding because it represents our patient.

Background

Lung cancer (LC) is the leading cause of cancer deaths worldwide, with 1.80 million deaths in 2020.¹ In patients with non-small cell LC (NSCLC), the use of immune checkpoint inhibitors (ICI) has revolutionised the field of oncology.² Still, only a selected group of patients respond to this therapy and have a durable clinical response with improvement in quality of life and overall survival (OS).^{3 4} To date, prediction of response to ICIs is difficult and available predictive markers are suboptimal.⁴

In NSCLC clinical trials of ICI, patients with a history of autoimmune disease (AID) have been excluded due to concerns of greater risk for developing serious immune-related adverse events (irAEs), like thyrotoxicosis, skin toxicity, pneumonitis and colitis.^{5 6} The only data available comes from case reports and retrospective analysis of small series or registry data, and includes heterogeneous groups of patients, both in terms of diagnosed cancers, type of immunotherapy used as well as the type of AID.⁷ This represents a tremendous knowledge gap, since an estimated 14%–25% of patients with LC also carry a diagnosis of AID.⁸ In stage IV NSCLC, this represents almost 14% of patients with previously diagnosis of AID, being rheumatoid arthritis, psoriasis and polymyalgia rheumatic the most frequent diseases.^{8 9} As patients with AID have an increased risk of developing several malignancies, including LC, there is an urgent need for prospective studies in this population to determine the best strategy to deliver ICIs.¹⁰

Approximately, 15%–30% of patients with LC receiving ICIs will develop grade 3 or 4 irAEs during their therapy, with pneumonitis and colitis being the most frequent ones.¹¹

We describe the clinical course of a patient with AID’s and pre-existing NSCLC who had an exceptional response to immunotherapy, with no treatment-related toxicities.

Case presentation

A 62-year-old man, Eastern Cooperative Oncology Group (ECOG) performance status 1, currently smoker with a 48 pack-year smoking history, 3-year history of subclinical hyperthyroidism, but without clinical investigation, and seronegative small joint arthritis controlled with 5 mg/day of prednisolone (no evidence of exposure to pathogens that cause arthritis, negative rheumatoid factor, negative anticitrullinate peptide antibody, negative antibodies to double-stranded DNA, negative anti-Smith antibodies, negative antibodies agains U1 small nuclear ribonucleoprotein (anti- U1 RNP) and negative antinuclear antibodies and normal uric acid concentration in blood test) was presented to the emergency room with a 2 months history of cough, dyspnoea, chest pain and 10% wt loss in 2 months.

At admission, he presented with new-onset atrial fibrillation on ECG, and exophthalmia on physical examination; therefore, due to his previous history of subclinical hyperthyroidism, and his findings in blood test, Grave’s disease was diagnosed. A chest CT scan was performed, showing right pleural effusion and multiple right pleural nodular thickenings.

A pleural drain was placed with an outflow of serohematic fluid, and a biopsy of the pleural implants was performed. He was diagnosed with stage IV right upper lobe LC with malignant pleural effusion and biopsy-proven pleural metastases (figures 1 and 2).

Figure 1.

(A) Axial contrast-enhanced CT scan at the level of the thoracic outlet shows metastatic adenopathy (long arrow). (B) An axial contrast-enhanced CT scan at the same level performed after 3 years shows complete resolution of the adenopathy previously described.

Figure 2.

An axial CT scan performed three years ago (A) and currently (B) at the lung window at the level of the diaphragmatic pillar shows complete remission of the pleural metastasis (long arrow).

Investigations

Pleural biopsy histology was compatible with adenocarcinoma, positive for CK7 and TTF1. Epidermal growth factor receptor (EGFR) and BRAF proto-oncogene mutation were negative, as were anaplastic lymphoma kinase (ALK) and ROS proto-oncogene 1 rearrangement. Programmed death-ligand 1 (PD-L1) expression was superior to 50%.

Thyroid function was also assessed during the admission process. He presented with suppressed thyroid-stimulation hormone (TSH), with TSH <0.010 μUI/mL, free T3 of 25.10 pg/mL (eight times above the normal upper limit (NUL)) and T4 of 2.57 ng/dL (two times above the NUL). Thyrotropin receptor antibodies were also positive, with the anti-TSH receptor being negative.

Treatment

As Grave’s disease was diagnosed, the patient was referred to endocrinology and he was given 20 mg two times per day of methimazole.

Although PD-L1 expression was above 50%, the first line of treatment choice was chemotherapy due to symptomatic and uncontrolled Grave’s disease. He started and completed four cycles of carboplatin AUC 5 plus pemetrexed 500 mg/m² with good tolerance and partial response (according to RECIST V.1.1) as best response in CT scan, followed by maintenance with pemetrexed. Grade 2 anaemia (according to CTCAE V.5) was the only toxicity of the chemotherapy.

Eight months later, he presented with disease progression, with new metastatic lesions in the right middle lobe and the mediastinum. At this time, there was no evidence of Grave’s diseases activity, with normal TSH and free T3 and T4, so, in multidisciplinary team, it was decided to switch to second-line treatment with pembrolizumab 200 mg intravenous, an anti-PD-1 antibody. He began pembrolizumab treatment in April 2019 with 200 mg intravenous every 3 weeks, which was switched to 400 mg every 6 weeks, 18 months later due to an excellent response.

Outcome and follow-up

Until now, he has completed 2 years of treatment, with good tolerance, and a durable and complete response (CR) in the CT scan (according to iRECIST) (figures 1 and 2). He maintained clinical and laboratory follow-up with Endocrinology every 3 to 6 months. During immunotherapy treatment, no signs of Grave’s disease flare-ups were observed, and he has already stopped taking methimazole with normal TSH, T4 and T3 levels. There was also no evidence of other irAEs. During this period, the only new comorbidity was new-onset diabetes, without evidence of immune-related adverse event (normal plasma peptide C level), but potentially caused by steroid treatment, with good control with metformin 1000 mg two times/day. At this time, he is still asymptomatic, with an ECOG performance status of 0, with excellent tolerance to immunotherapy, with a 15 kg weight gain, and he has returned to work. He will maintain pembrolizumab 400 mg every 6 weeks until diseases progression or toxicity related to immunotherapy.

Discussion

Our case report highlights the management of a patient with metastatic NSCLC with an AID (Grave’s disease), which had CR and a durable response to immunotherapy without any adverse events. This clinical case emphasises the major benefit of immunotherapy, in a small cluster of patients, that can achieve CR and durable response to ICI. To our knowledge, this is the first case report that shows the safety and efficacy of ICIs in patients with cancer and pre-existing Grave’s disease.

Several observational studies have demonstrated that patients with autoimmune and chronic inflammatory diseases have a higher susceptibility to the development of cancer, possibly due to factors such as aberrant immune function surveillance.^{8 12 13} This is more evident in LC, with 14%–25% of these patients having known prior AID.⁸ However, the relationship between Graves’ disease and LC is not well established.

Currently, ICIs are used as effective therapies for LC treatment.^{14 15} Through their unique activation of T-cells, immunotherapy leads to unique toxicity profiles compared with traditional chemotherapy, especially with irAEs. While irAEs can affect any organ tissue, they most commonly involve endocrine, skin, gastrointestinal, pulmonary and musculoskeletal systems.¹⁶

So, an important question is the safety and efficacy of ICI use in patients with AID. Some reports show that these therapies can be administered safely in patients with cancer with pre-existing AID, with manageable toxicity that infrequently requires treatment discontinuation.^{8 17} In NSCLC, a retrospective analysis that included patients with history of AID, five of them with Graves’ disease, the use of ICI as monotherapy seems to be safe, with only 23% of patients developing an AID flare, but none of them requiring immunotherapy discontinuation. In this study, discontinuation was more frequent in patients with uncontrolled AID at the beginning of immunotherapy treatment.¹⁸ As previously stated, in this clinical case, we demonstrated that pembrolizumab could be safely administered to a patient with quiescent Grave disease without AID flare or other irAEs.

Another important area of research is determining which patients will benefit the most from these expensive therapies while avoiding major side effects, and consequently highly efficient and specific biomarkers is in an urgent need. At this time in the literature, the clinical predictive biomarkers of response to immunotherapy identified were male gender, high rates of PD-L1 expression, non-EGFR mutation of ALK rearrangement, active smoking status, high tumour mutational burden, higher CD8+ tumour-infiltrating lymphocytes, irAEs during treatment and a change in the neutrophil to lymphocyte ratio during treatment.^{19 20} Still, all these biomarkers are imperfect. In our clinical case, the male gender, high PD-L1 expression, current smokers, EGFR and ALK wild types could be biomarkers of response to IC presented at baseline. Nevertheless, more studies are needed to identify valid biomarkers.

In patients treated with immunotherapy even in those who respond, CR is uncommon and has been reported in only 1%–6% of patients with NSCLC. Limited data suggest that CR may be more common in patients with PD-L1-positive tumours and may be associated with the development of irAEs during treatment, but prognosis biomarkers are still unknown.¹⁷ In a multicentric observational real-word study, irAEs of any grade, ‘single-site’ irAEs, endocrine irAEs and skin irAEs were associated to better clinical outcomes (better overall response rate, progression-free survival and OS).²⁰ In this clinical case, the patient achieved a completed response to ICI but did not develop any irAEs, so it is necessary to clarify which biomarkers can be associated with CR.

An important question is the long-term side effects of immunotherapy, due to chronic immune deregulation. There is a growing body of evidence that chronic immune deregulation can influence the development of many common medical problems, like atherosclerosis, heart failure, hypertension and diabetes. So, the real impact of ICI in this process has not been thoroughly investigated. There is some evidence that these patients had body fat increase due to improved health status following control of acute cancer-related symptoms.²⁰ Our patient developed diabetes as a new comorbidity during ICI treatment, without evidence of autoimmunity. This factor could be related to steroids’ long-time treatment and/or ICI long-term side effects. Further research is needed to explore this relationship in this selected group of patients.

Finally, the ideal duration of treatment with immunotherapy in responders is still unknown. This is an area of active investigation, with some studies showing better progression-free survival and OS in patients who did not stop using ICI.²¹ The analysis of long-term outcomes of the KEYNOTE-010 study shows that 79 of the 690 patients who were treated with pembrolizumab completed 35 cycles/2 years. The objective response rate was 94.9%, with an ongoing response rate of 48 (64%) (median follow-up of 43.4 months). Fourteen patients started a second course of pembrolizumab after disease progression (12 of them had completed 2 years of pembrolizumab). Six patients (42.9%) had a partial response and five patients (35.7%) had stable disease as the best overall response in the second-course treatment.²²

In conclusion, more in-depth investigation is needed to sustain our clinical practice in patients with AID and LC, as well as in the identification and development of predictive biomarkers for the response of ICIs, and appropriate management of treatment-related side effects.

In this clinical case, excellent response to immunotherapy with completed response and without exacerbation of autoimmune disease reflected the clinical response of one patient, so caution is needed when interpreting these findings and clinical outcomes.

Learning points.

• Immunotherapy appears to be safe in patients with non-small cell lung cancer and well-controlled Grave’s disease.

• No exacerbation of autoimmune disease and no immune-related adverse events were observed with anti-PD-L1 treatment in this patient.

• Immunotherapy can provide a complete and curable response in second-line treatment.

• Immunotherapy is well tolerated with important gains in terms of quality of life.

Ethics statements

Patient consent for publication

Consent obtained directly from patient(s)