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CASE REPORT
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Long-term survival of a patient with programmed death ligand 1-negative lung adenocarcinoma and oligoprogressive disease treated with nivolumab and stereotactic body radiation therapy


1 Department of Medical Oncology, Hospital Universitario Infanta Cristina, Madrid, Spain
2 Department of Medical Oncology, Hospital Universitario Clínico San Carlos, Madrid, Spain

Date of Submission31-Jan-2019
Date of Decision17-Apr-2019
Date of Acceptance11-Sep-2019
Date of Web Publication09-Jun-2020

Correspondence Address:
Miguel J Sotelo,
Department of Medical Oncology, Hospital Universitario Infanta Cristina, Avenida 9 de Junio, 228981 Parla, Madrid
Spain
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/jcrt.JCRT_81_19

 > Abstract 


Immune-checkpoint inhibitors have shown to prolong survival in patients with metastatic non-small cell lung cancer. Programmed death ligand 1 (PD-L1) expression is associated with a higher probability of response, although some patients with PD-L1 negative tumors may also respond or show durable stabilizations. However, the optimal strategy after progression to immunotherapy (IO) is not yet defined. Patients with oligometastatic disease may benefit from local treatments such as radiotherapy (RT), achieving significant local control rates. In addition, RT is claimed to have numerous immunogenic effects that could synergize with IO. We present the case of a complete responder to nivolumab that after a monotopic adrenal relapse received stereotactic body radiation therapy, followed by maintenance nivolumab achieving a partial response that is still ongoing. Aspects such as mechanisms of acquired resistance to PD-L1 inhibitors, the optimal management after progression, and the potential interplay between IO and RT are briefly reviewed and discussed.

Keywords: Lung adenocarcinoma, nivolumab, oligoprogressive disease, stereotactic body radiation therapy, synergistic effects



How to cite this URL:
Sotelo MJ, Cabezas-Camarero S, Riquelme A, Bueno C. Long-term survival of a patient with programmed death ligand 1-negative lung adenocarcinoma and oligoprogressive disease treated with nivolumab and stereotactic body radiation therapy. J Can Res Ther [Epub ahead of print] [cited 2020 Jul 12]. Available from: http://www.cancerjournal.net/preprintarticle.asp?id=286254




 > Introduction Top


Programmed death ligand 1 (PD[L] 1) inhibitors increase tumor responses and prolong survival in patients with non-small cell lung cancer (NSCLC) progressing to platinum-based chemotherapy, a scenario historically associated with a dismal prognosis. However, only a small subgroup, of up to 20% of cases, may actually respond to these agents.[1],[2],[3]

PD-L1 expression can help in the selection of patients that will benefit from PD(L)1 inhibitors, but it is not an accurate biomarker. Indeed, some PD-L1-negative patients may show brilliant and durable responses to these agents.[4]

Patients with oncogene-driven lung cancer oligoprogressing, while on tyrosine kinase inhibitors (TKIs), are commonly managed with local interventions (i.e., surgery, radiotherapy [RT]) followed by maintenance TKI therapy.[5] However, there is insufficient evidence yet to adopt a similar strategy in patients oligoprogressing to immunotherapy (IO) agents.

Stereotactic body radiation therapy (SBRT) allows the administration of very high RT doses while minimizing the irradiation of the adjacent normal tissues.[6] In addition to its direct antitumor activity, RT has powerful immunogenic effects that support its combination with immune-checkpoint inhibitors.[7]

We present the case of a patient with lung adenocarcinoma initially responding to nivolumab, and a monotopic right adrenal progression that was treated with SBRT followed by maintenance nivolumab without evidence of disease progression to date.


 > Case Report Top


A 64-year-old woman, active smoker of 30 pack-years, consulted in October 2014, because of a soft-tissue lesion of 4.8 cm × 3.5 cm in the abdominal wall. After a complete excisional biopsy, pathology informed of a metastasis of lung adenocarcinoma, epidermal growth factor receptor, and anaplastic lymphoma kinase negative. In December 2014, computed tomography (CT) scan showed a 2.4 cm × 1.2 cm pulmonary nodule in the left upper lobe, a 1-cm subcutaneous chest implant and a 1-cm left adrenal lesion [Figure 1]. A 18F-fluorodeoxyglucose (FDG)-positron emission tomography/CT (PET/CT) scan showed pathological FDG uptake in the pulmonary nodule and left adrenal lesion as well as in multiple subcutaneous implants.
Figure 1: (a and b) Computed tomography scan in December 2014 showing a 2.4 cm × 1.2 cm pulmonary nodule in the left upper lobe and a 1 cm subcutaneous chest implant. (c and d) Computed tomography scan after 4 cycles of cisplatin plus pemetrexed, showing a complete radiological response

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Four cycles of cisplatin plus pemetrexed were administered between January and April 2015, achieving a complete radiological response [Figure 1] followed by maintenance with pemetrexed (four additional cycles) until June 2015, when CT scan showed recurrence of the left upper lobe nodule, which measured 2.1 cm × 1.2 cm [Figure 2].
Figure 2: (a) Computed tomography scan in June 2015 before the start of nivolumab showing a 2.1 cm × 1.2 cm left upper lobe nodule. (b) Computed tomography scan after 7 cycles of nivolumab, showing a complete radiological response

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In August 2015, treatment with nivolumab was started. A complete radiological response was achieved after seven cycles [Figure 2], and it was maintained for a total of 26 cycles until August 2016, when a right adrenal lesion of 3.2 cm × 2.7 cm was evidenced. Nivolumab was continued and a 18F-FDG-PET/CT scan was performed in October 2016, that only showed pathological FDG uptake (maximum standardized uptake value 10.5) on the right adrenal lesion, which then measured 4 cm [Figure 3]. Nivolumab was continued, and SBRT was administered in the right adrenal metastasis in December 2016 (45 Gy in 9 fractions of 5 Gy), achieving a 70% reduction in the size of the lesion (1.2 cm in the control CT scan) in February 2017 [Figure 3].
Figure 3: (a and b) Computed tomography and positron emission tomography scans in October 2016, showing a single adrenal lesion with pathological fluorodeoxyglucose uptake and measuring 4 cm (c) Computed tomography scan in February 2017 showing a partial response after stereotactic body radiation therapy. (d) Computed tomography scan in August 2018 showing a sustained partial response

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Interestingly, PD-L1 expression was performed in March 2017 in the biopsy of initial diagnosis, and it was negative (<1%).

The patient is still on treatment to date and continues showing a sustained partial response [Figure 3] with good tolerance (asthenia Grade 1, anorexia Grade 2) and no evidence of immune-related toxicity.


 > Discussion Top


PD(L)1 inhibitors have shown to prolong survival in patients with NSCLC who have progressed to platinum-based chemotherapy, achieving long-lasting responses in a subset of patients.[1],[2],[3] Unfortunately, therapeutic options are scarce after progression to these agents, and the prognosis is poor.

Patients with oncogene-driven lung cancer with oligoprogressive disease during TKI therapy may benefit from local treatments, maintaining the same TKI.[5] Although this therapeutic strategy is not yet common practice in patients treated with immune-checkpoint inhibitors, it could be an option for those patients who after showing a sustained control of the disease, progress in a limited number of metastatic locations.[7] In addition, evidence from prospective and retrospective studies supports the use of aggressive local therapies in patients with NSCLC and oligometastatic disease, as this strategy may significantly increase survival in selected patients.[6]

RT is a widely used therapeutic tool in oligometastatic lung cancer. In particular, SBRT is increasingly employed, given the high biologic doses that can be administered with minimal toxicity.[6] Our patient obtained a complete radiological response with nivolumab and after a year of treatment, presented right adrenal progression. Given the important benefit obtained so far and the monotopic nature of the progression, SBRT was administered in the right adrenal metastasis, followed by continuation of nivolumab. This strategy has allowed to control the disease to date with minimal toxicity, in a setting with few and minimally effective chemotherapy options. Although adrenalectomy for single adrenal metastases has shown favorable results,[8] the use of SBRT is currently preferred given its favorable safety profile, high rates of local control, and prolonged survival demonstrated in multiple published series [Table 1].
Table 1: Series of nonsmall cell lung cancer patients and adrenal metastases treated with stereotactic body radiation therapy

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We chose SBRT considering its well-known local effects, low morbidity, and potential synergy with IO.[7] Thus, the known immunogenic effects of RT may have favored the prolonged disease stabilization with nivolumab after SBRT. Although RT exerts a direct antitumor effect, it also induces immunogenic cell death through the promotion of antigen presentation, effector T-cell activation, and regulatory T-cell inhibition.[7],[22] Several preclinical studies and a few case reports suggest a powerful synergy from the combination of RT and IO. Indeed, increases in PD-L1 expression have been described as an adaptive immune resistance mechanism after RT.[23] On the other hand, higher radiation doses per fraction, as those administered with SBRT, seem to synergize better with PD(L)1 inhibition compared to standard fractionation regimens of several weeks duration, that usually are more toxic and less convenient for the patients. Of note, the magnitude and duration of the response seen in our patient, with a 70% reduction in the size of the right adrenal lesion, may not simply be the result of SBRT, but instead, reflect the presumed synergy derived from PD-L1 inhibition and RT [Figure 3].[24] Finally, it could be hypothesized that both RT and IO could enhance the systemic control of the disease through an abscopal-like effect by favoring antigen presentation.[7] In the PACIFIC trial, the increased progression-free survival and overall survival observed in the durvalumab arm may have been, in part, related to the recent administration of chemoradiation.[25] Currently, multiple clinical trials (some of them in the metastatic setting) are evaluating the combination of IO and RT in patients with lung cancer [Table 2]. These studies will provide information about the optimal dose, timing, activity, and safety of this therapeutic strategy.
Table 2: Studies evaluating the combination of immune checkpoint blockade and radiotherapy in nonsmall cell lung cancer

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While a high expression of PD-L1 may be associated with a higher probability of response to immune checkpoint blockade, PD-L1 negative tumors may also respond or show durable stabilizations.[1],[3] Indeed, it is well known that PD-L1 expression is dynamic and may be modulated by both local and systemic treatments.[4] In our patient, prior administration of cisplatin-based chemotherapy may have favored tumor antigen presentation and immune cell activation, thus potentially enhancing the response to subsequent nivolumab.

The duration of treatment is also a point to discuss. We decided to continue nivolumab after SBRT, given the prolonged control of the disease and excellent tolerance in an initially widely metastatic patient. The CheckMate 153 study[26] demonstrated that continuing nivolumab after 1 year of treatment was significantly associated with better progression-free survival (hazard ratio 0.43, 95% confidence interval, 0.25–0.76) with a trend toward better overall survival. Likewise, treatment with nivolumab beyond progression may be associated with increased survival and even objective responses in NSCLC and other solid tumors.[27],[28],[29]


 > Conclusion Top


In patients with previous long-lasting response to PD(L)1 inhibitors and oligoprogressive disease, irradiation of the progressing lesions followed by the reintroduction of IO is an option to consider given the limited therapeutic options, good safety profile, and the potential synergistic effects between RT and IO.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
 > References Top

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    Figures

  [Figure 1], [Figure 2], [Figure 3]
 
 
    Tables

  [Table 1], [Table 2]



 

 
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