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Lack of response to nivolumab in a patient with EGFR-mutant non-small cell lung cancer adenocarcinoma sub-type transformed to small cell lung cancer
Accepted Manuscript Title: Lack of response to nivolumab in a patient with EGFR-mutant non-small cell lung cancer adenocarcinoma sub-type transformed to small cell lung cancer Authors: Nadza Tokaca, Andrew Wotherspoon, Andrew G. Nicholson, Nicos Fotiadis, Lisa Thompson, Sanjay Popat PII: DOI: Reference:
S0169-5002(17)30391-4 http://dx.doi.org/doi:10.1016/j.lungcan.2017.07.012 LUNG 5409
To appear in:
Lung Cancer
Received date: Revised date: Accepted date:
10-5-2017 4-7-2017 9-7-2017
Please cite this article as: Tokaca Nadza, Wotherspoon Andrew, Nicholson Andrew G, Fotiadis Nicos, Thompson Lisa, Popat Sanjay.Lack of response to nivolumab in a patient with EGFR-mutant non-small cell lung cancer adenocarcinoma sub-type transformed to small cell lung cancer.Lung Cancer http://dx.doi.org/10.1016/j.lungcan.2017.07.012 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
TITLE PAGE
Lack of response to nivolumab in a patient with EGFR-mutant non-small cell lung cancer adenocarcinoma sub-type transformed to small cell lung cancer Nadza Tokacaa, Andrew Wotherspoonb, Andrew G Nicholsonc,d, Nicos Fotiadise, Lisa Thompsonf, Sanjay Popata,d. a b
Lung Unit, Royal Marsden Hospital, Fulham Road, London, SW3 6JJ. Department of Histopathology, Royal Marsden Hospital, Fulham Road, London,
SW3 6JJ. c
Department of Histopathology, Royal Brompton Hospital, Sydney Street, London,
SW3 6NP. d
National Heart and Lung Institute, Imperial College London, Cale Street, London,
SW3 6LY. e
Department of Interventional Radiology, Royal Marsden Hospital, Fulham Road,
London, SW3 6JJ. f
The Centre of Molecular Pathology, Institute of Cancer Research, Downs Road,
Sutton, SM2 5PT, UK.
Corresponding author: Dr Sanjay Popat, Royal Marsden Hospital, Fulham Road, London, SW3 6JJ, 02078082132.
Word Count: 1312/1500
HIGHLIGHTS
A rare case of EGFR-mutant NSCLC transformed to SCLC treated with nivolumab chemotherapy.
PD-L1 expression was 0% in transformed tumour cells.
No response to nivolumab was observed in this rare transformed tumour.
ABSTRACT (Word count: 53) Small cell transformation is a rare but well recognised mechanism of acquired resistance to EGFR-TKI therapy in EGFR-mutated NSCLC, but optimal drug therapy thereof is unknown. Nivolumab has demonstrated activity in relapsed de novo small
cell lung cancer in early phase trials. Here, we report a case of transformed EGFRmutant SCLC treated with nivolumab with no benefit. Key Words: NSCLC; adenocarcinoma; EGFR; small cell lung cancer; transformation; nivolumab
1. INTRODUCTION
Small cell transformation is a well-recognised mechanism of acquired resistance to EGFR-TKI therapy in EGFR-mutant advanced non-small cell lung cancer (NSCLC), accounting for up to 14% of cases[1,2].
Due to rarity of cases optimal treatment for these patients is unknown with several case reports documenting sensitivity to standard chemotherapy regimes for small cell lung cancer (SCLC), albeit with short duration of response, alongside lack of benefit from continuation of TKI therapy[2–5]. Despite the advent of immune checkpoint inhibitor (ICI) therapy for the treatment of metastatic NSCLC, together with promising efficacy data in SCLC, it’s potential role in this group of patients remains unknown.
Here, we report a case of a patient with EGFR-mutant adenocarcinoma subtype NSCLC with acquired resistance to gefitinib and transformation to small cell lung carcinoma who received treatment with nivolumab.
2. CASE REPORT
A 60 year-old South Asian never-smoker female patient with a diagnosis of T1aN0M1a adenocarcinoma with EGFR exon 19 deletion was treated with gefitinib, with a near complete response, maintained for 40 months, at which time she underwent local consolidation treatment to a solitary residual left upper lobe lung lesion with stereotactic body radiotherapy (SBRT, 55Gy in 5#).
She continued on gefitinib for a further 12 months, but developed oligoprogression of a new small right lower lobe lung nodule (T1a), with no radiographic evidence of other disease by PET-CT and brain MRI. CT-guided biopsy of this lesion identified islands of basaloid tumour with neuroendocrine features and crowding of cells with minimal
cytoplasm,
(paranuclear
dot),
positive but
for
CD56, synaptophysin,
negative
for Chromogranin
TTF1 A
and and
MNF116 p63
by
immunohistochemistry. The proliferation index was almost 100%. These findings were consistent with small cell lung carcinoma. Molecular analysis of this material (cobas® 480 assay) confirmed the original EGFR exon 19 deletion and no evidence of T790M.
After multidisciplinary discussion of therapeutic options, the patient declined surgery and definitive chemoradiotherapy, and completed SBRT (55Gy in 5#) to this lesion, followed by 4 cycles of adjuvant carboplatin and etoposide chemotherapy.
Restaging CT, PET-CT and MRI brain scans 2 months following completion of carboplatin/etoposide chemotherapy revealed an ongoing complete remission and after further discussion with the patient gefitinib was restarted. However, 6 months after completion of carboplatin/etoposide chemotherapy and 8 months after completion of SBRT, surveillance CT imaging identified 2 new liver lesions consistent with metastases.
CT-guided biopsy of one of these liver lesions confirmed small cell lung carcinoma, with cells displaying dot-like staining for cytokeratin, expression of CD56 and synaptophysin, but negative for chromogranin by immunohistochemistry (Figure 1., image (a)), with proliferation index of 100%. Again, EGFR genotyping of this material using the same platform confirmed an exon 19 deletion.
Gefitinib was discontinued at this time and rechallenge with carboplatin/etoposide commenced. Unfortunately, PET-CT following 2 cycles identified further progressive disease in the liver. She then commenced dose attenuated cyclophosphamidedoxorubicin-vincristine (CAV) chemotherapy, tolerated well with no major toxicities. Reassessment imaging following 2 and then 4 cycles of CAV showed an excellent incremental partial response (Figure 2., images (a) and (b)).
The patient completed 5 cycles of CAV chemotherapy, and then discontinued due to progressive myelosuppression. Unfortunately CT imaging 2 months later showed disease progression in the lung and the liver.
After a full discussion on treatment options, including best supportive care, knowing the benefits previously identified from nivolumab treatment in SCLC, she commenced nivolumab 3mg/kg q2w understanding this was an unlicenced indication. Nivolumab was well tolerated with the principal toxicities of grade 1 rash and grade 2 hyperthyroidism, but no other immune-mediated toxicities. Unfortunately, following 6 cycles (10 weeks) of nivolumab therapy, response assessment imaging confirmed marked hepatic disease progression with progressive and numerous new lesions (Figure 2., images (c) and (d)). Immunohistochemistry for PD-L1 expression retrospectively performed on liver re-biopsy material (using the 22C3 pharmDx assay) was negative at 0% expression (Figure 1., image (b)). Rapid clinical deterioration followed and the patient’s care was transferred to the community palliative care services. The sequence of anticancer treatments is summarised in Table 1. 3. DISCUSSION
We report a case of transformation to SCLC as a mechanism of acquired resistance to EGFR-TKI, showing lack of response to PD-1 inhibitor nivolumab and absence of PD-L1 expression in histologically transformed small cell tumour cells.
Immune-checkpoint inhibitors are superior to chemotherapy in patients with relapsed advanced/metastatic
squamous
and
non-squamous
NSCLC[6–8]
and
pembrolizumab is also licenced in the first-line setting for strongly PD-L1 expressing tumours (≥50% expression). There is also evidence of efficacy in small cell lung cancer from early phase trials. In an ongoing phase I/II trial of nivolumab alone or in combination with a CTLA-4 inhibitor ipilimumab in pretreated SCLC with a primary endpoint of overall response rate, interim analysis showed ORR of 13% for nivolumab alone and 31% for the combination[9]. Responses were durable (median response duration not reached and 6.9 months for monotherapy and combination respectively) and safety profiles acceptable. Pembrolizumab is also being investigated in SCLC. In the KEYNOTE-028 trial, a subset of patients with programmed cell death ligand 1 (PD-L1)–positive small cell lung cancer previously treated with chemotherapy received pembrolizumab[10]. The overall response rate
was 37.5%, with median PFS of 1.9 months and median OS 9.7 months. Larger phase II and randomized III trials of ICIs in SCLC are ongoing (NCT01928394, NCT02481830, NCT02054806, NCT02359019).
The role of ICIs in oncogene-addicted NSCLC is unproven with relatively low response rates in this population[11] and no definitive superior survival over docetaxel[8,12,13].
We report the case of a patient with EGFR-mutant adenocarcinoma and subsequent transformed SCLC negative for PD-L1 expression that progressed through nivolumab therapy. Therapy with nivolumab was initiated after all standard systemic treatment options were exhausted and without the knowledge of the patient’s PD-L1 status at the time. PD-L1 testing was performed retrospectively on the rebiopsy liver tumour cells, using the PD-L1 IHC 22C3 pharmDx assay which is not the companion diagnostic for therapy with nivolumab. The PD-L1 IHC 28-8 pharmDx assay was used to assess the predictive value of PD-L1 for nivolumab therapy in advanced NSCLC in phase III studies[7, 14], and is identified as a complementary rather than companion diagnostic test, as these trials have shown that patients with tumours not expressing PD-L1 may also benefit.
Two similar cases have been described thus far. In one, nivolumab was ineffective in a
similar
EGFR-mutated
lung
adenocarcinoma
patient
with
high-grade
neuroendocrine transformation[15]. Here, whilst PD-L1 expression was <1% in the rebiopsy specimen, expression in the diagnostic specimen pre-gefitinib was 30%, suggesting that exposure to EGFR-TKI may have resulted in PD-L1 expression attenuation, as has previously been demonstrated in EGFR-mutant cell-line models[16]. The original diagnostic material in our case was not available for similar PD-L1 testing. In a second case[17] of EGFR-mutated NSCLC with two different and mutually exclusive acquired resistance mechanisms occurring in two separate metastatic sites, differential PD-L1 expression was noted: partial PD-L1 expression (5%) in metastatic tumour cells with adenocarcinoma histology and EGFR T790M acquired resistance mutation, but no PD-L1 expression (0%) in cells with SCLC transformation. Previous studies have reported homogeneity of PD-L1 expression in paired primary and metastatic NSCLC sites[18], therefore suggesting the possibility that SCLC transformation as a mechanism of acquired TKI resistance may alter PDL1 expression status in tumour cells. Whether the differential PD-L1 expression
would have predicted for immunotherapy response is unclear, as this patient did not receive an ICI.
Our report illustrates that SCLC transformation as an acquired resistance mechanism in EGFR-mutated lung cancer remains a significant treatment challenge with shortlived responses to standard SCLC chemotherapy. Moreover, we additionally demonstrate the negative PD-L1 expression level in this rare tumour-type, and add further evidence that nivolumab is not beneficial in this setting. Nevertheless, in view of growing evidence for efficacy of ICIs in SCLC, and the lack of PD-L1 expression in this case, further evidence is required prior to concluding that immune checkpoint inhibition should not be pursued in this patient population.
ACKNOWLEDGEMENTS We acknowledge NHS funding to the Royal Marsden Hospital, RM NIHR-Biomedical Research Centre and the Institute of Cancer Research.
CONFLICT OF INTEREST STATEMENT
Sanjay Popat is consultant to AstraZeneca, BMS and MSD. Andrew Nicholson has undertaken consultancy for AstraZeneca, BMS, Pfizer, Merck, Boehringer Ingelheim, Novartis, Eli Lilly and Roche. Other authors declare no conflict of interest.
REFERENCES
1
Oser MG, Niederst MJ, Sequist L V, et al. Transformation from non-small-cell lung cancer to small-cell lung cancer: molecular drivers and cells of origin. Lancet Oncol 2015;16:e165–72. doi:10.1016/S1470-2045(14)71180-5
2
Sequist L V., Waltman BA, Dias-Santagata D, et al. Genotypic and Histological Evolution of Lung Cancers Acquiring Resistance to EGFR Inhibitors. Sci Transl Med 2011;3:75ra26-75ra26. doi:10.1126/scitranslmed.3002003
3
Popat S, Wotherspoon A, Nutting CM, et al. Transformation to ‘high grade’ neuroendocrine carcinoma as an acquired drug resistance mechanism in EGFR-mutant
lung
adenocarcinoma.
Lung
Cancer
2013;80:1–4.
doi:10.1016/j.lungcan.2012.12.019 4
Kim W-J, Kim S, Choi H, et al. Histological transformation from non-small cell to small cell lung carcinoma after treatment with epidermal growth factor receptor-tyrosine
kinase
inhibitor.
Thorac
Cancer
2015;6:800–4.
doi:10.1111/1759-7714.12217 5
Hwang K-E, Jung J-W, Oh S-J, et al. Transformation to small cell lung cancer as an acquired resistance mechanism in EGFR-mutant lung adenocarcinoma: a case report of complete response to etoposide and cisplatin. Tumori J 2015;101:0–0. doi:10.5301/tj.5000276
6
Reck M, Rodríguez-Abreu D, Robinson AG, et al. Pembrolizumab versus Chemotherapy for PD-L1–Positive Non–Small-Cell Lung Cancer. N Engl J Med 2016;375:1823–33. doi:10.1056/NEJMoa1606774
7
Borghaei H, Paz-Ares L, Horn L, et al. Nivolumab versus Docetaxel in Advanced Nonsquamous Non-Small-Cell Lung Cancer. N Engl J Med 2015;373:1627–39. doi:10.1056/NEJMoa1507643
8
Rittmeyer A, Barlesi F, Waterkamp D, et al. Atezolizumab versus docetaxel in patients with previously treated non-small-cell lung cancer (OAK): a phase 3, open-label, multicentre randomised controlled trial. Lancet (London, England) Published
Online
First:
12
December
2016.
doi:10.1016/S0140-
6736(16)32517-X 9
Antonia SJ, López-Martin JA, Bendell J, et al. Nivolumab alone and nivolumab plus ipilimumab in recurrent small-cell lung cancer (CheckMate 032): a multicentre, open-label, phase 1/2 trial. Lancet Oncol 2016;17:883–95. doi:10.1016/S1470-2045(16)30098-5
10
Ott P, Elez E, Hiret A, et al. OA05.01 Pembrolizumab in Patients with Extensive-Stage Small Cell Lung Cancer: Updated Survival Results from
KEYNOTE-028. J Thorac Oncol 2017; Volume 12 , Issue 1 , S259. 11
Gainor JF, Shaw AT, Sequist L V, et al. EGFR Mutations and ALK Rearrangements Are Associated with Low Response Rates to PD-1 Pathway Blockade in Non-Small Cell Lung Cancer: A Retrospective Analysis. Clin Cancer Res 2016;22:4585–93. doi:10.1158/1078-0432.CCR-15-3101
12
Borghaei H, Paz-Ares L, Horn L, et al. Nivolumab versus Docetaxel in Advanced Nonsquamous Non–Small-Cell Lung Cancer. N Engl J Med 2015;373:1627–39. doi:10.1056/NEJMoa1507643
13
Herbst RS, Baas P, Kim D-W, et al. Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomised controlled trial. Lancet 2016;387:1540–50. doi:10.1016/S0140-6736(15)01281-7
14
Brahmer J, Reckamp KL, Baas P et al. Nivolumab versus docetaxel in advanced squamous-cell non-small-cell lung cancer. N Engl J Med 2015; 373: 123–135. doi:10.1056/NEJMoa1504627
15
Nishikawa S, Tambo Y, Ninomiya H, et al. A case treated with nivolumab after small cell lung cancer transformation of mutant EGFR non-small cell lung cancer. Ann Oncol 2016;27:2300–2. doi:10.1093/annonc/mdw431
16
Akbay EA, Koyama S, Carretero J, et al. Activation of the PD-1 pathway contributes to immune escape in EGFR-driven lung tumors. Cancer Discov 2013;3:1355–63. doi:10.1158/2159-8290.CD-13-0310
17
Suda K, Murakami I, Yu H, et al. Heterogeneity in immune marker expression after acquisition of resistance to EGFR kinase inhibitors: analysis of a case with small cell lung cancer transformation. J Thorac Oncol Published Online First: February 2017. doi:10.1016/j.jtho.2017.02.002
18
Mansfield AS, Murphy SJ, Peikert T, et al. Heterogeneity of Programmed Cell Death Ligand 1 Expression in Multifocal Lung Cancer. Clin Cancer Res 2016;22:2177–82. doi:10.1158/1078-0432.CCR-15-2246
FIGURE LEGENDS
Figure 1: (a) A core of liver is infiltrated by small cell carcinoma (H&E, x400). (b) Staining for PD-L1 is completely negative (0%) (22C3 pharmDxTM assay, x400).
Figure 2: PET and CT images showing liver metastases (a) At baseline and (b) good partial response after 4 cycles of CAV chemotherapy. (c) Before nivolumab and (d) after 6 cycles of nivolumab.
Table 1. Sequence of anticancer treatments. Date
Treatment Commenced
May 2010
T1aN0M1a
EGFR
mutant
Received consolidative SBRT to solitary LUL lung lesion and thereafter restarted gefitinib
November 2014 2014
Received SBRT to oligoprogressive RLL lung lesion -
February 2015 March
for
adenocarcinoma
September 2013
December
gefitinib
2015
-
September 2015
Received adjuvant carboplatin and etoposide chemotherapy
Received maintenance gefitinib
September 2015 -
Received rechallenge carboplatin-etoposide chemotherapy
November 2015
due to liver progression: progression as best overall response
November
2015
-
Received CAV chemotherapy due to liver progression: partial
February 2016
response as best overall response
April 2016 – June
Received nivolumab with disease progression as best overall
2016
response
S0169-5002(17)30391-4 http://dx.doi.org/doi:10.1016/j.lungcan.2017.07.012 LUNG 5409
To appear in:
Lung Cancer
Received date: Revised date: Accepted date:
10-5-2017 4-7-2017 9-7-2017
Please cite this article as: Tokaca Nadza, Wotherspoon Andrew, Nicholson Andrew G, Fotiadis Nicos, Thompson Lisa, Popat Sanjay.Lack of response to nivolumab in a patient with EGFR-mutant non-small cell lung cancer adenocarcinoma sub-type transformed to small cell lung cancer.Lung Cancer http://dx.doi.org/10.1016/j.lungcan.2017.07.012 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
TITLE PAGE
Lack of response to nivolumab in a patient with EGFR-mutant non-small cell lung cancer adenocarcinoma sub-type transformed to small cell lung cancer Nadza Tokacaa, Andrew Wotherspoonb, Andrew G Nicholsonc,d, Nicos Fotiadise, Lisa Thompsonf, Sanjay Popata,d. a b
Lung Unit, Royal Marsden Hospital, Fulham Road, London, SW3 6JJ. Department of Histopathology, Royal Marsden Hospital, Fulham Road, London,
SW3 6JJ. c
Department of Histopathology, Royal Brompton Hospital, Sydney Street, London,
SW3 6NP. d
National Heart and Lung Institute, Imperial College London, Cale Street, London,
SW3 6LY. e
Department of Interventional Radiology, Royal Marsden Hospital, Fulham Road,
London, SW3 6JJ. f
The Centre of Molecular Pathology, Institute of Cancer Research, Downs Road,
Sutton, SM2 5PT, UK.
Corresponding author: Dr Sanjay Popat, Royal Marsden Hospital, Fulham Road, London, SW3 6JJ, 02078082132.
Word Count: 1312/1500
HIGHLIGHTS
A rare case of EGFR-mutant NSCLC transformed to SCLC treated with nivolumab chemotherapy.
PD-L1 expression was 0% in transformed tumour cells.
No response to nivolumab was observed in this rare transformed tumour.
ABSTRACT (Word count: 53) Small cell transformation is a rare but well recognised mechanism of acquired resistance to EGFR-TKI therapy in EGFR-mutated NSCLC, but optimal drug therapy thereof is unknown. Nivolumab has demonstrated activity in relapsed de novo small
cell lung cancer in early phase trials. Here, we report a case of transformed EGFRmutant SCLC treated with nivolumab with no benefit. Key Words: NSCLC; adenocarcinoma; EGFR; small cell lung cancer; transformation; nivolumab
1. INTRODUCTION
Small cell transformation is a well-recognised mechanism of acquired resistance to EGFR-TKI therapy in EGFR-mutant advanced non-small cell lung cancer (NSCLC), accounting for up to 14% of cases[1,2].
Due to rarity of cases optimal treatment for these patients is unknown with several case reports documenting sensitivity to standard chemotherapy regimes for small cell lung cancer (SCLC), albeit with short duration of response, alongside lack of benefit from continuation of TKI therapy[2–5]. Despite the advent of immune checkpoint inhibitor (ICI) therapy for the treatment of metastatic NSCLC, together with promising efficacy data in SCLC, it’s potential role in this group of patients remains unknown.
Here, we report a case of a patient with EGFR-mutant adenocarcinoma subtype NSCLC with acquired resistance to gefitinib and transformation to small cell lung carcinoma who received treatment with nivolumab.
2. CASE REPORT
A 60 year-old South Asian never-smoker female patient with a diagnosis of T1aN0M1a adenocarcinoma with EGFR exon 19 deletion was treated with gefitinib, with a near complete response, maintained for 40 months, at which time she underwent local consolidation treatment to a solitary residual left upper lobe lung lesion with stereotactic body radiotherapy (SBRT, 55Gy in 5#).
She continued on gefitinib for a further 12 months, but developed oligoprogression of a new small right lower lobe lung nodule (T1a), with no radiographic evidence of other disease by PET-CT and brain MRI. CT-guided biopsy of this lesion identified islands of basaloid tumour with neuroendocrine features and crowding of cells with minimal
cytoplasm,
(paranuclear
dot),
positive but
for
CD56, synaptophysin,
negative
for Chromogranin
TTF1 A
and and
MNF116 p63
by
immunohistochemistry. The proliferation index was almost 100%. These findings were consistent with small cell lung carcinoma. Molecular analysis of this material (cobas® 480 assay) confirmed the original EGFR exon 19 deletion and no evidence of T790M.
After multidisciplinary discussion of therapeutic options, the patient declined surgery and definitive chemoradiotherapy, and completed SBRT (55Gy in 5#) to this lesion, followed by 4 cycles of adjuvant carboplatin and etoposide chemotherapy.
Restaging CT, PET-CT and MRI brain scans 2 months following completion of carboplatin/etoposide chemotherapy revealed an ongoing complete remission and after further discussion with the patient gefitinib was restarted. However, 6 months after completion of carboplatin/etoposide chemotherapy and 8 months after completion of SBRT, surveillance CT imaging identified 2 new liver lesions consistent with metastases.
CT-guided biopsy of one of these liver lesions confirmed small cell lung carcinoma, with cells displaying dot-like staining for cytokeratin, expression of CD56 and synaptophysin, but negative for chromogranin by immunohistochemistry (Figure 1., image (a)), with proliferation index of 100%. Again, EGFR genotyping of this material using the same platform confirmed an exon 19 deletion.
Gefitinib was discontinued at this time and rechallenge with carboplatin/etoposide commenced. Unfortunately, PET-CT following 2 cycles identified further progressive disease in the liver. She then commenced dose attenuated cyclophosphamidedoxorubicin-vincristine (CAV) chemotherapy, tolerated well with no major toxicities. Reassessment imaging following 2 and then 4 cycles of CAV showed an excellent incremental partial response (Figure 2., images (a) and (b)).
The patient completed 5 cycles of CAV chemotherapy, and then discontinued due to progressive myelosuppression. Unfortunately CT imaging 2 months later showed disease progression in the lung and the liver.
After a full discussion on treatment options, including best supportive care, knowing the benefits previously identified from nivolumab treatment in SCLC, she commenced nivolumab 3mg/kg q2w understanding this was an unlicenced indication. Nivolumab was well tolerated with the principal toxicities of grade 1 rash and grade 2 hyperthyroidism, but no other immune-mediated toxicities. Unfortunately, following 6 cycles (10 weeks) of nivolumab therapy, response assessment imaging confirmed marked hepatic disease progression with progressive and numerous new lesions (Figure 2., images (c) and (d)). Immunohistochemistry for PD-L1 expression retrospectively performed on liver re-biopsy material (using the 22C3 pharmDx assay) was negative at 0% expression (Figure 1., image (b)). Rapid clinical deterioration followed and the patient’s care was transferred to the community palliative care services. The sequence of anticancer treatments is summarised in Table 1. 3. DISCUSSION
We report a case of transformation to SCLC as a mechanism of acquired resistance to EGFR-TKI, showing lack of response to PD-1 inhibitor nivolumab and absence of PD-L1 expression in histologically transformed small cell tumour cells.
Immune-checkpoint inhibitors are superior to chemotherapy in patients with relapsed advanced/metastatic
squamous
and
non-squamous
NSCLC[6–8]
and
pembrolizumab is also licenced in the first-line setting for strongly PD-L1 expressing tumours (≥50% expression). There is also evidence of efficacy in small cell lung cancer from early phase trials. In an ongoing phase I/II trial of nivolumab alone or in combination with a CTLA-4 inhibitor ipilimumab in pretreated SCLC with a primary endpoint of overall response rate, interim analysis showed ORR of 13% for nivolumab alone and 31% for the combination[9]. Responses were durable (median response duration not reached and 6.9 months for monotherapy and combination respectively) and safety profiles acceptable. Pembrolizumab is also being investigated in SCLC. In the KEYNOTE-028 trial, a subset of patients with programmed cell death ligand 1 (PD-L1)–positive small cell lung cancer previously treated with chemotherapy received pembrolizumab[10]. The overall response rate
was 37.5%, with median PFS of 1.9 months and median OS 9.7 months. Larger phase II and randomized III trials of ICIs in SCLC are ongoing (NCT01928394, NCT02481830, NCT02054806, NCT02359019).
The role of ICIs in oncogene-addicted NSCLC is unproven with relatively low response rates in this population[11] and no definitive superior survival over docetaxel[8,12,13].
We report the case of a patient with EGFR-mutant adenocarcinoma and subsequent transformed SCLC negative for PD-L1 expression that progressed through nivolumab therapy. Therapy with nivolumab was initiated after all standard systemic treatment options were exhausted and without the knowledge of the patient’s PD-L1 status at the time. PD-L1 testing was performed retrospectively on the rebiopsy liver tumour cells, using the PD-L1 IHC 22C3 pharmDx assay which is not the companion diagnostic for therapy with nivolumab. The PD-L1 IHC 28-8 pharmDx assay was used to assess the predictive value of PD-L1 for nivolumab therapy in advanced NSCLC in phase III studies[7, 14], and is identified as a complementary rather than companion diagnostic test, as these trials have shown that patients with tumours not expressing PD-L1 may also benefit.
Two similar cases have been described thus far. In one, nivolumab was ineffective in a
similar
EGFR-mutated
lung
adenocarcinoma
patient
with
high-grade
neuroendocrine transformation[15]. Here, whilst PD-L1 expression was <1% in the rebiopsy specimen, expression in the diagnostic specimen pre-gefitinib was 30%, suggesting that exposure to EGFR-TKI may have resulted in PD-L1 expression attenuation, as has previously been demonstrated in EGFR-mutant cell-line models[16]. The original diagnostic material in our case was not available for similar PD-L1 testing. In a second case[17] of EGFR-mutated NSCLC with two different and mutually exclusive acquired resistance mechanisms occurring in two separate metastatic sites, differential PD-L1 expression was noted: partial PD-L1 expression (5%) in metastatic tumour cells with adenocarcinoma histology and EGFR T790M acquired resistance mutation, but no PD-L1 expression (0%) in cells with SCLC transformation. Previous studies have reported homogeneity of PD-L1 expression in paired primary and metastatic NSCLC sites[18], therefore suggesting the possibility that SCLC transformation as a mechanism of acquired TKI resistance may alter PDL1 expression status in tumour cells. Whether the differential PD-L1 expression
would have predicted for immunotherapy response is unclear, as this patient did not receive an ICI.
Our report illustrates that SCLC transformation as an acquired resistance mechanism in EGFR-mutated lung cancer remains a significant treatment challenge with shortlived responses to standard SCLC chemotherapy. Moreover, we additionally demonstrate the negative PD-L1 expression level in this rare tumour-type, and add further evidence that nivolumab is not beneficial in this setting. Nevertheless, in view of growing evidence for efficacy of ICIs in SCLC, and the lack of PD-L1 expression in this case, further evidence is required prior to concluding that immune checkpoint inhibition should not be pursued in this patient population.
ACKNOWLEDGEMENTS We acknowledge NHS funding to the Royal Marsden Hospital, RM NIHR-Biomedical Research Centre and the Institute of Cancer Research.
CONFLICT OF INTEREST STATEMENT
Sanjay Popat is consultant to AstraZeneca, BMS and MSD. Andrew Nicholson has undertaken consultancy for AstraZeneca, BMS, Pfizer, Merck, Boehringer Ingelheim, Novartis, Eli Lilly and Roche. Other authors declare no conflict of interest.
REFERENCES
1
Oser MG, Niederst MJ, Sequist L V, et al. Transformation from non-small-cell lung cancer to small-cell lung cancer: molecular drivers and cells of origin. Lancet Oncol 2015;16:e165–72. doi:10.1016/S1470-2045(14)71180-5
2
Sequist L V., Waltman BA, Dias-Santagata D, et al. Genotypic and Histological Evolution of Lung Cancers Acquiring Resistance to EGFR Inhibitors. Sci Transl Med 2011;3:75ra26-75ra26. doi:10.1126/scitranslmed.3002003
3
Popat S, Wotherspoon A, Nutting CM, et al. Transformation to ‘high grade’ neuroendocrine carcinoma as an acquired drug resistance mechanism in EGFR-mutant
lung
adenocarcinoma.
Lung
Cancer
2013;80:1–4.
doi:10.1016/j.lungcan.2012.12.019 4
Kim W-J, Kim S, Choi H, et al. Histological transformation from non-small cell to small cell lung carcinoma after treatment with epidermal growth factor receptor-tyrosine
kinase
inhibitor.
Thorac
Cancer
2015;6:800–4.
doi:10.1111/1759-7714.12217 5
Hwang K-E, Jung J-W, Oh S-J, et al. Transformation to small cell lung cancer as an acquired resistance mechanism in EGFR-mutant lung adenocarcinoma: a case report of complete response to etoposide and cisplatin. Tumori J 2015;101:0–0. doi:10.5301/tj.5000276
6
Reck M, Rodríguez-Abreu D, Robinson AG, et al. Pembrolizumab versus Chemotherapy for PD-L1–Positive Non–Small-Cell Lung Cancer. N Engl J Med 2016;375:1823–33. doi:10.1056/NEJMoa1606774
7
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FIGURE LEGENDS
Figure 1: (a) A core of liver is infiltrated by small cell carcinoma (H&E, x400). (b) Staining for PD-L1 is completely negative (0%) (22C3 pharmDxTM assay, x400).
Figure 2: PET and CT images showing liver metastases (a) At baseline and (b) good partial response after 4 cycles of CAV chemotherapy. (c) Before nivolumab and (d) after 6 cycles of nivolumab.
Table 1. Sequence of anticancer treatments. Date
Treatment Commenced
May 2010
T1aN0M1a
EGFR
mutant
Received consolidative SBRT to solitary LUL lung lesion and thereafter restarted gefitinib
November 2014 2014
Received SBRT to oligoprogressive RLL lung lesion -
February 2015 March
for
adenocarcinoma
September 2013
December
gefitinib
2015
-
September 2015
Received adjuvant carboplatin and etoposide chemotherapy
Received maintenance gefitinib
September 2015 -
Received rechallenge carboplatin-etoposide chemotherapy
November 2015
due to liver progression: progression as best overall response
November
2015
-
Received CAV chemotherapy due to liver progression: partial
February 2016
response as best overall response
April 2016 – June
Received nivolumab with disease progression as best overall
2016
response