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Tumor flare after start of RAF inhibition in KRAS mutated NSCLC: A case report
G Model LUNG-4735; No. of Pages 3
ARTICLE IN PRESS Lung Cancer xxx (2014) xxx–xxx
Contents lists available at ScienceDirect
Lung Cancer journal homepage: www.elsevier.com/locate/lungcan
Case report
Tumor flare after start of RAF inhibition in KRAS mutated NSCLC: A case report Wouter W. Mellema a , Sjaak A. Burgers b , Egbert. F. Smit a,∗ a b
Department of Pulmonary Diseases, VU University Medical Center, Amsterdam, The Netherlands Department of Thoracic Oncology, Netherlands Cancer Institute, Amsterdam, The Netherlands
a r t i c l e
i n f o
Article history: Received 3 September 2014 Received in revised form 8 November 2014 Accepted 23 November 2014 Keywords: Non-small cell lung cancer KRAS mutation Sorafenib RAF inhibitor Paradoxal activation Tumor flare
a b s t r a c t Here we describe a case of striking tumor flare after start of treatment with sorafenib and metformin as part of a phase II clinical trial. Previous reports have described a paradoxal activation of the MAPK pathway after treatment with a weak RAF inhibitor. This mechanism is based on inhibition of a negative feedback loop to upstream effectors of RAF and subsequently increased stimulation of the RAS-RAFMEK-ERK (MAPK) pathway. We suggest that sorafenib may contribute to tumor progression through this mechanism and clinicians should be aware of this phenomenon when treating NSCLC patients with sorafenib. © 2014 Elsevier Ireland Ltd. All rights reserved.
Sorafenib, a multi-target tyrosine kinase inhibitor, has been intensively studied in non-small cell lung cancer (NSCLC). Sorafenib targets amongst others RAF kinases, downstream of RAS and is believed to be suitable for treatment in advanced NSCLC patients harboring a KRAS mutation. We performed 2 phase II clinical trials in advanced KRAS mutated NSCLC with single-agent sorafenib and sorafenib in combination with metformin, as treatment in secondline or beyond [1,2]. Here, we describe a case of tumor “flare” immediately after start of treatment with sorafenib and metformin, which we believe may be the result of paradoxal activation of the RAS-MAPK pathway.
was enrolled in a phase II clinical trial with sorafenib 400 mg BID and metformin 1000 mg BID. Prior to start of treatment a thoracic CT scan was repeated showing stable disease by RECIST (+9%) 8 weeks after end of first-line treatment. Tumor assessment after 3 weeks of treatment with sorafenib and metformin showed significant progression (+226%) of the intrathoracic lesion, lymfangitis carcinomatosa and a pleural effusion. Treatment was discontinued and third-line treatment with single-agent pemetrexed 500 mg/m2 was initiated. CT evaluation after 2 cycles of pemetrexed showed a partial response (−66%; Fig. 1).
1. Case
2. Discussion
A 43-year-old female with stage IV non-small cell lung cancer (NSCLC) of the right lower lobe and lymph node metastasis in the right upper neck was treated in first-line setting with carboplatin/paclitaxel/bevacizumab. Evaluation after 4 cycles showed a mixed response with regression of the intrathoracic lesion, but progression of the lymph node metastasis. Treatment was halted and the lymph node metastasis subsequently irradiated. The primary tumor was known to harbor a KRAS ‘G12V’ mutation. She
Rapid progression of cancer has been described previously in studies with BRAF inhibitors. For example, in melanoma proliferative skin lesions are a well-known phenomenon in patients treated with BRAF inhibitors such as vemurafenib. It has been suggested that vemurafenib does not initiate these lesions, but accelerates growth by paradoxal activation of MAPK signaling [3]. An illustrative case report described a stage IV melanoma patient who was treated with vemurafenib [4]. During treatment a previously unrecognized NRAS mutant chronic myelomonocytic leukemia (CMML) became clinically evident characterized by proliferation of a leukemic cell population with high ERK expression. Treatment with vemurafenib was interrupted showing decrease of leukemic cell count and a concomitant decrease of ERK expression. After restart of vemurafenib, the leukemic
∗ Corresponding author at: Department of Pulmonary Diseases, VU University Medical Center, PO Box 7057, 1007 MB Amsterdam, The Netherlands. Tel.: +31 020 444 4349; fax: +31 020 444 4328. E-mail address: [email protected] (Egbert.F. Smit). http://dx.doi.org/10.1016/j.lungcan.2014.11.014 0169-5002/© 2014 Elsevier Ireland Ltd. All rights reserved.
Please cite this article in press as: Mellema WW, et al. Tumor flare after start of RAF inhibition in KRAS mutated NSCLC: A case report. Lung Cancer (2014), http://dx.doi.org/10.1016/j.lungcan.2014.11.014
G Model LUNG-4735; No. of Pages 3 2
ARTICLE IN PRESS W.W. Mellema et al. / Lung Cancer xxx (2014) xxx–xxx
Fig. 1. (A) A graph of tumor volume of the intrathoracic lesion followed in time (weeks). Black dots () represent tumor measurement assessed by CT scan. (B) CT scan images of the intrathoracic lesion followed in time.
Fig. 2. A model of paradoxal activation of the MAPK pathway. Sorafenib induces activation of RAF by inhibition of its auto-inhibitory state. This results in increased stimulation of the MAPK signaling pathway and induces accelerated tumor growth.
cell count rapidly increased. Fig. 2 illustrates a possible mechanism by which sorafenib induces activation of the MAPK pathway. Under physiological conditions, wild-type RAF protein exists in an auto-inhibitory state [5]. Inhibition of RAF leads to its activation and can promote tumor progression in KRAS mutated cells and models. To our knowledge, we are the first to report possible tumor flare after treatment of KRAS mutated NSCLC with sorafenib. We believe
that paradoxal activation of a growth signaling pathway may drive this rapid progression based on previous reports in other malignancies treated with RAF inhibitors. Clinicians treating KRAS mutated (NSCLC) patients with RAF inhibitors should be aware of this phenomenon and treating patients with novel treatments or treatment with agents available for other diseases outside the context of a clinical trial should be avoided due to the potential of unforeseen adverse events.
Please cite this article in press as: Mellema WW, et al. Tumor flare after start of RAF inhibition in KRAS mutated NSCLC: A case report. Lung Cancer (2014), http://dx.doi.org/10.1016/j.lungcan.2014.11.014
G Model LUNG-4735; No. of Pages 3
ARTICLE IN PRESS W.W. Mellema et al. / Lung Cancer xxx (2014) xxx–xxx
Conflict of interest statement All authors state they have no financial supports or conflict of interest. References [1] Dingemans AC, Mellema WW, Groen HJM, van Wijk A, Burgers SA, Kunst PW, et al. A phase II study of sorafenib in patients with platinum-pretreated, advanced (Stage IIIb or IV) non-small cell lung cancer with a KRAS mutation. Clin Cancer Res 2013;19(February (3)):743–51.
3
[2] Mellema WW, Burgers SA, Groen HJM, Dingemans AC, Thunnissen E, Heideman DAM, et al. Sorafenib and metformin in pretreated patients with stage IV nonsmall cell lung cancer with a KRAS mutation: a multicenter single arm phase II study. J Clin Oncol 2014;32 (suppl; abstr e19015). [3] Su F, Viros A, Milagre C, Trunzer K, Bollag G, Spleiss O, et al. RAS mutations in cutaneous squamous-cell carcinomas in patients treated with BRAF inhibitors. N Engl J Med 2012;366(January (3)):207–15. [4] Callahan MK, Rampal R, Harding JJ, Klimek VM, Chung YR, Merghoub T, et al. Progression of RAS-mutant leukemia during RAF inhibitor treatment. N Engl J Med 2012;367(December (24)):2316–21. [5] Holderfield M, Merritt H, Chan J, Wallroth M, Tandeske L, Zhai H, et al. RAF inhibitors activate the MAPK pathway by relieving inhibitory autophosphorylation. Cancer Cell 2013;23(May (5)):594–602.
Please cite this article in press as: Mellema WW, et al. Tumor flare after start of RAF inhibition in KRAS mutated NSCLC: A case report. Lung Cancer (2014), http://dx.doi.org/10.1016/j.lungcan.2014.11.014
ARTICLE IN PRESS Lung Cancer xxx (2014) xxx–xxx
Contents lists available at ScienceDirect
Lung Cancer journal homepage: www.elsevier.com/locate/lungcan
Case report
Tumor flare after start of RAF inhibition in KRAS mutated NSCLC: A case report Wouter W. Mellema a , Sjaak A. Burgers b , Egbert. F. Smit a,∗ a b
Department of Pulmonary Diseases, VU University Medical Center, Amsterdam, The Netherlands Department of Thoracic Oncology, Netherlands Cancer Institute, Amsterdam, The Netherlands
a r t i c l e
i n f o
Article history: Received 3 September 2014 Received in revised form 8 November 2014 Accepted 23 November 2014 Keywords: Non-small cell lung cancer KRAS mutation Sorafenib RAF inhibitor Paradoxal activation Tumor flare
a b s t r a c t Here we describe a case of striking tumor flare after start of treatment with sorafenib and metformin as part of a phase II clinical trial. Previous reports have described a paradoxal activation of the MAPK pathway after treatment with a weak RAF inhibitor. This mechanism is based on inhibition of a negative feedback loop to upstream effectors of RAF and subsequently increased stimulation of the RAS-RAFMEK-ERK (MAPK) pathway. We suggest that sorafenib may contribute to tumor progression through this mechanism and clinicians should be aware of this phenomenon when treating NSCLC patients with sorafenib. © 2014 Elsevier Ireland Ltd. All rights reserved.
Sorafenib, a multi-target tyrosine kinase inhibitor, has been intensively studied in non-small cell lung cancer (NSCLC). Sorafenib targets amongst others RAF kinases, downstream of RAS and is believed to be suitable for treatment in advanced NSCLC patients harboring a KRAS mutation. We performed 2 phase II clinical trials in advanced KRAS mutated NSCLC with single-agent sorafenib and sorafenib in combination with metformin, as treatment in secondline or beyond [1,2]. Here, we describe a case of tumor “flare” immediately after start of treatment with sorafenib and metformin, which we believe may be the result of paradoxal activation of the RAS-MAPK pathway.
was enrolled in a phase II clinical trial with sorafenib 400 mg BID and metformin 1000 mg BID. Prior to start of treatment a thoracic CT scan was repeated showing stable disease by RECIST (+9%) 8 weeks after end of first-line treatment. Tumor assessment after 3 weeks of treatment with sorafenib and metformin showed significant progression (+226%) of the intrathoracic lesion, lymfangitis carcinomatosa and a pleural effusion. Treatment was discontinued and third-line treatment with single-agent pemetrexed 500 mg/m2 was initiated. CT evaluation after 2 cycles of pemetrexed showed a partial response (−66%; Fig. 1).
1. Case
2. Discussion
A 43-year-old female with stage IV non-small cell lung cancer (NSCLC) of the right lower lobe and lymph node metastasis in the right upper neck was treated in first-line setting with carboplatin/paclitaxel/bevacizumab. Evaluation after 4 cycles showed a mixed response with regression of the intrathoracic lesion, but progression of the lymph node metastasis. Treatment was halted and the lymph node metastasis subsequently irradiated. The primary tumor was known to harbor a KRAS ‘G12V’ mutation. She
Rapid progression of cancer has been described previously in studies with BRAF inhibitors. For example, in melanoma proliferative skin lesions are a well-known phenomenon in patients treated with BRAF inhibitors such as vemurafenib. It has been suggested that vemurafenib does not initiate these lesions, but accelerates growth by paradoxal activation of MAPK signaling [3]. An illustrative case report described a stage IV melanoma patient who was treated with vemurafenib [4]. During treatment a previously unrecognized NRAS mutant chronic myelomonocytic leukemia (CMML) became clinically evident characterized by proliferation of a leukemic cell population with high ERK expression. Treatment with vemurafenib was interrupted showing decrease of leukemic cell count and a concomitant decrease of ERK expression. After restart of vemurafenib, the leukemic
∗ Corresponding author at: Department of Pulmonary Diseases, VU University Medical Center, PO Box 7057, 1007 MB Amsterdam, The Netherlands. Tel.: +31 020 444 4349; fax: +31 020 444 4328. E-mail address: [email protected] (Egbert.F. Smit). http://dx.doi.org/10.1016/j.lungcan.2014.11.014 0169-5002/© 2014 Elsevier Ireland Ltd. All rights reserved.
Please cite this article in press as: Mellema WW, et al. Tumor flare after start of RAF inhibition in KRAS mutated NSCLC: A case report. Lung Cancer (2014), http://dx.doi.org/10.1016/j.lungcan.2014.11.014
G Model LUNG-4735; No. of Pages 3 2
ARTICLE IN PRESS W.W. Mellema et al. / Lung Cancer xxx (2014) xxx–xxx
Fig. 1. (A) A graph of tumor volume of the intrathoracic lesion followed in time (weeks). Black dots () represent tumor measurement assessed by CT scan. (B) CT scan images of the intrathoracic lesion followed in time.
Fig. 2. A model of paradoxal activation of the MAPK pathway. Sorafenib induces activation of RAF by inhibition of its auto-inhibitory state. This results in increased stimulation of the MAPK signaling pathway and induces accelerated tumor growth.
cell count rapidly increased. Fig. 2 illustrates a possible mechanism by which sorafenib induces activation of the MAPK pathway. Under physiological conditions, wild-type RAF protein exists in an auto-inhibitory state [5]. Inhibition of RAF leads to its activation and can promote tumor progression in KRAS mutated cells and models. To our knowledge, we are the first to report possible tumor flare after treatment of KRAS mutated NSCLC with sorafenib. We believe
that paradoxal activation of a growth signaling pathway may drive this rapid progression based on previous reports in other malignancies treated with RAF inhibitors. Clinicians treating KRAS mutated (NSCLC) patients with RAF inhibitors should be aware of this phenomenon and treating patients with novel treatments or treatment with agents available for other diseases outside the context of a clinical trial should be avoided due to the potential of unforeseen adverse events.
Please cite this article in press as: Mellema WW, et al. Tumor flare after start of RAF inhibition in KRAS mutated NSCLC: A case report. Lung Cancer (2014), http://dx.doi.org/10.1016/j.lungcan.2014.11.014
G Model LUNG-4735; No. of Pages 3
ARTICLE IN PRESS W.W. Mellema et al. / Lung Cancer xxx (2014) xxx–xxx
Conflict of interest statement All authors state they have no financial supports or conflict of interest. References [1] Dingemans AC, Mellema WW, Groen HJM, van Wijk A, Burgers SA, Kunst PW, et al. A phase II study of sorafenib in patients with platinum-pretreated, advanced (Stage IIIb or IV) non-small cell lung cancer with a KRAS mutation. Clin Cancer Res 2013;19(February (3)):743–51.
3
[2] Mellema WW, Burgers SA, Groen HJM, Dingemans AC, Thunnissen E, Heideman DAM, et al. Sorafenib and metformin in pretreated patients with stage IV nonsmall cell lung cancer with a KRAS mutation: a multicenter single arm phase II study. J Clin Oncol 2014;32 (suppl; abstr e19015). [3] Su F, Viros A, Milagre C, Trunzer K, Bollag G, Spleiss O, et al. RAS mutations in cutaneous squamous-cell carcinomas in patients treated with BRAF inhibitors. N Engl J Med 2012;366(January (3)):207–15. [4] Callahan MK, Rampal R, Harding JJ, Klimek VM, Chung YR, Merghoub T, et al. Progression of RAS-mutant leukemia during RAF inhibitor treatment. N Engl J Med 2012;367(December (24)):2316–21. [5] Holderfield M, Merritt H, Chan J, Wallroth M, Tandeske L, Zhai H, et al. RAF inhibitors activate the MAPK pathway by relieving inhibitory autophosphorylation. Cancer Cell 2013;23(May (5)):594–602.
Please cite this article in press as: Mellema WW, et al. Tumor flare after start of RAF inhibition in KRAS mutated NSCLC: A case report. Lung Cancer (2014), http://dx.doi.org/10.1016/j.lungcan.2014.11.014