- Email: [email protected]
Monitoring reversible and irreversible EGFR inhibition with erlotinib and afatinib in a patient with EGFR-mutated non-small cell lung cancer (NSCLC) using sequential [18F]fluorothymidine (FLT-)PET
Lung Cancer 77 (2012) 617–620
Contents lists available at SciVerse ScienceDirect
Lung Cancer journal homepage: www.elsevier.com/locate/lungcan
Case report
Monitoring reversible and irreversible EGFR inhibition with erlotinib and afatinib in a patient with EGFR-mutated non-small cell lung cancer (NSCLC) using sequential [18 F]fluorothymidine (FLT-)PET Matthias Scheffler a,b,∗ , Carsten Kobe b,c , Thomas Zander a,b , Lucia Nogova a,b , Deniz Kahraman b,c , Roman Thomas a,b,d , Bernd Neumaier d , Markus Dietlein b,c , Jürgen Wolf a,b a
Department I for Internal Medicine, University Hospital of Cologne, Germany Center for Integrated Oncology Köln Bonn, Germany c Clinic for Nuclear Medicine, University Hospital of Cologne, Germany d Max-Planck Institute for Neurological Research, Cologne, Germany b
a r t i c l e
i n f o
Article history: Received 19 April 2012 Received in revised form 22 May 2012 Accepted 27 May 2012 Keywords: EGFR mutation Treatment monitoring FLT-PET Targeted therapy
a b s t r a c t Non-small cell lung cancer (NSCLC) patients with activating epidermal growth factor receptor (EGFR) mutations benefit from treatment with EGFR-targeted therapy. While first-generation (“reversible”) EGFR tyrosine kinase inhibitors (TKIs) are well established in the treatment of these patients, the remarkably lower efficacy of second-generation (“irreversible”) EGFR-TKIs after failure of reversible EGFR inhibition is far less understood. Here we describe an EGFR-mutated patient treated sequentially with both reversible (erlotinib) and irreversible (afatinib) EGFR-TKIs monitored by sequential [18 F]fluorothymidine (FLT-)PET. Our observations confirm the value of molecular imaging for assessment of pharmacodynamics and early prediction of response and relapse in these patients. © 2012 Elsevier Ireland Ltd. All rights reserved.
1. Case report A 66-year-old female patient without smoking history or remarkable preexisting illness presented in January 2009 with cerebral ischemia on the stroke unit. MRI scan of the brain revealed numerous older and newer ischemic areas, and a CT scan of the chest showed pulmonary tumors, mediastinal lymph node enlargement, and osteolytic lesions in the spine. Transbronchial biopsy led to the diagnosis NSCLC with adenocarcinoma histology. While no sensitizing EGFR mutation could be detected with dideoxy (sensitivity: 20–30% mutated alleles) and pyrosequencing (sensitivity: 5–10% mutant alleles), exon 19 E746 A750del [Del-1b] was detected using massively parallel sequencing (the sample had 60% tumor content with 6% mutant allele). The cerebral ischemias were considered paraneoplastic. Treatment with enoxaparin and salycyclic acid was initiated, and the patient subsequently was enrolled into a clinical trial evaluating the use of early FDG- and FLT-PET for prediction of nonprogression in NSCLC patients treated first-line
∗ Corresponding author at: Department I for Internal Medicine, Center for Integrated Oncology Köln Bonn, University Hospital of Cologne, 50924 Cologne, Germany. Tel.: +49 221 478 89712; fax: +49 221 478 87010. E-mail address: matthias.scheffl[email protected] (M. Scheffler). 0169-5002/$ – see front matter © 2012 Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.lungcan.2012.05.110
with erlotinib [1]. Erlotinib treatment started in February 2009, with an initial dose of 150 mg/d. After one week of therapy, FLT maximum standardized uptake value (SUVmax ) of the most active tumor manifestation in PET assessment decreased dramatically, with a reduction of 60%. After six weeks of therapy, SUVmax further decreased, leading to a total reduction of 74% (Fig. 1 A: reductions in SUVmax in weeks 2 and 7 compared with baseline during initial erlotinib treatment). A CT scan confirmed a partial response (PR). The patient continued with erlotinib treatment, but the dosage had to be reduced stepwise during the following months to 25 mg/d due to adverse reactions (limb weakness, loss of appetite, paronychia). Eventually, the patient insisted on a treatment interruption in March 2010. At this time the CT scans confirmed the initial response. Sequential FLT-PET (which due to the drastic initial SUV decrease was considered to be more specific than FDG-PET) and CT scans were performed to monitor disease activity without therapy. From March 2010 to June 2010, there was a constant stable disease state in CT scans. However, in FLT-PET SUVmax , which already had shown a relative increase directly before treatment interruption (Fig. 1A: week 53), further increased and finally exceeded baseline values (Fig. 1 A: changes in SUVmax during therapy pause in weeks 59 and 66). In addition, the patient again suffered from transient ischemic attacks (TIA). These neurological symptoms were quite similar to the situation during first diagnosis of her lung
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M. Scheffler et al. / Lung Cancer 77 (2012) 617–620
Fig. 1. (A) Changes in SUVmax compared with baseline (%). Red bars: erlotinib treatment/gray bars: therapy pause. (B) Changes in SUVmax compared with baseline (%) under afatinib treatment in two lesions (lesion #1 and lesion #2). (For interpretation of the references to color in this figure legend, the reader is referred to the web version of the article.)
cancer and were interpreted to be of paraneoplastic origin. Thus, even though CT still confirmed the initial PR, we decided to restart with therapy and readministered erlotinib with 150 mg/d. In FLTPET SUVmax rose about 42% from June 2010 to July 2010, and a resistance to erlotinib was supposed (Fig. 1A: increase in SUVmax during retreatment with erlotinib in week 72). Unfortunately, rebiopsy could not be performed because of the anatomical localization of the active lesion. A change of therapy was proposed, but the patient strictly rejected chemotherapy. Therefore, therapy with the irreversible EGFR-inhibitor afatinib (BIBW2992), 50 mg/d, was started within a compassionate use program on August 10th, 2010, 14 days after demonstrating the SUV increase under erlotinib therapy and the discontinuation of erlotinib on July 26th, 2010. The FDG values from the last scan prior to afatinib start were considered the new baseline values for afatinib treatment. FLT-PET was performed after one week of therapy with afatinib, and again, a reduction in SUVmax in the most active tumor lesion of 37% could be detected (Fig. 1B: lesion #1, week 2, Fig. 2A: before afatinib, B: after 1 week of afatinib), as well as reductions in less active lesions, as shown here exemplarily for lesion 2 (Fig. 1B; lesion #2, week 2; Fig. 2D: before afatinib, E: after 1 week of afatinib). In parallel the neurological symptoms of the patient notably improved afterwards. The dosage of afatinib nevertheless had to be reduced stepwise to 30 mg/d due to diarrhea.
After 6 weeks of afatinib treatment, FLT-PET and CT was performed in September 2010. While CT confirmed the still ongoing response according to RECIST [2], in FLT-PET the initial responding most active lesion #1 showed an increase of 43% compared to week 2 (Fig. 1B; lesion #1, week 7; Fig. 2C). By comparison, lesion 2 showed an even more pronounced decrease in SUVmax compared to week 2 (Fig. 1B; lesion #2, week 7; Fig. 2F). Taken together, there was a mixed response in FLT-PET after six weeks of afatinib treatment, with one lesion progressing, another still showing a continuing response. During these six weeks, the patient’s performance state decreased and afatinib treatment had to be interrupted. After discontinuation of afatinib treatment, again paraneoplastic cerebral ischemia occurred, in addition the patient developed seizures and, finally, died in November 2010. Fig. 3. 2. Discussion The presented case-report exemplifies several aspects of visualizing EGFR-TKI effects in EGFR-mutated NSCLC by PET analysis. First, to our knowledge this is the first report demonstrating visualization of afatinib-induced G1 cell cycle arrest in NSCLC resistant to initial EGFR-TKI treatment by FLT-PET. We have shown previously in a murine xenotransplant model that early FLT-PET
M. Scheffler et al. / Lung Cancer 77 (2012) 617–620
619
Fig. 2. Lesion #1 (A–C) and lesion #2 (D–F) in FLT-PET scans during afatinib treatment. Scans were performed at baseline (A, D), after one week of afatinib treatment (B, E) and after six weeks of treatment (C, F).
Fig. 3. Course of the treatment and the changes in SUVmax compared with baseline. *This value was used as baseline value for the afatinib treatment period. All values refer to lesion #1.
can act as an imaging biomarker of proliferation stop induced by erlotinib treatment in NSCLC cells carrying activating EGFR mutations [3]. Furthermore, we have shown recently that a SUVmax decrease of >30% in FLT-PET activity already after one week of erlotinib treatment of NSCLC patients predicts PFS. This early predictive value of FLT-PET is also apparent in the patient presented. In addition, here FLT-PET also allowed to monitor continuing response, early relapse and, finally, resistance after reinduction with erlotinib. The SUVmax decrease of >30% in our patient as early as after 1 week of onset of afatinib treatment indicates an early pharmacodynamic effect of afatinib at a dose level of 50 mg/d. Although the irreversible EGFR-TKI afatinib can overcome acquired resistance to reversible EGFR-TKIs in preclinical settings [4], the overall response rate in this clinical situation is only 8% [5]. Thus, the question raises, whether the high rate of non-responders is due to resistance on a molecular level, or due to inadequate serum concentrations of afatinib [6]. Our observation suggests that FLT-PET might serve as pharmacodynamic tool for demonstrating proliferation stop and thus sufficient in vivo concentrations of afatinib. To which extent this early pharmacodynamic effect correlates with a predictive value with regard to duration of response remains to be elucidated in a prospective clinical trial. Unfortunately, in
our patient FLT-PET after six weeks of afatinib treatment showed increasing SUVmax of the lesion of interest, whereas other manifestations continued to decrease in their activities. While the increase of the SUVmax of the most active lesion alone might have been explained by dose reduction, as afatinib pharmacokinetics behave dose-proportionally [7], this does not explain the “mixed response” and the further decrease of SUVmax in other manifestations. This situation illustrates, that rebiopsy of distinct metastases in relapse for genetic analysis of resistance does not necessarily capture the whole situation and that molecular imaging might contribute important information concerning the heterogeneity of metastases. Moreover, molecular analysis suffers from well-known problems [8]. In the present case, the initial detection of the sensitizing EGFR mutation took several weeks and was only successful by use of massive parallel sequencing. In addition, rebiopsy after progression had a questionable risk-benefit ratio, due to the anatomical localization of the lesions. Here, the course of the treatment was monitored by FLT-PETs, and the resistance was non-invasively assessed by the lack of decrease in SUVmax and, even more, an increase of activity under erlotinib therapy, in contrast to the initial findings. This was also strongly correlated with clinical findings, as were the sequential PETs during the whole course of therapy with erlotinib and afatinib. Further investigations are required to
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M. Scheffler et al. / Lung Cancer 77 (2012) 617–620
validate the use of molecular imaging markers in cases where molecular analyses are not feasible, and how these markers could add to these analyses. Taken together, this case report suggests that FLT-PET is a suitable tool for early pharmacodynamic assessment as well as for therapy monitoring of both reversible and irreversible EGFRinhibition with erlotinib and afatinib. Of special interest, FLT-PET allowed visualization of an initial antitumor activity of afatinib in tumors resistant to erlotinib and heterogeneity of progress under afatinib treatment. Further investigation is needed to evaluate the use of molecular imaging markers as well as the molecular basis of afatinib-responsiveness and erlotinib-resistance regarding both pharmacokinetic and pharmacodynamic issues.
[2]
[3]
[4]
[5]
Conflict of interest statement [6]
Roles in advisory boards: TZ, RT, JW: Roche and Boehringer Ingelheim, MS: Boehringer Ingelheim, and LN: Roche. The other authors do not have conflicts of interest to declare. References [1] Zander T, Scheffler M, Nogova L, Kobe C, Engel-Riedel W, Hellmich M, et al. Early prediction of nonprogression in advanced non-small-cell lung cancer treated
[7]
[8]
with erlotinib by using [18 F]fluorodeoxyglucose and [18 F]fluorothymidine positron emission tomography. J Clin Oncol 2011;29(13):1701–8. Therasse P, Arbuck SG, Eisenhauer EA, Wanders J, Kaplan RS, Rubinstein L, et al. New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst 2000;92(3):205–16. Ullrich RT, Zander T, Neumaier B, Koker M, Shimamura T, Waerzeggers Y, et al. Early detection of erlotinib treatment response in NSCLC by 3 -deoxy-3 [F]-fluoro-l-thymidine ([F]FLT) positron emission tomography (PET). PLoS One 2008;3(12):e3908. PMCID: 2592703. Li D, Ambrogio L, Shimamura T, Kubo S, Takahashi M, Chirieac LR, et al. BIBW2992, an irreversible EGFR/HER2 inhibitor highly effective in preclinical lung cancer models. Oncogene 2008;27(34):4702–11. PMCID: 2748240. Miller V. Phase IIb/III double-blind randomized trial of BIBW 2992, an irreversible inhibitor of EGFR/HER1 and HER2, +best supportive care (BSC) versus placebo + BSC in patients with NSCLC failing 1–2 lines of chemotherapy and erlotinib or gefitinib (LUX-Lung 1). In: The European Society of Medical Oncology (ESMO) annual meeting. 2010. Sos ML, Rode HB, Heynck S, Peifer M, Fischer F, Kluter S, et al. Chemogenomic profiling provides insights into the limited activity of irreversible EGFR Inhibitors in tumor cells expressing the T790M EGFR resistance mutation. Cancer Res 2010;70(3):868–74. Yap TA, Vidal L, Adam J, Stephens P, Spicer J, Shaw H, et al. Phase I trial of the irreversible EGFR and HER2 kinase inhibitor BIBW 2992 in patients with advanced solid tumors. J Clin Oncol 2010;28(25):3965–72. Querings S, Altmuller J, Ansen S, Zander T, Seidel D, Gabler F, et al. Benchmarking of mutation diagnostics in clinical lung cancer specimens. PLoS One 2011;6(5):e19601. PMCID: 3088700.
Contents lists available at SciVerse ScienceDirect
Lung Cancer journal homepage: www.elsevier.com/locate/lungcan
Case report
Monitoring reversible and irreversible EGFR inhibition with erlotinib and afatinib in a patient with EGFR-mutated non-small cell lung cancer (NSCLC) using sequential [18 F]fluorothymidine (FLT-)PET Matthias Scheffler a,b,∗ , Carsten Kobe b,c , Thomas Zander a,b , Lucia Nogova a,b , Deniz Kahraman b,c , Roman Thomas a,b,d , Bernd Neumaier d , Markus Dietlein b,c , Jürgen Wolf a,b a
Department I for Internal Medicine, University Hospital of Cologne, Germany Center for Integrated Oncology Köln Bonn, Germany c Clinic for Nuclear Medicine, University Hospital of Cologne, Germany d Max-Planck Institute for Neurological Research, Cologne, Germany b
a r t i c l e
i n f o
Article history: Received 19 April 2012 Received in revised form 22 May 2012 Accepted 27 May 2012 Keywords: EGFR mutation Treatment monitoring FLT-PET Targeted therapy
a b s t r a c t Non-small cell lung cancer (NSCLC) patients with activating epidermal growth factor receptor (EGFR) mutations benefit from treatment with EGFR-targeted therapy. While first-generation (“reversible”) EGFR tyrosine kinase inhibitors (TKIs) are well established in the treatment of these patients, the remarkably lower efficacy of second-generation (“irreversible”) EGFR-TKIs after failure of reversible EGFR inhibition is far less understood. Here we describe an EGFR-mutated patient treated sequentially with both reversible (erlotinib) and irreversible (afatinib) EGFR-TKIs monitored by sequential [18 F]fluorothymidine (FLT-)PET. Our observations confirm the value of molecular imaging for assessment of pharmacodynamics and early prediction of response and relapse in these patients. © 2012 Elsevier Ireland Ltd. All rights reserved.
1. Case report A 66-year-old female patient without smoking history or remarkable preexisting illness presented in January 2009 with cerebral ischemia on the stroke unit. MRI scan of the brain revealed numerous older and newer ischemic areas, and a CT scan of the chest showed pulmonary tumors, mediastinal lymph node enlargement, and osteolytic lesions in the spine. Transbronchial biopsy led to the diagnosis NSCLC with adenocarcinoma histology. While no sensitizing EGFR mutation could be detected with dideoxy (sensitivity: 20–30% mutated alleles) and pyrosequencing (sensitivity: 5–10% mutant alleles), exon 19 E746 A750del [Del-1b] was detected using massively parallel sequencing (the sample had 60% tumor content with 6% mutant allele). The cerebral ischemias were considered paraneoplastic. Treatment with enoxaparin and salycyclic acid was initiated, and the patient subsequently was enrolled into a clinical trial evaluating the use of early FDG- and FLT-PET for prediction of nonprogression in NSCLC patients treated first-line
∗ Corresponding author at: Department I for Internal Medicine, Center for Integrated Oncology Köln Bonn, University Hospital of Cologne, 50924 Cologne, Germany. Tel.: +49 221 478 89712; fax: +49 221 478 87010. E-mail address: matthias.scheffl[email protected] (M. Scheffler). 0169-5002/$ – see front matter © 2012 Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.lungcan.2012.05.110
with erlotinib [1]. Erlotinib treatment started in February 2009, with an initial dose of 150 mg/d. After one week of therapy, FLT maximum standardized uptake value (SUVmax ) of the most active tumor manifestation in PET assessment decreased dramatically, with a reduction of 60%. After six weeks of therapy, SUVmax further decreased, leading to a total reduction of 74% (Fig. 1 A: reductions in SUVmax in weeks 2 and 7 compared with baseline during initial erlotinib treatment). A CT scan confirmed a partial response (PR). The patient continued with erlotinib treatment, but the dosage had to be reduced stepwise during the following months to 25 mg/d due to adverse reactions (limb weakness, loss of appetite, paronychia). Eventually, the patient insisted on a treatment interruption in March 2010. At this time the CT scans confirmed the initial response. Sequential FLT-PET (which due to the drastic initial SUV decrease was considered to be more specific than FDG-PET) and CT scans were performed to monitor disease activity without therapy. From March 2010 to June 2010, there was a constant stable disease state in CT scans. However, in FLT-PET SUVmax , which already had shown a relative increase directly before treatment interruption (Fig. 1A: week 53), further increased and finally exceeded baseline values (Fig. 1 A: changes in SUVmax during therapy pause in weeks 59 and 66). In addition, the patient again suffered from transient ischemic attacks (TIA). These neurological symptoms were quite similar to the situation during first diagnosis of her lung
618
M. Scheffler et al. / Lung Cancer 77 (2012) 617–620
Fig. 1. (A) Changes in SUVmax compared with baseline (%). Red bars: erlotinib treatment/gray bars: therapy pause. (B) Changes in SUVmax compared with baseline (%) under afatinib treatment in two lesions (lesion #1 and lesion #2). (For interpretation of the references to color in this figure legend, the reader is referred to the web version of the article.)
cancer and were interpreted to be of paraneoplastic origin. Thus, even though CT still confirmed the initial PR, we decided to restart with therapy and readministered erlotinib with 150 mg/d. In FLTPET SUVmax rose about 42% from June 2010 to July 2010, and a resistance to erlotinib was supposed (Fig. 1A: increase in SUVmax during retreatment with erlotinib in week 72). Unfortunately, rebiopsy could not be performed because of the anatomical localization of the active lesion. A change of therapy was proposed, but the patient strictly rejected chemotherapy. Therefore, therapy with the irreversible EGFR-inhibitor afatinib (BIBW2992), 50 mg/d, was started within a compassionate use program on August 10th, 2010, 14 days after demonstrating the SUV increase under erlotinib therapy and the discontinuation of erlotinib on July 26th, 2010. The FDG values from the last scan prior to afatinib start were considered the new baseline values for afatinib treatment. FLT-PET was performed after one week of therapy with afatinib, and again, a reduction in SUVmax in the most active tumor lesion of 37% could be detected (Fig. 1B: lesion #1, week 2, Fig. 2A: before afatinib, B: after 1 week of afatinib), as well as reductions in less active lesions, as shown here exemplarily for lesion 2 (Fig. 1B; lesion #2, week 2; Fig. 2D: before afatinib, E: after 1 week of afatinib). In parallel the neurological symptoms of the patient notably improved afterwards. The dosage of afatinib nevertheless had to be reduced stepwise to 30 mg/d due to diarrhea.
After 6 weeks of afatinib treatment, FLT-PET and CT was performed in September 2010. While CT confirmed the still ongoing response according to RECIST [2], in FLT-PET the initial responding most active lesion #1 showed an increase of 43% compared to week 2 (Fig. 1B; lesion #1, week 7; Fig. 2C). By comparison, lesion 2 showed an even more pronounced decrease in SUVmax compared to week 2 (Fig. 1B; lesion #2, week 7; Fig. 2F). Taken together, there was a mixed response in FLT-PET after six weeks of afatinib treatment, with one lesion progressing, another still showing a continuing response. During these six weeks, the patient’s performance state decreased and afatinib treatment had to be interrupted. After discontinuation of afatinib treatment, again paraneoplastic cerebral ischemia occurred, in addition the patient developed seizures and, finally, died in November 2010. Fig. 3. 2. Discussion The presented case-report exemplifies several aspects of visualizing EGFR-TKI effects in EGFR-mutated NSCLC by PET analysis. First, to our knowledge this is the first report demonstrating visualization of afatinib-induced G1 cell cycle arrest in NSCLC resistant to initial EGFR-TKI treatment by FLT-PET. We have shown previously in a murine xenotransplant model that early FLT-PET
M. Scheffler et al. / Lung Cancer 77 (2012) 617–620
619
Fig. 2. Lesion #1 (A–C) and lesion #2 (D–F) in FLT-PET scans during afatinib treatment. Scans were performed at baseline (A, D), after one week of afatinib treatment (B, E) and after six weeks of treatment (C, F).
Fig. 3. Course of the treatment and the changes in SUVmax compared with baseline. *This value was used as baseline value for the afatinib treatment period. All values refer to lesion #1.
can act as an imaging biomarker of proliferation stop induced by erlotinib treatment in NSCLC cells carrying activating EGFR mutations [3]. Furthermore, we have shown recently that a SUVmax decrease of >30% in FLT-PET activity already after one week of erlotinib treatment of NSCLC patients predicts PFS. This early predictive value of FLT-PET is also apparent in the patient presented. In addition, here FLT-PET also allowed to monitor continuing response, early relapse and, finally, resistance after reinduction with erlotinib. The SUVmax decrease of >30% in our patient as early as after 1 week of onset of afatinib treatment indicates an early pharmacodynamic effect of afatinib at a dose level of 50 mg/d. Although the irreversible EGFR-TKI afatinib can overcome acquired resistance to reversible EGFR-TKIs in preclinical settings [4], the overall response rate in this clinical situation is only 8% [5]. Thus, the question raises, whether the high rate of non-responders is due to resistance on a molecular level, or due to inadequate serum concentrations of afatinib [6]. Our observation suggests that FLT-PET might serve as pharmacodynamic tool for demonstrating proliferation stop and thus sufficient in vivo concentrations of afatinib. To which extent this early pharmacodynamic effect correlates with a predictive value with regard to duration of response remains to be elucidated in a prospective clinical trial. Unfortunately, in
our patient FLT-PET after six weeks of afatinib treatment showed increasing SUVmax of the lesion of interest, whereas other manifestations continued to decrease in their activities. While the increase of the SUVmax of the most active lesion alone might have been explained by dose reduction, as afatinib pharmacokinetics behave dose-proportionally [7], this does not explain the “mixed response” and the further decrease of SUVmax in other manifestations. This situation illustrates, that rebiopsy of distinct metastases in relapse for genetic analysis of resistance does not necessarily capture the whole situation and that molecular imaging might contribute important information concerning the heterogeneity of metastases. Moreover, molecular analysis suffers from well-known problems [8]. In the present case, the initial detection of the sensitizing EGFR mutation took several weeks and was only successful by use of massive parallel sequencing. In addition, rebiopsy after progression had a questionable risk-benefit ratio, due to the anatomical localization of the lesions. Here, the course of the treatment was monitored by FLT-PETs, and the resistance was non-invasively assessed by the lack of decrease in SUVmax and, even more, an increase of activity under erlotinib therapy, in contrast to the initial findings. This was also strongly correlated with clinical findings, as were the sequential PETs during the whole course of therapy with erlotinib and afatinib. Further investigations are required to
620
M. Scheffler et al. / Lung Cancer 77 (2012) 617–620
validate the use of molecular imaging markers in cases where molecular analyses are not feasible, and how these markers could add to these analyses. Taken together, this case report suggests that FLT-PET is a suitable tool for early pharmacodynamic assessment as well as for therapy monitoring of both reversible and irreversible EGFRinhibition with erlotinib and afatinib. Of special interest, FLT-PET allowed visualization of an initial antitumor activity of afatinib in tumors resistant to erlotinib and heterogeneity of progress under afatinib treatment. Further investigation is needed to evaluate the use of molecular imaging markers as well as the molecular basis of afatinib-responsiveness and erlotinib-resistance regarding both pharmacokinetic and pharmacodynamic issues.
[2]
[3]
[4]
[5]
Conflict of interest statement [6]
Roles in advisory boards: TZ, RT, JW: Roche and Boehringer Ingelheim, MS: Boehringer Ingelheim, and LN: Roche. The other authors do not have conflicts of interest to declare. References [1] Zander T, Scheffler M, Nogova L, Kobe C, Engel-Riedel W, Hellmich M, et al. Early prediction of nonprogression in advanced non-small-cell lung cancer treated
[7]
[8]
with erlotinib by using [18 F]fluorodeoxyglucose and [18 F]fluorothymidine positron emission tomography. J Clin Oncol 2011;29(13):1701–8. Therasse P, Arbuck SG, Eisenhauer EA, Wanders J, Kaplan RS, Rubinstein L, et al. New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst 2000;92(3):205–16. Ullrich RT, Zander T, Neumaier B, Koker M, Shimamura T, Waerzeggers Y, et al. Early detection of erlotinib treatment response in NSCLC by 3 -deoxy-3 [F]-fluoro-l-thymidine ([F]FLT) positron emission tomography (PET). PLoS One 2008;3(12):e3908. PMCID: 2592703. Li D, Ambrogio L, Shimamura T, Kubo S, Takahashi M, Chirieac LR, et al. BIBW2992, an irreversible EGFR/HER2 inhibitor highly effective in preclinical lung cancer models. Oncogene 2008;27(34):4702–11. PMCID: 2748240. Miller V. Phase IIb/III double-blind randomized trial of BIBW 2992, an irreversible inhibitor of EGFR/HER1 and HER2, +best supportive care (BSC) versus placebo + BSC in patients with NSCLC failing 1–2 lines of chemotherapy and erlotinib or gefitinib (LUX-Lung 1). In: The European Society of Medical Oncology (ESMO) annual meeting. 2010. Sos ML, Rode HB, Heynck S, Peifer M, Fischer F, Kluter S, et al. Chemogenomic profiling provides insights into the limited activity of irreversible EGFR Inhibitors in tumor cells expressing the T790M EGFR resistance mutation. Cancer Res 2010;70(3):868–74. Yap TA, Vidal L, Adam J, Stephens P, Spicer J, Shaw H, et al. Phase I trial of the irreversible EGFR and HER2 kinase inhibitor BIBW 2992 in patients with advanced solid tumors. J Clin Oncol 2010;28(25):3965–72. Querings S, Altmuller J, Ansen S, Zander T, Seidel D, Gabler F, et al. Benchmarking of mutation diagnostics in clinical lung cancer specimens. PLoS One 2011;6(5):e19601. PMCID: 3088700.