Initial presentation

• The 58-year-old female was diagnosed in October 2009 with multifocal primary GBM;6 three lesions were initially identified: right frontal lesion, subcortical left basal frontal area lesion, left inferior frontal gyrus lesion

Continuation of afatinib treatment within the 1200.36 clinical trial (Mar 2015–Jan 2016)

• TMZ was discontinued in March 2015 after a total of 63 cycles, due to a lack of evidence to support maintenance TMZ treatment for periods longer than the standard of care, 6 cycles

• The patient received afatinib monotherapy (20 mg/day) for a further 10 months (total of 74 cycles)

Afatinib discontinuation and characterisation of progressive disease (Jan–Mar 2016)

• In January 2016, afatinib was discontinued due to skin toxicity, and in March 2016, the patient developed progressive disease and withdrew from the clinical trial

• MRI performed on 23 March 2016, 2 months after afatinib discontinuation, showed evidence of a larger lesion in the right frontal lobe

– This was characterised by prolonged enhancement and a significant increase in signal in the T2 sequence, without evidence of significant mass effect (Figure 2)

– This lesion was not present on the previous examination, and was suggestive of a recurrent tumour with associated pseudo-progression

– No distant metastases or neurologic symptoms were evident at follow-up on 30 March 2016

Third-line treatment and afatinib re-initiation (Apr 2016–Feb 2017)

• In April 2016, the patient underwent surgical resection followed by adjuvant RT (35 Gy/10 fr) for 14 days

– Executive function declined significantly after this second surgery and worsened after RT

• In June 2016, afatinib monotherapy (30 mg/day) was resumed within a compassionate use program

• Between July 2016 and February 2017, MRIs showed controlled disease with radionecrosis (Figure 2)

Physical and cognitive decline (Feb–Jun 2017)

• By February 2017, the patient had extremely limited cognitive function and was almost bedridden

• She was hospitalised from early February until March 2017, due to seizures

• Afatinib was continued while the patient was admitted

– Last known afatinib dose (30 mg/day) was in March 2017, at the time of hospital discharge

• The last MRI, conducted in April 2017, showed neurologically asymptomatic pseudo-progression with evidence of a 4 mm lesion affecting the posterior aspect of the medulla, raising the possibility of a secondary tumour localisation

• The patient passed away in June 2017 due to progressive disease; she had survived for ~7.5 years since diagnosis

Scott Owen,1* Jad Alshami,1 Marie-Christine Guiot,1 Petr Kavan,1 Neil Gibson,2 Flavio Solca,3 Agnieszka Cseh,3

David A. Reardon,4 Thierry Muanza1,5

Afatinib in multifocal glioblastoma: a case of extended survival and follow-up

1Montreal Neurological Institute and Hospital, McGill University Health Center, Montreal, Canada; 2Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, Germany; 3Boehringer Ingelheim RCV GmbH & Co. KG, Vienna, Austria; 4Dana-Farber Cancer Institute, Boston, Massachusetts, USA; 5Jewish General Hospital, Montreal, Canada

#EPO2307

This study was funded by Boehringer Ingelheim. The authors were fully responsible for all content and editorial decisions, were involved at all stages of poster development and have approved the final version. Medical writing assistance, supported financially by Boehringer Ingelheim, was provided by Lucinda Sinclair MSc, of GeoMed, an Ashfield company, part of UDG Healthcare plc, during the development of this poster.

*Corresponding author email address: scott.owen@mcgill.ca

Key findings and conclusions

Scan the QR code for an electronic copy of the poster and supplementary content†

Background

References

• ErbB pathway dysregulation is believed to play a role in GBM, with mutation, rearrangement, altered splicing and/or focal amplification of the EGFR gene observed in up to 57% of GBM cases1

• In light of these observations, inhibition of the ErbB pathway has been investigated in GBM

– However, first-generation EGFR TKIs, gefitinib and erlotinib, had limited efficacy in patients with recurrent GBM2,3

• Afatinib is an ErbB family blocker that irreversibly binds and inhibits the activity of all ErbB family homo- and hetero-dimers4

• In a phase I/II study (1200.36), limited efficacy was seen with afatinib, in unselected patients with recurrent GBM, either alone or in combination with TMZ5

– However, progression-free survival was longer in patients with tumours that were highly immunoreactive for the EGFRvIII mutation than those with EGFRvIII-negative tumours (3.65 vs 1.05 months for afatinib + TMZ)

– Outcomes with afatinib were also modestly improved in patients with EGFR amplification and loss of PTEN

• One patient enrolled in the 1200.36 study experienced prolonged benefit from afatinib + TMZ therapy

• Her case has previously been described.6 Here, we present an update of over 2 years of additional follow-up

†These materials are for personal use only and may not be reproduced without written permission of the authors and the appropriate copyright permissions

• In the case report presented here, the patient showed a favourable and prolonged response to afatinib (overall survival was over 7.5 years from diagnosis)

• While afatinib was generally well tolerated, the patient eventually discontinued afatinib due to intolerable skin toxicity, and subsequently experienced progressive disease; this highlights the importance of proactively and effectively managing adverse events to enable patients to remain on therapy

• Next-generation sequencing identified alterations in a number of cancer-related genes, including mutations in, and amplification of, EGFR. Brain tumour samples from the primary and secondary surgical resections were largely genetically identical

• It is possible that the prolonged benefits associated with afatinib treatment observed in this patient are related to the presence of one or more EGFR mutations and/or amplification of EGFR in GBM cells

– The surgery and RT received prior to second-line afatinib may also have contributed to the prolonged disease-free period

• Taken together, these findings suggest that afatinib may be a promising treatment for patients with GBM that harbours ErbB family aberrations

http://tago.ca/A4G

Scan the QR code for an electronic copy of the poster and supplementary material

Case update Molecular analysis (cont’d)

1. Brennan CW, et al. Cell 2013;155:462–77; 2. Franceschi E, et al. Br J Cancer 2007;96:1047–51; 3. Brown PD, et al. J ClinOncol 2008;26:5603–9; 4. Solca F, et al. J Pharmacol Exp Ther 2012;343:342–50; 5. Reardon DA, et al. Neuro-Oncology 2015;17:430–9; 6. Alshami J, et al. OncoTarget 2015;6:34031–7; 7. Frampton GM, et al. Nat Biotech 2013;31:1023–31.

Case report overview

Molecular Analysis

• Next-generation sequencing, performed by Foundation Medicine,7 revealed alterations in 15 cancer-related genes in the primary tumour, including amplification of EGFR, and EGFRvIII rearrangement

• Brain tumour samples from the primary and secondary surgical resections (assessed April 2016) were largely genetically identical (Table 1)

– However, minor clones carrying the EGFR alleles EGFRvIII, P596L and G598V identified in the primary tumour were not detectable in tumour tissue from the secondary surgical resection

• Of note, fewer copies of the EGFR gene were likely to be present in the recurrent tumour compared with the primary tumour (20 vs 60)

• No additional alleles were detected in the sample from the secondary surgical resection that were considered to be clinically relevant; as such, no novel genetic alterations that could have led to acquired resistance to afatinib were detected

Table 1. Genetic profile of primary and recurrent tumours

† Variant of unknown significance; ‡ Allele not detected in recurrent tumour

GeneAllele in tumour obtained at

first diagnosis

Evidence in

primary tumour

Evidence in

recurrent tumour

EGFRAmplification of full gene, estimated gene copy number = 60

Amplification of full gene, estimated gene copy number = 20

EGFR Known Somatic Mutation P596L [c.1787C>T] 2% of 6153 reads c.1787C>T = 0.1% of 4067 reads ‡

EGFR Known Somatic Mutation G598V [c.1793G>T] 2% of 6108 reads c.1793G>T = 0.1% of 3788 reads ‡

EGFR Known Somatic Mutation EGFRvIII 5 supporting reads No evidence for EGFRvIII ‡

EGFR D247Y [c.739G>T] † 89% of 3206 reads c.739G>T = 90% of 1209 reads

PTEN Known Somatic mutation R130* [c.388C>T] 35% of 369 reads c.388C>T = 52% of 386 reads

CDKN2A (p16) Homozygous deletion of full gene Homozygous deletion of full gene

CDKN2B (p15) Homozygous deletion of full gene Homozygous deletion of full gene

BAP1 V447I [c.1339G>A] † 54% of 466 reads c.1339G>A = 45% of 185 reads

BCORL1 T1111M [c.3332C>T] † 44% of 325 reads c.3332C>T = 48% of 121 reads

CDH1 P30T [c.88C>A] † 46% of 296 reads c.88C>A = 38% of 50 reads

EPHA5 M987T [c.2960T>C] † 50% of 579 reads c.2960T>C 48% of 462 reads

ESR1 H6Y [c.16C>T] † 50% of 301 reads c.16C>T 43% of 130 reads

GRIN2A C800* [c.2400C>A] † 26% of 263 reads c.2400C>A 32% of 149 reads

MAP3K1 S939C [c.2816C>G] † 50% of 240 reads c.2816C>G 46% of 615 reads

NOTCH3 R1669H [c.5006G>A] † 19% of 409 reads c.5006G>A 15% of 79 reads

STAG2 Splice [c.2026-1G>C] † 32% of 457 reads c.2026-1G>C 34% of 210 reads

IKZF1Amplification of full gene, estimated gene copy number = 51

Amplification of full gene, estimated gene copy number = 20

Figure 1. Treatment overview

Presented at the 5th congress of the European Academy of Neurology (EAN), Oslo, Norway, June 29–July 2 2019

EGFR, epidermal growth factor receptor; GBM, glioblastoma, TKIs, tyrosine kinase inhibitors; TMZ, temozolomide

Tumour genetic alterations, including:• Multiple alterations to

EGFR including amplification, point mutations and EGFRvIIIgene rearrangement

• Methylated MGMTpromoter

Two dose reductions and two treatment interruptions due to Grade 3 AEs

Intermittent pauses (1–2 weeks) due to paronychia

MRI showed larger lesion in right frontal lobe

• Sequencing of brain tumour sample from secondary surgical resection

• Tumour samples from the primary and secondary surgical resections were largely genetically identical

Tumour progression after 9 months

Executive function declined significantly

Patient condition worsened after 14 days

Skin toxicity

Significant disease regression for 4.5 years

Progression after 3 TMZ cycles

Case update

March 2015

April 2010

October 2009

March 2016

January 2016

June 2016

June 2017

April 2016

Surgical resection

Patient diagnosed with multifocal GBM

First-line RT (60 Gy over 6 weeks) + TMZ (75 mg/m2/day for 42 days; adjuvant

TMZ 150–200 mg/m2 every 5/28 days)

Enrolled in a Phase I/II trial

Afatinib 20–40 mg/day + TMZ (50 mg/m2 every 21/28 days)

TMZ discontinued after 63 cycles

Afatinib monotherapy (20 mg/day)

Discontinued afatinib

Disease progression

Adjuvant RT (35 Gy/10 fr)

Surgical resection

Afatinib monotherapy (30 mg/day)

Death 7.5 years after diagnosis

AE, adverse event; MGMT, O6-methylguanine-DNA methyltransferase; RT, radiotherapy

Feb 2017

Controlled disease

Mar 2016

Disease progression

Jul 2016

Apr2017

Final assessment

Figure 2. Radiological assessment of disease progression from first to final assessment

Recurrence

Feb 2010

Preoperative

11 Oct 2009

16 Oct 2009

Postoperative

Afatinib in multifocal glioblastoma: a case of extended survival and follow-up

Scott Owen,1 Jad Alshami,1 Marie-Christine Guiot,1 Petr Kavan,1

Neil Gibson,2 Flavio Solca,3 Agnieszka Cseh,3 David A. Reardon,4

Thierry Muanza1,5

1Montreal Neurological Institute and Hospital, McGill University Health Center, Montreal, Canada; 2Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, Germany; 3Boehringer Ingelheim RCV GmbH & Co. KG, Vienna, Austria; 4Dana-Farber Cancer Institute, Boston,

Massachusetts, USA; 5Jewish General Hospital, Montreal, Canada

Presented at the 5th congress of the European Academy of Neurology (EAN), Oslo, Norway, June 29–July 2 2019

Background: targeting the ErbB pathway in GBM

• ErbB pathway dysregulation is believed to play a role in GBM, with mutation, rearrangement, altered splicing and/or focal amplification of the EGFR gene observed in up to 57% of GBM cases1

• In light of these observations, inhibition of the ErbB pathway has been investigated in GBM

– However, first-generation EGFR TKIs, gefitinib and erlotinib, had limited efficacy in patients with recurrent GBM2,3

EGFR, epidermal growth factor receptor; GBM, glioblastoma, TKIs, tyrosine kinase inhibitors

Background: afatinib in multifocal GBM

• Afatinib is an ErbB family blocker that irreversibly binds and inhibits the activity of all ErbB family homo- and hetero-dimers4

• In a phase I/II study (1200.36), limited efficacy was seen with afatinib, in unselected patients with recurrent GBM, either alone or in combination with TMZ5

– However, progression-free survival was longer in patients with tumours that were highly immunoreactive for the EGFRvIII mutation than those with EGFRvIII-negative tumours (3.65 vs 1.05 months for afatinib + TMZ)

– Outcomes with afatinib were also modestly improved in patients with EGFR amplification and loss of PTEN

• One patient enrolled in the 1200.36 study experienced prolonged benefit from afatinib + TMZ therapy

• Her case has previously been described.6 Here, we present an update of over 2 years of additional follow-up

TMZ, temozolomide

Initial presentation

• The 58-year-old female was diagnosed in October 2009 with multifocal primary GBM6

– three lesions were initially identified:

• right frontal lesion

• subcortical left basal frontal area lesion

• left inferior frontal gyrus lesion

Case overview

AE, adverse event; MGMT, O6-methylguanine-DNA methyltransferase; RT, radiotherapy

Case update: continuation of afatinib treatment within the 1200.36 clinical trial (Mar 2015–Jan 2016)

• TMZ was discontinued in March 2015 after a total of 63 cycles, due to a lack of evidence to support maintenance TMZ treatment for periods longer than the standard of care, 6 cycles

• The patient received afatinib monotherapy (20 mg/day) for a further 10 months (total of 74 cycles)

Case update: afatinib discontinuation and characterisation of progressive disease (Jan–Mar 2016)

• In January 2016, afatinib was discontinued due to skin toxicity, and in March 2016, the patient developed progressive disease and withdrew from the clinical trial

• MRI performed on 23 March 2016, 2 months after afatinib discontinuation, showed evidence of a larger lesion in the right frontal lobe

– This was characterised by prolonged enhancement and a significant increase in signal in the T2 sequence, without evidence of significant mass effect

– This lesion was not present on the previous examination, and was suggestive of a recurrent tumour with associated pseudo-progression

– No distant metastases or neurologic symptoms were evident at follow-up on 30 March 2016

Case update: third-line treatment and afatinib re-initiation (Apr 2016–Feb 2017)

• In April 2016, the patient underwent surgical resection followed by adjuvant RT (35 Gy/10 fr) for 14 days

– Executive function declined significantly after this second surgery and worsened after RT

• In June 2016, afatinib monotherapy (30 mg/day) was resumed within a compassionate use program

• Between July 2016 and February 2017, MRIs showed controlled disease with radionecrosis

Case update: physical and cognitive decline (Feb–Jun 2017)

• By February 2017, the patient had extremely limited cognitive function and was almost bedridden

• She was hospitalised from early February until March 2017, due to seizures

• Afatinib was continued while the patient was admitted

– Last known afatinib dose (30 mg/day) was in March 2017, at the time of hospital discharge

• The last MRI, conducted in April 2017, showed neurologically asymptomatic pseudo-progression with evidence of a 4 mm lesion affecting the posterior aspect of the medulla, raising the possibility of a secondary tumour localisation

• The patient died in June 2017 due to progressive disease; she had survived for ~7.5 years since diagnosis

Case update: radiological assessment of disease progression from first to final assessment

Feb 2017

Controlled disease

Mar2016

Disease progression

Jul 2016

Apr2017

Final assessmentRecurrence

Feb 2010

Preoperative

11 Oct 2009

16 Oct 2009

Postoperative

Molecular analysis

• Next-generation sequencing, performed by Foundation Medicine,7 revealed alterations in 15 cancer-related genes in the primary tumour, including amplification of EGFR, and EGFRvIII rearrangement

• Brain tumour samples from the primary and secondary surgical resections (assessed April 2016) were largely genetically identical

– However, minor clones carrying the EGFR alleles EGFRvIII, P596L and G598Videntified in the primary tumour were not detectable in tumour tissue from the secondary surgical resection

• Of note, fewer copies of the EGFR gene were likely to be present in the recurrent tumour compared with the primary tumour (20 vs 60)

• No additional alleles were detected in the sample from the secondary surgical resection that were considered to be clinically relevant; as such, no novel genetic alterations that could have led to acquired resistance to afatinib were detected

Molecular analysis: genetic profile of primary and recurrent tumours

GeneAllele in tumour obtained at

first diagnosis

Evidence in

primary tumour

Evidence in

recurrent tumour

EGFR Amplification of full gene, estimated gene copy number = 60 Amplification of full gene, estimated gene copy number = 20

EGFR Known Somatic Mutation P596L [c.1787C>T] 2% of 6153 reads c.1787C>T = 0.1% of 4067 reads ‡

EGFR Known Somatic Mutation G598V [c.1793G>T] 2% of 6108 reads c.1793G>T = 0.1% of 3788 reads ‡

EGFR Known Somatic Mutation EGFRvIII 5 supporting reads No evidence for EGFRvIII ‡

EGFR D247Y [c.739G>T] † 89% of 3206 reads c.739G>T = 90% of 1209 reads

PTEN Known Somatic mutation R130* [c.388C>T] 35% of 369 reads c.388C>T = 52% of 386 reads

CDKN2A (p16) Homozygous deletion of full gene Homozygous deletion of full gene

CDKN2B (p15) Homozygous deletion of full gene Homozygous deletion of full gene

BAP1 V447I [c.1339G>A] † 54% of 466 reads c.1339G>A = 45% of 185 reads

BCORL1 T1111M [c.3332C>T] † 44% of 325 reads c.3332C>T = 48% of 121 reads

CDH1 P30T [c.88C>A] † 46% of 296 reads c.88C>A = 38% of 50 reads

EPHA5 M987T [c.2960T>C] † 50% of 579 reads c.2960T>C 48% of 462 reads

ESR1 H6Y [c.16C>T] † 50% of 301 reads c.16C>T 43% of 130 reads

GRIN2A C800* [c.2400C>A] † 26% of 263 reads c.2400C>A 32% of 149 reads

MAP3K1 S939C [c.2816C>G] † 50% of 240 reads c.2816C>G 46% of 615 reads

NOTCH3 R1669H [c.5006G>A] † 19% of 409 reads c.5006G>A 15% of 79 reads

STAG2 Splice [c.2026-1G>C] † 32% of 457 reads c.2026-1G>C 34% of 210 reads

IKZF1 Amplification of full gene, estimated gene copy number = 51 Amplification of full gene, estimated gene copy number = 20

†Variant of unknown significance; ‡Allele not detected in recurrent tumour

Key findings and conclusions

• In the case report presented here, the patient showed a favourable and prolonged response to afatinib (overall survival was over 7.5 years from diagnosis)

• While afatinib was generally well tolerated, the patient eventually discontinued afatinib due to intolerable skin toxicity, and subsequently experienced progressive disease; this highlights the importance of proactively and effectively managing adverse events to enable patients to remain on therapy

• Next-generation sequencing identified alterations in a number of cancer-related genes, including mutations in, and amplification of, EGFR. Brain tumour samples from the primary and secondary surgical resections were largely genetically identical

• It is possible that the prolonged benefits associated with afatinib treatment observed in this patient are related to the presence of one or more EGFRmutations and/or amplification of EGFR in GBM cells

– The surgery and RT received prior to second-line afatinib may also have contributed to the prolonged disease-free period

• Taken together, these findings suggest that afatinib may be a promising treatment for patients with GBM that harbours ErbB family aberrations

References

1. Brennan CW, et al. Cell 2013;155:462–77; 2. Franceschi E, et al. Br J Cancer 2007;96:1047–51; 3. Brown PD, et al. J Clin Oncol 2008;26:5603–9; 4. Solca F, et al. J Pharmacol Exp Ther 2012;343:342–50; 5. Reardon DA, et al. Neuro-Oncology 2015;17:430–9; 6. Alshami J, et al. OncoTarget 2015;6:34031–7; 7. Frampton GM, et al. Nat Biotech 2013;31:1023–31.

Acknowledgments

• This study is funded by Boehringer Ingelheim. The authors were fully responsible for all content and editorial decisions, were involved at all stages of poster development and have approved the final version

• Medical writing assistance, supported financially by Boehringer Ingelheim, was provided by by Lucinda Sinclair MSc, of GeoMed, an Ashfield company, part of UDG Healthcare plc, during the development of this poster

• These materials are for personal use only and may not be reproduced without written permission of the authors and the appropriate copyright permissions