AZD9291, an Irreversible EGFR TKI, Overcomes T790M-Mediated Resistance to EGFR Inhibitors in Lung Cancer

May combine two claims.

AZ5104 had greater potency against ex19del (2 nM PC-9), T790M (2 nM H1975), and wild-type EGFR (33 nM LOVO).

“whilst AZ5104 harbored somewhat greater potency against ex19del (2 nM in PC-9), T790M (2 nM in H1975) and wild-type EGFR (33 nM in LOVO) cell lines.”

May combine two claims.

Afatinib and dacomitinib had much less activity against T790M lines and greater potency against wild-type EGFR.

“Again, this contrasted to second generation TKIs, afatinib and dacomitinib, which showed much less activity against T790M lines and were associated with much greater potency towards wild-type EGFR (Fig. 3A).”

Probably not a substantial claim: may not pass S3 (load-bearing).

AZD9291 is metabolized to at least two circulating metabolites, AZ5104 and AZ7550.

“Subsequent murine in vivo studies revealed that AZD9291 was metabolized to produce at least two circulating metabolite species, AZ5104 and AZ7550.”

May combine two claims.

In H3255, 5 mg/kg/day AZD9291 caused non-measurable tumors in all 8 mice by day 53, while only one gefitinib-treated mouse achieved this.

“Similar long term dosing studies were performed in the H3255 model, with 5 mg/kg/day AZD9291 causing non-measurable tumors in all 8 dosed mice by day 53. By contrast, only one mouse treated with 6.25 mg/kg gefitinib achieved non-measurable tumor status (Supplementary Fig. S6A).”

May combine two claims.

AZD9291 had good bioavailability, wide tissue distribution, moderate clearance, and ~3 h half-life after oral dosing in mice.

“AZD9291 demonstrated good bioavailability, was widely distributed in tissues, and had moderate clearance resulting in a half-life of around 3 hours after oral dosing in the mouse (Supplementary Fig. S5).”

May combine two claims.

AZD9291 had moderate potency against H1781 HER2 exon20 G776 VC insertion cells (IC50 80 nM) and was more effective than erlotinib.

“Compared to afatinib and AZ5104, AZD9291 exhibited moderate potency against H1781 cells, which harbor a VC insertion at G776 in exon 20 of HER2 (42), with an IC50 of 80 nM (Supplementary Fig. S4A). However, AZD9291 was more effective at inhibiting growth of these cells than erlotinib.”

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

Metabolites had similar half-lives; AZ7550 and AZ5104 total AUC were ~68% and 33% of parent.

“The circulating active metabolites in plasma each had a similar half-life, and the total exposure levels (AUC) were approximately 68 and 33% compared to the parent compound for AZ7550 and AZ5104, respectively (Supplementary Fig S5).”

Probably not a substantial claim: may not pass S3 (load-bearing).

H1650 cells retained higher phospho-AKT due to PTEN loss.

“although H1650 cells retained higher phospho-AKT levels due to loss of PTEN (38).”

• cites [38] Sos, 2009, PTEN loss contributes to erlotinib resistance in EGFR-mutant lung cancer by activation of Akt and EGFR., Cancer Res sourceNot checked yet

  Not checked in the free run.

May combine two claims.

AZD9291 is a novel oral, potent, selective, irreversible third-generation EGFR TKI that inhibits sensitizing and T790M mutant EGFR while sparing wild-type EGFR.

“AZD9291 is a novel oral, potent and selective third generation irreversible inhibitor of both EGFRm+ sensitizing and T790M resistance mutants that spares wild-type EGFR.”

Probably not a substantial claim: may not pass S3 (load-bearing).

AZ5104 was more potent than AZD9291 against phospho-HER2.

“However, consistent with its greater wild-type EGFR potency, the AZ5104 metabolite showed more potency than AZD9291 against phospho-HER2 (Supplementary Fig. S2A-C).”

May combine two claims.

Gefitinib 6.25 mg/kg/day caused less regression and tumors regrew after ~90 days.

“As a comparison, gefitinib at 6.25 mg/kg/day, a clinically representative dose, induced less tumor regression, and tumors began to re-grow after approximately 90 days.”

Probably not a substantial claim: may not pass S3 (load-bearing).

A single mouse with ex19del-driven tumor responded rapidly to AZD9291.

“Furthermore, preliminary data in a single mouse with tumor driven by an ex19del mutant alone (45) also responded rapidly to AZD9291 (Supplementary Fig. S7A).”

May combine two claims.

AZD9291 shows minimal off-target kinase activity across ~280 kinases, with only a few kinases inhibited >60% at 1 μM.

“AZD9291 showed minimal off-target kinase activity, with only a limited number of additional kinases showing greater than 60% inhibition at 1 μM and moderate IC50 potencies such as ErbB2/4, ACK1, ALK, BLK, BRK, MLK1 and MNK2 (Supplementary Table S1B).”

May combine two claims.

AZ5104 was more potent across cell lines in phenotypic assays, while AZ7550 was broadly similar.

“Consistent with phospho-EGFR data, the metabolite AZ5104 again demonstrated much greater potency across cell lines in a phenotypic assay, whereas AZ7550 was broadly similar, with the same overall profile maintained (Supplementary Table S1E).”

May combine two claims.

For EGFRvIII, AZD9291 had lower potency than afatinib and AZD8931, while AZ5104 had higher activity.

“For the EGFRvIII mutant, AZD9291 demonstrated lower potency compared to afatinib and AZD8931. AZ5104, however displayed a higher level of activity (Supplementary Figure S3C).”

May combine two claims.

In C/L858R mice, AZD9291 or afatinib caused ~80% tumor volume reduction in 5/5 by MRI, while vehicle-treated mice showed growth.

“Within days of treatment, 5 of 5 C/L858R mice displayed nearly 80% reduction in tumor volume by magnetic resonance imaging MRI (see Methods and (47)) after therapy with both afatinib or AZD9291, while 5 of 5 mice treated with vehicle showed tumor growth (Figs. 5A (top) and 5B).”

May combine two claims.

AZ5104 is more potent than AZD9291 against mutant and wild-type EGFR and has a smaller selectivity margin.

“In contrast, although AZ5104 exhibited the same overall profile, it was more potent against mutant and wild-type EGFR forms, thus demonstrating a smaller selectivity margin compared to parent (Supplementary Table S1A).”

May combine two claims.

In recombinant enzyme assays, AZD9291 had apparent IC50 of 12 nM for L858R and 1 nM for L858R/T790M.

“In EGFR recombinant enzyme assays (Millipore), AZD9291 showed an apparent IC50 of 12 nM against L858R and 1 nM against L858R/T790M; these are called apparent since the amount of active enzyme changes over time and thus IC50 is time-dependent for irreversible agents.”

May combine two claims.

Once-daily AZD9291 caused dose-dependent regression in PC-9 and H1975 xenografts, with shrinkage at 2.5 mg/kg/day after 14 days.

“Once daily dosing of AZD9291 induced significant dose-dependent regression in both PC-9 (ex19del) and H1975 (L858R/T790M) tumor xenograft models, with tumor shrinkage observed at doses as low as 2.5mg/kg/day in both models after 14 days (Fig. 4A, B).”

May combine two claims.

In H1975, 5 mg/kg/day AZD9291 produced complete responses in 10/12; 1 mg/kg/day regrowth after ~50 days; 25 mg/kg/day re-induced regression.

“In H1975 xenografts, 5 mg/kg/day AZD9291 resulted in complete responses in 10 of 12 tumors. Re-growth was observed after approximately 50 days treatment with 1 mg/kg/day, but an increased dose of 25 mg/kg/day AZD9291 re-induced tumor regression possibly suggesting re-growth was still driven by T790M EGFR.”

May combine two claims.

In Sytox assays, AZD9291 had high potency in sensitizing-mutant PC-9 (mean IC50 8 nM) and T790M H1975/PC-9VanR (11 and 40 nM) but much less in wild-type Calu3/H2073 (650 and 461 nM).

“In line with the phosphorylation data, AZD9291 showed high levels of phenotype potency in both sensitizing-mutant (mean IC50 of 8 nM in PC-9) and T790M (mean IC50 of 11 and 40 nM in H1975 and PC-9VanR respectively) EGFR cell lines, whilst having much less activity towards wild-type EGFR (mean IC50 of 650 and 461 nM in Calu3 and H2073 respectively) (Fig. 3A).”

May combine two claims.

All tested EGFR TKIs were effective against L861Q, G719S, and exon 19 insertion mutants, though AZD9291 was somewhat less potent than AZ5104.

“All EGFR TKIs were effective against EGFR L861Q (consistent with kinase profiling data (Table 1)), G719S, and the exon 19 insertion, although AZD9291 was somewhat less potent compared with the AZ5104 metabolite against these mutant EGFR forms (Supplementary Figure S3A).”

May combine two claims.

In C/L+T mice, only AZD9291 caused significant tumor shrinkage; vehicle and afatinib groups had viable tumor.

“By contrast, in C/L+T animals, only AZD9291 treatment induced significant tumor shrinkage (Figs. 5A (middle&bottom) and 5C), while both vehicle- and afatinib-treated mice showed viable tumor (Fig. 5C).”

May combine two claims.

Chronic gefitinib or afatinib treatment commonly caused acquired T790M resistance in PC-9 cells, whereas acquired T790M resistance to AZD9291 was not observed.

“Indeed, whilst chronic treatment with gefitinib or afatinib commonly caused acquired resistance in PC-9 cells in vitro through gain of T790M, acquired resistance to AZD9291 through T790M was not observed (Fig. 3C).”

May combine two claims.

AZ7550 has potency and selectivity similar to AZD9291.

“In biochemical assays, AZ7550 had a comparable potency and selectivity profile to the parent (Supplementary Table S1A).”

May combine two claims.

AZD9291 inhibited EGFR phosphorylation in sensitizing-mutant lines PC-9, H3255, H1650 with mean IC50 13-54 nM, similar to early-generation TKIs.

“AZD9291 showed similar potency to early generation TKIs in inhibiting EGFR phosphorylation in EGFR cells harboring sensitising EGFR mutants including PC-9 (ex19del), H3255 (L858R) and H1650 (ex19del) (Fig. 2A), with mean IC50 values ranging from 13 to 54 nM for AZD9291.”

May combine two claims.

Downstream signaling molecules showed maximal inhibition at 6 hours but more transient inhibition than phospho-EGFR.

“Interestingly, although downstream signaling molecules similarly showed maximal inhibition after 6 hours, in contrast to phospho-EGFR, they displayed more transient inhibition (Fig. 6A).”

May combine two claims.

In H1975, 25 mg/kg/day AZD9291 produced no visible tumors after 20 days, responses maintained 200 days, and no growth 30 days after stopping.

“No visible tumors were evident after 20 days dosing of 25 mg/kg/day AZD9291 in the H1975 xenograft model. Moreover, the complete responses were maintained for the duration of the study period with no evidence of tumor progression during 200 days of treatment. No growth was observed for an additional 30 days after treatment was stopped.”

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

AZD9291 and AZ5104 may be effective against lung cancer-associated HER2 mutants.

“and potentially lung cancer-associated HER2 mutants”

Probably not a substantial claim: may not pass S3 (load-bearing).

The authors have not yet observed resistance to AZD9291 caused by direct mutation of cysteine 797.

“It is also interesting to note that we not yet seen resistance to AZD9291 due to direct mutation of cysteine 797 (data not shown), which would render the receptor refractory to irreversible agents, in an analogous manner T790M prevents inhibition by early generation drugs.”

May combine two claims.

AZD9291 is a novel oral irreversible third-generation TKI with a distinct profile from gefitinib, erlotinib, afatinib, and dacomitinib.

“We describe here the identification, characterization and early clinical development of AZD9291, a novel oral, irreversible, third generation TKI with a distinct profile from gefitinib, erlotinib, afatinib, and dacomitinib.”

Probably not a substantial claim: may not pass S3 (load-bearing).

In vitro data suggest AZD9291 and AZ5104 may target HER2 and HER4 kinase activity.

“but in vitro data suggests the potential to target both HER2 and HER4 kinase activity.”

May combine two claims.

Both patients had ~9-month duration of response and were progression-free on 20 mg/day AZD9291 for ~11 months until progression.

“Both patients had a duration of response of approximately 9 months and were progression-free on 20 mg/day AZD9291 for approximately 11 months, until disease progression by RECIST 1.1.”

May combine two claims.

Both patients continued AZD9291 and derived clinical benefit per treating physicians.

“Both patients continue to receive AZD9291 treatment on study as per protocol, as they continue to derive clinical benefit according to their treating physicians.”

Probably not a substantial claim: may not pass S3 (load-bearing).

AZD9291 and AZ5104 appear effective against other rare drug-sensitive EGFR mutants.

“AZD9291 and AZ5104 also appear to be effective against other rare drug-sensitive EGFR mutants”

May combine two claims.

Rash and diarrhea were mostly mild and in a minority of patients, consistent with low wild-type EGFR activity.

“Rash and diarrhea were mostly mild and reported in only a minority of patients, consistent with low activity against wild-type EGFR.”

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

These two patients had no rash and only one CTCAE Grade 1 diarrhea.

“Consistent with AZD9291 being less active against wild-type EGFR, in these two cases there were no rash events and only one reported CTCAE Grade 1 diarrhea.”

Probably not a substantial claim: may not pass S3 (load-bearing).

Neither patient had significant blood glucose abnormalities.

“No significant aberration of blood glucose levels were noted in either patient during the study.”

May combine two claims.

Both responding patients' tumors had drug-sensitive EGFR mutations and documented T790M.

“Both patients’ tumors harbored drug sensitive EGFR mutations in addition to documented T790M mutations (according to local testing results).”

• AssumptionRests on an assumption: The two responding patients' tumors truly harbored T790M according to the local testing results.

May combine two claims.

Preliminary PK showed AZD9291, AZ5104, and AZ7550 half-life at least 50 hours, longer than predicted preclinically, with flat PK after multiple daily doses.

“Preliminary clinical pharmacokinetic analysis indicates that AZD9291, AZ5104 and AZ7550 have a half-life of at least 50 hours, longer than would be predicted from the preclinical data, which results in a desirable flat PK profile after multiple once daily dosing (Fig 7A).”

May combine two claims.

Patient 1 had 39.7% tumor shrinkage at scan 1, 48.3% at scan 2, remained 48.3% at scans 3-4, and 51.7% at scan 5.

“Tumor shrinkage on AZD9291 was 39.7% at scan 1, 48.3% by scan 2 (Fig. 7B), remained at 48.3% at both scan 3 and scan 4, and was 51.7% at scan 5 (data not shown).”

Probably not a substantial claim: may not pass S3 (load-bearing).

AZD9291 and AZ5104 are not potent against EGFR exon 20 insertion.

“but like other EGFR TKIs are not potent against an EGFR exon 20 insertion.”

May combine two claims.

T790M is the most common acquired resistance mechanism and is detected in more than half of patients after progression.

“However, it is now well established that acquisition of a second mutation in EGFR, resulting in substitution of threonine at the “gatekeeper” amino acid 790 to methionine (T790M) is the most common resistance mechanism and is detected in tumor cells from more than 50% of patients after disease progression (20, 21).”

• cites [20] Kobayashi, 2005, EGFR mutation and resistance of non-small-cell lung cancer to gefitinib., N Engl J Med sourceNot checked yet

  Not checked in the free run.

• cites [21] Pao, 2005, Acquired resistance of lung adenocarcinomas to gefitinib or erlotinib is associated with a second mutation in the EGFR kinase domain., PLoS Med sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Patients with EGFR-mutant NSCLC usually respond to first-generation TKIs but most progress after about 9-14 months.

“Unfortunately, whilst patients with EGFRm+ tumors typically show good initial responses to first generation TKIs, most patients who respond to therapy ultimately develop disease progression after about 9-14 months of treatment (7-11).”

• cites [7] Maemondo, 2010, Gefitinib or chemotherapy for non-small-cell lung cancer with mutated EGFR., N Engl J Med sourceNot checked yet

  Not checked in the free run.

• cites [8] Mitsudomi, 2009, Gefitinib versus cisplatin plus docetaxel in patients with non-small-cell lung cancer harbouring mutations of the epidermal growth factor receptor (WJTOG3405): an open label, randomised phase 3 trial., Lancet Oncol sourceNot checked yet

  Not checked in the free run.

• cites [9] Mok, 2009, Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma., N Engl J Med sourceNot checked yet

  Not checked in the free run.

• cites [10] Rosell, 2012, Erlotinib versus standard chemotherapy as first-line treatment for European patients with advanced EGFR mutation-positive non-small-cell lung cancer (EURTAC): a multicentre, open-label, randomised phase 3 trial., Lancet Oncol sourceNot checked yet

  Not checked in the free run.

• cites [11] Zhou, 2011, Erlotinib versus chemotherapy as first-line treatment for patients with advanced EGFR mutation-positive non-small-cell lung cancer (OPTIMAL, CTONG-0802): a multicentre, open-label, randomised, phase 3 study., Lancet Oncol sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Phospho-EGFR staining remained significantly diminished at 30 hours despite ~3 h half-life, consistent with irreversible action.

“Although in mice, the pharmacokinetic half-life of AZD9291 is only ~3 hours, phospho-EGFR staining remained significantly diminished even after the 30 hour time point, consistent with its expected irreversible mode of action.”

May combine two claims.

The same 5 mg/kg/day dose caused profound sustained shrinkage in H1975 and PC-9, consistent with a significant selectivity margin over wild-type EGFR.

“By contrast, this same 5 mg/kg/day dose level was sufficient to induce profound and sustained tumor shrinkage in both H1975 and PC-9 mutant EGFR tumor xenograft models (Figs. 4A-B), consistent with AZD9291 having a significant selectivity margin over wild-type EGFR.”

Probably not a substantial claim: may not pass S3 (load-bearing).

Second-generation irreversible TKIs afatinib and dacomitinib are effective in untreated EGFR-mutant lung cancer.

“Second-generation irreversible EGFR TKIs such as afatinib (24) and dacomitinib (25) are effective in untreated EGFR mutant lung cancer (26, 27).”

• cites [24] Li, 2008, BIBW2992, an irreversible EGFR/HER2 inhibitor highly effective in preclinical lung cancer models., Oncogene sourceNot checked yet

  Not checked in the free run.

• cites [25] Engelman, 2007, PF00299804, an irreversible pan-ERBB inhibitor, is effective in lung cancer models with EGFR and ERBB2 mutations that are resistant to gefitinib., Cancer Res sourceNot checked yet

  Not checked in the free run.

• cites [26] Ramalingam, 2012, Randomized phase II study of dacomitinib (PF-00299804), an irreversible pan-human epidermal growth factor receptor inhibitor, versus erlotinib in patients with advanced non-small-cell lung cancer., J Clin Oncol sourceNot checked yet

  Not checked in the free run.

May combine two claims.

AZD9291 has third-generation TKI properties: equivalent activity against sensitizing mutant EGFR, superior activity against T790M, and increased selectivity margin against wild-type EGFR compared with earlier agents.

“However, taken together, this mechanistic data confirmed the third generation TKI properties of AZD9291 compared to earlier generation agents: equivalent activity against sensitizing mutant EGFR, superior activity towards T790M and increased selectivity margin against wild-type EGFR.”

Probably not a substantial claim: may not pass S3 (load-bearing).

First-generation TKIs cause skin rash and diarrhea by inhibiting wild-type EGFR in skin and gut.

“Furthermore, these first generation TKIs are associated with side effects that include skin rash and diarrhea that are due to the inhibition of wild-type EGFR in skin and gastrointestinal organs (12).”

• cites [12] Burtness, 2009, NCCN Task Force Report: Management of dermatologic and other toxicities associated with EGFR inhibition in patients with cancer., J Natl Compr Cancer Netw sourceNot checked yet

  Not checked in the free run.

May combine two claims.

As monotherapy, afatinib and dacomitinib fail to overcome T790M-mediated resistance in patients because effective preclinical concentrations cannot be reached due to wild-type EGFR toxicity.

“However, as monotherapy, they have failed to overcome T790M-mediated resistance in patients (28, 29), because concentrations at which these irreversible TKIs overcome T790M activity pre-clinically are not achievable in humans due to dose-limiting toxicity related to non-selective inhibition of wild-type EGFR (30).”

• cites [28] Miller, 2012, Afatinib versus placebo for patients with advanced, metastatic non-small-cell lung cancer after failure of erlotinib, gefitinib, or both, and one or two lines of chemotherapy (LUX-Lung 1): a phase 2b/3 randomised trial., Lancet Oncol sourceNot checked yet

  Not checked in the free run.

• cites [29] Katakami, 2013, LUX-lung 4: a phase II trial of afatinib in patients with advanced non-small-cell lung cancer who progressed during prior treatment with erlotinib, gefitinib, or both., J Clin Oncol sourceNot checked yet

  Not checked in the free run.

• cites [30] Eskens, 2008, A phase I dose escalation study of BIBW 2992, an irreversible dual inhibitor of epidermal growth factor receptor 1 (EGFR) and 2 (HER2) tyrosine kinase in a 2-week on, 2-week off schedule in patients with advanced solid tumours., Br J Cancer sourceNot checked yet

  Not checked in the free run.

May combine two claims.

C/L858R tumors were sensitive to erlotinib, while C/L+T tumors were resistant.

“As expected, tumors harboring EGFRL858R were sensitive to erlotinib, while tumors expressing EGFRL858R + T790M were resistant (46).”

• cites [46] Regales, 2007, Development of new mouse lung tumor models expressing EGFR T790M mutants associated with clinical resistance to kinase inhibitors., PLoS ONE sourceNot checked yet

  Not checked in the free run.

May combine two claims.

In the afatinib plus cetuximab study, tumors with undetectable T790M also shrank, suggesting a T790M-independent EGFR-dependent resistance pathway.

“A surprising finding in the afatinib plus cetuximab study was that tumors with undetectable levels of T790M also displayed tumor shrinkage, suggesting that a T790M-independent but EGFR-dependent pathway of resistance exists.”

Probably not a substantial claim: may not pass S3 (load-bearing).

EGFR cDNAs were re-sequenced to verify that no additional codon-changing mutations were present.

“All cDNAs were re-sequenced to verify that no additional codon-changing mutations were present.”

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

All patients were treated on trial NCT01802632 with written informed consent and appropriate IRB approval.

“All patients were treated on trial NCT01802632 with written informed consent from patients and approval appropriate Institutional Review Boards (For the two patients disclosed in this manuscript the Ethics committees are as follows; Korean patient: Seoul National University Hospital (EC), UK patient: North West – GM Central, North West Centre of REC, Manchester).”

Probably not a substantial claim: may not pass S3 (load-bearing).

All AZ cell lines were authenticated by short-tandem repeat analysis.

“All AZ cell lines were tested and authenticated by short-tandem repeat analysis (STR).”

Probably not a substantial claim: may not pass S3 (load-bearing).

Before treatment, mice were scanned at least twice to confirm growing lung nodules and avoid treating false-positive animals.

“Prior to treatment, mice were scanned at least twice to confirm the presence of growing lung nodules and to avoid treating false-positive animals.”

Classified as probably not a substantial claim. May combine two claims.

EGFR mutations occur in 10-35% of NSCLC and confer sensitivity to erlotinib, gefitinib, and afatinib.

“Mutations in EGFR occur in 10-35% of NSCLCs and confer sensitivity to the EGFR TKIs erlotinib, gefitinib, and afatinib (6).”

• cites [6] Pao, 2010, Rational, biologically based treatment of EGFR-mutant non-small-cell lung cancer., Nat Rev Cancer sourceNot checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S3 (load-bearing).

Pao lab cell lines were re-genotyped multiple times by Sanger sequencing to confirm known EGFR mutations and ensure experimental accuracy.

“Pao lab cell lines were re-genotyped multiple times to confirm the presence of known EGFR mutations by standard Sanger sequencing to ensure the accuracy of experiments.”

May combine two claims.

AZD9291 could be an attractive treatment option in EGFRm+ TKI-naïve patients by targeting both sensitizing and T790M populations, potentially delaying progression and increasing survival.

“Therefore, taken together, this supports the hypothesis that AZD9291 could also offer an attractive treatment option in EGFRm+ TKI-naïve patients, through targeting both sensitizing and T790M tumour cell populations that co-exist in a proportion of tumors, which may then lead to delayed disease progression and ultimately increased survival benefit.”

Probably not a substantial claim: may not pass S3 (load-bearing).

In pharmacodynamic studies, mice were randomized at a mean tumor volume of approximately 0.5-0.8 cm3 using the same randomization criteria as tumor growth inhibition studies.

“For pharmacodynamic studies, mice were randomized at a mean tumor volume of approximately 0.5-0.8cm3 using the same randomization criteria as the tumor growth inhibition studies.”

Probably not a substantial claim: may not pass S3 (load-bearing).

Mice in xenograft studies were randomized into vehicle or treatment groups based on initial tumor volumes to ensure equal distribution.

“Randomisation for animal studies is based on initial tumor volumes to ensure equal distribution across groups.”

Probably not a substantial claim: may not pass S3 (load-bearing).

A power analysis was performed to calculate group sizes for statistically robust detection of tumor growth inhibition.

“A power analysis is performed whereby group sizes are calculated to enable statistically robust detection of tumor growth inhibition.”

May combine two claims.

Afatinib plus cetuximab produced 32% response rate and median PFS 4.7 months with significant skin and GI toxicity.

“Prior to identification of “third generation” EGFR TKIs, the most promising targeted regimen in patients with acquired resistance had been the combination of afatinib plus cetuximab, which induced a 32% response rate and median progression-free survival of 4.7 months in a heavily pre-treated cohort (52) with a significant degree of skin and gastrointestinal (diarrhea) toxicity.”

• cites [52] Sequist, 2013, First-in-human evaluation of CO-1686, an irreversible, selective, and potent tyrosine kinase inhibitor of EGFR T790M., J Clin Oncol sourceNot checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S3 (load-bearing).

HER2 amplification may mediate acquired resistance to EGFR TKI in some cases.

“This property may be important as HER2 amplification may mediate acquired resistance to EGFR TKI in some cases (13).”

• cites [13] Takezawa, 2012, HER2 amplification: a potential mechanism of acquired resistance to EGFR inhibition in EGFR-mutant lung cancers that lack the second-site EGFRT790M mutation., Cancer Discov sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Third-generation EGFR TKIs such as AZD9291 may overcome the limitations of earlier TKIs and improve treatment options for patients who progressed on TKI therapy due to T790M.

“Third generation EGFR TKI agents such as AZD9291 have the potential to overcome these limitations and improve markedly the treatment options to patients who have progressed on TKI treatment due to T790M.”

• AssumptionRests on an assumption: Earlier generation EGFR TKIs have toxicities related to wild-type EGFR and resistance mechanisms that limit their effectiveness.

May combine two claims.

In >half of patients, tumor cells at progression harbor T790M, which confers resistance to EGFR TKIs.

“In more than half of patients, tumor cells at the time of progression harbor a second-site T790M mutation, which confers resistance to these EGFR TKIs (23).”

• cites [23] Yun, 2008, The T790M mutation in EGFR kinase causes drug resistance by increasing the affinity for ATP., Proc Natl Acad Sci U S A sourceNot checked yet

  Not checked in the free run.

May combine two claims.

In the AZD9291 phase I trial, efficacy was seen at all doses, with partial radiographic responses in T790M patients from the first dose cohort.

“In the phase I trial of AZD9291 in EGFRm+ NSCLC patients that had progressed on earlier generation TKIs, evidence of efficacy has been seen at all doses studied so far, with AZD9291 induced partial radiographic responses in patients whose tumors were known to harbor T790M, from the first dose cohort onwards (49, 53).”

• cites [49] Ranson, 2013, Preliminary results from a Phase I study with AZD9291: an irreversible inhibitor of epidermal growth factor receptor (EGFR) activating and resistance mutations in non-small cell lung cancer (NSCLC)., Eur J CancerNot checked yet

  Not checked in the free run.

• cites [53] Soria, 2013, First-in-human evaluation of CO-1686, an irreversible, highly selective tyrosine kinase inhibitor of mutations of EGFR (activating and T790M)., J Thoracic OncolNot checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S3 (load-bearing).

In the first-in-man study, a starting dose cohort size of 6 is standard practice to provide sufficient safety and tolerability data without exposing too many patients to a potentially non-beneficial dose.

“In the first into man study a cohort size of 6 for the starting dose is standard practice, to provide sufficient safety and tolerability data about a dose level without exposing too many patients to a dose which may not be clinically beneficial.”

May combine two claims.

AZD9291 is highly potent against EGFRm+ and T790M mutants with wide selectivity over wild-type EGFR and high selectivity against other kinases.

“Biochemical profiling together with in vitro cellular phosphorylation and phenotype studies have collectively shown that AZD9291 is highly potent against EGFRm+ and T790M resistant EGFR mutants with a wide margin of selectivity against wild type EGFR activity and exhibits a high degree of selectivity against other kinases outside the EGFR family.”