Epidermal growth factor receptor T790M mutation-positive metastatic non-small-cell lung cancer: focus on osimertinib (AZD9291)

Figures & data

Table 1 Phase III trials of first- and second-generation EGFR TKIs

Phase III	Sample size/population group	TKI	Comparator	Median OS in months (TKI vs chemotherapy)	Hazard ratio for OS, P-value	ORR	PFS in months (TKI vs chemotherapy)	Hazard ratio for PFS, trial P-value
LUX-Lung 3^Citation11	345/stage IIIB or IV	Afatinib	Pemetrexed + cisplatin	16.6 vs 14.8 (OS not reached in any group)	HR 1.12, 95% CI (0.73–1.73), P=0.60	56% vs 23% (independent review) and 69% vs 44% (investigator review)	11.1 vs 6.9	HR 0.58, 95% CI (0.43–0.78), P=0.001
LUX-Lung 6^Citation12	364/stage IIIB or IV	Afatinib	Gemcitabine + cisplatin	22.1 vs 22.2	HR 0.95, 95% CI (0.68–1.33), P=0.76	66.9% vs 23% (independent review)	11.0 vs 5.6 (independent review) and 13.7 vs 5.6 (investigator assessment)	Independent review: HR 0.28, 95% CI (0.20–0.39), P<0.0001 Investigator assessment: HR 0.26, (95% CI 0.19–0.36), P<0.0001
IPASS Iressa Pan-Asia Study^Citation21	1217/stage IV- All patients without prior treatment patients	Gefitinib	Carboplatin + paclitaxel	18.8 vs 17.4	HR 0.90, 95% CI (0.79–1.02), P=0.109	43% vs 32%	5.7 vs 5.8	HR 0.74, 95% CI (0.65–0.85), P<0.0001
WJTOG3405^Citation22	177/stage IIIB/IV	Gefitinib	Cisplatin and docetaxel	30.9 vs not reached	HR 1.638, 95% CI (0.749–3.582), P=0.211	62.1% vs 32.2%	9.2 vs 6.3	HR 0.489, 95% CI (0.336–0.710), P<0.0001
EURTAC^Citation6	174/stage IV chemo-naive NSCLC	Erlotinib	Cisplatin + docetaxel or gemcitabine; carboplatin + docetaxel or gemcitabine	22.9 vs 19.5	HR, 95% CI (0.64–1.35), P=0.93	65% vs 16%	10.4 vs 5.2	HR 0.34, 95% CI (0.23–0.49), P<0.0001
OPTIMAL study^Citation8	165/stage IIIB/IV NSCLC with EGFR mutation	Erlotinib	Carboplatin + gemcitabine	Not reported	Not reported	83% vs 36%	13.1 vs 4.6	HR 0.16, 95% CI (0.10–0.26), P<0.0001

Abbreviations: EGFR, epidermal growth factor receptor; NSCLC, non-small-cell lung cancer; ORR, objective response rate; OS, overall survival; PFS, progression-free survival; TKIs, tyrosine kinase inhibitors; HR, hazard ratio.

Table 2 Early-phase osimertinib trial

Trial	N (number of patients)	Partial response, n (%)*	ORR (%)	CR/SD/PD, n (%)	Disease control, n (%)*	PFS (months)
AURA Phases I and II
All patients	239	123 (51%)		1/78 (33%)/34 (14%)	84%	8.2
Positive EGFR T790M	127	61% (78)			95% (121)	9.6
Negative EGFR T790M	61	13 (21%)			37 (61%)	2.8
AURA2 Phase II		71%			92%	8.6
Phase I first line
All patients	60		77		97%	19.3
Dose 80 mg	30		67			Not reached
Dose 160 mg	30		87			19.3

Note:

* Unless indicated.

Abbreviations: CR, complete response; EGFR, epidermal growth factor receptor; ORR, overall response rate; PD, progressive disease; PFS, progression-free survival; SD, stable disease.

Table 3 Ongoing Phase II and III osimertinib trials

National clinical trial ID number	Phase	Primary outcome measures	Clinical trial status	Official title
NCT02511106	III	DFS	Recruiting	AZD9291 vs placebo in patients with stages IB and IIIA NSCLC, following complete tumor resection with or without adjuvant chemotherapy (ADAURA)
NCT02736513	II	Intracranial overall response rate as defined by modified RECIST	Recruiting	Pilot, Phase II study assessing intracranial activity of AZD9291 (TAGRISSO) in advanced EGFRm NSCLC patients with asymptomatic brain metastases
NCT02296125	III	PFS	Active, not recruiting	A Phase III, double-blind, randomized study to assess the safety and efficacy of AZD9291 vs a standard of care EGFR TKI as first- line treatment in patients with EGFRm-positive, locally advanced or metastatic NSCLC
NCT02474355	III	Efficacy of AZD9291 by the analysis of overall survival; safety of AZD9291 by the assessment of serious adverse events; adverse events of special interest	Recruiting	Open-label, multinational, multicenter, real-world treatment study of single agent AZD9291 for patients with advanced/metastatic EGFR T790M mutation-positive NSCLC who have received prior therapy with an EGFR TKI
NCT02151981	III	PFS	Active, not recruiting	A Phase III, open-label, randomized study of AZD9291 vs platinum-based doublet chemotherapy for patients with locally advanced or metastatic NSCLC whose disease has progressed with previous EGFR TKI therapy and whose tumors harbor a T790M mutation within the EGFR gene (AURA3)
NCT02811354	II	ORR	Not yet recruiting	Phase II study of AZD9291 in patients with advanced stage NSCLC following prior EGFR TKI therapy with EGFR and T790M mutations detected in plasma circulating tumor DNA (PLASMA)
NCT02454933	III	PFS according to RECIST 1.1	Active, not recruiting	A Phase III, multicenter, open-label, randomized study to assess the efficacy and safety of AZD9291 in combination with MEDI4736 vs AZD9291 monotherapy in patients with locally advanced or metastatic EGFR T790M mutation-positive NSCLC who have received prior EGFR TKI therapy (CAURAL)
NCT02442349	II	ORR according to RECIST 1.1	Active, not recruiting	A Phase II, open-label, single-arm study to assess the safety and efficacy of AZD9291 in Asia Pacific patients with locally advanced/metastatic NSCLC whose disease has progressed with previous EGFR TKI therapy and whose tumors harbor a T790M mutation within the EGFR gene (AURA17)
NCT02769286	II	Efficacy	Not yet recruiting	Phase II trial of AZD9291 in first-line treatment of lung cancer harboring activating EGFRm from circulating tumor DNA and second-line treatment after acquired resistance with T790M mutation detected from circulating tumor DNA
NCT02803203	I and II	MTD (Phase I) and PFS (Phase II)	Not yet recruiting	A Phase I/II study of combination osimertinib and bevacizumab as a treatment for patients with EGFR-mutant lung cancers
NCT02094261	II	ORR	Active, not recruiting, has results	Phase II, open-label, single-arm study to assess safety and efficacy of AZD9291 in patients with locally advanced/metastatic NSCLC whose disease has progressed with previous EGFR TKI and whose tumors are EGFR and T790M mutation positive (AURA2)
NCT02179671	II	Confirmed CR rate	Active, not recruiting	A Phase IIa, open-label, multicenter, multicohort, immune- modulated study of selected small molecules (gefitinib, AZD9291, or selumetinib + docetaxel) or a first IMT (tremelimumab) with a sequential switch to a second IMT (MEDI4736) in patients with locally advanced or metastatic NSCLC (stages IIIB–IV)
NCT02759835	II	Determine PFS in patients with oligoprogressive disease after treatment with LAT followed by osimertinib patients who progress on their initial treatment with osimertinib and receive LAT therapy (surgery, radiation therapy, or RFA) followed by osimertinib will be evaluated for their time to second progression (PFS2)	Recruiting	A pilot study of local ablative therapy for treatment of oligoprogressive, EGFR-mutated, NSCLC after treatment with osimertinib (AZD9291, Tagrisso)
NCT02504346	II	ORR	Recruiting	AZD9291, an irreversible EGFR TKI, in relapsed EGFR-mutated NSCLC patients previously treated with an EGFR TKI, coupled to extensive translational studies

Abbreviations: CR, complete response; DFS, disease-free survival; EGFR, epidermal growth factor receptor; EGFRm, EGFR mutation; IMT, immune-mediated therapy; MTD, maximum tolerated dose; NSCLC, non-small-cell lung cancer; ORR, objective response rate; PFS, progression-free survival; TKI, tyrosine kinase inhibitor; LAT, local ablative therapy; RFA, radiofrequency ablation.

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