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Caicun Zhou
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ES10 - Oncology Drug Approval: Challenges and Opportunities (ID 13)
- Event: WCLC 2019
- Type: Educational Session
- Track: Advanced NSCLC
- Presentations: 5
- Now Available
- Moderators:Caicun Zhou, Alice T. Shaw
- Coordinates: 9/08/2019, 13:30 - 15:00, Toronto (1985)
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ES10.01 - US Food and Drug Administration (Now Available) (ID 3205)
13:30 - 15:00 | Presenting Author(s): Gideon M Blumenthal
- Abstract
- Presentation
Abstract
Dr Blumenthal will provide the US FDA Oncology Center of Excellence perspective on Oncology Drug Approval: Challenges and Opportunity. With the recent influx of novel targeted therapies, immunotherapy and chemotherapy to treat patients with lung cancers, there are increased challenges to ensuring that safe and effective therapies are available to patients as efficiently as possible while ensuring that the evidence generated is robust and reliable. This talk will discuss FDA's perspective on global drug development.
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ES10.02 - Japan Pharmaceuticals and Medical Devices Agency (Now Available) (ID 3206)
13:30 - 15:00 | Presenting Author(s): Sumimasa Nagai
- Abstract
- Presentation
Abstract
The Pharmaceuticals and Medical Devices Agency (PMDA) and the Ministry of Health, Labour and Welfare (MHLW) are responsible for reviewing applications and approving the marketing authorization of drugs, medical devices, and regenerative medicines in Japan. All applications for marketing authorization in Japan are submitted to the PMDA. The PMDA conducts scientific review. Review reports prepared by the PMDA are then submitted to MHLW. The MHLW approves the marketing authorization.
Japanese regulation has two categories of regulatory review: standard review and priority review. Priority review is applied to orphan drugs and products designated by the MHLW. Other than orphan drugs, the MHLW designates medical products as priority review products based on the following criteria described: 1. Seriousness of the target disease and 2. Clinical usefulness of the drug: no standard therapy exists, and clinical usefulness is superior to the existing products in terms of efficacy, safety, or the patient’s quality of life. The target total review time for standard review products and priority review products is 12 months and 9 months, respectively.
The conditional and term-limited approval system has been first introduced for regenerative medical products since November, 2014. Regenerative medical products may be granted conditional and term-limited approval if their efficacy can be assumed and safety is confirmed in early-phase (phase I and/or II) registration trials. In the approval system, sponsors of the products must confirm their efficacy and safety after marketing authorization in postmarketing clinical studies etc and by resubmitting applications for regular approval within a predetermined period (not more than 7 years). The conditional and term-limited approval for regenerative medical products is similar to the accelerated approval in the US.
In addition, the conditional approval system for drugs has been newly instituted since October, 2017 in Japan. This may be granted if all of the following requirements are met: 1. seriousness of the target disease, 2. clinical usefulness of the drug: no standard therapy exists, and clinical usefulness is superior to the existing products in terms of efficacy, safety, or quality of life, 3. it is difficult or it takes too long time to conduct a confirmatory study, 4. exploratory clinical studies can show efficacy and safety, and 5. surveillance or clinical studies must be conducted as post-marketing requirement. Because these requirements include the requirements for priority review (seriousness of the target disease and clinical usefulness of the drug), drugs granted conditional approval can automatically enjoy priority review. Moreover, the requirement for conditional approval “it is difficult or it takes too long time to conduct a confirmatory study” in Japan is totally different from accelerated approval based on surrogate endpoint in the US. The requirement is similar to the requirement for marketing authorization under exceptional circumstances “companies cannot provide comprehensive clinical data because of the rarity of the disease” in the EU. Although the requirements for conditional approval for drugs in Japan include “surveillance or clinical studies must be conducted as post-marketing requirement”, the term of validity for conditional approval of drugs in Japan is not established, which is different from the conditional and term-limited approval for regenerative medical products in Japan. As of May 31, 2019, only lorlatinib for ALK fusion-positive non-small cell lung cancer and pembrolizumab for MSI-high solid cancer have been granted conditional approval for drugs in Japan. Conducting confirmatory comparative studies is not included in postmarketing requirements for the both drugs.
The MHLW instituted in 2015 the SAKIGAKE (meaning pioneer or forerunner in Japanese) designation system for medical products for diseases in urgent medical need of innovative therapy and that may satisfying the following two conditions: 1. The medical product has been first developed in Japan, and a sponsor is planning to submit a marketing authorization application; and 2. Prominent effectiveness can be expected based on data from the mechanism of action, non-clinical studies, and early-phase clinical studies. Advantages of sponsors who have medical products granted SAKIGAKE designation are as follows: prioritized consultation (reduced waiting time), substantial pre-application consultation, prioritized review (target total review time of 6 months only for drugs, devices, and IVDs), assigning a PMDA manager as a concierge, and an extension of the reexamination period. Total review time for SAKIGAKE-designated regenerative medical products is not established. Although the SAKIGAKE designation is similar to a breakthrough therapy designation in the US and PRIME in the EU, the requirement “the medical product has been first developed in Japan” and the advantage of specific shortened total review time are unique to the SAKIGAKE.
Companion diagnostics (CDx) are important for oncology drug development. Current regulatory considerations regarding CDx and tumor profiling test in Japan are similar to those in the US. As of May 31, 2019, three next generation sequencing-based oncology panel tests have been approved as CDx and/or tumor profiling test in Japan. However, more flexible regulations regarding CDx are necessary for efficient clinical practice and drug development.
I will give an overview of regulatory frameworks and challenges regarding oncology drugs and companion diagnostics in Japan.
References:
・Nagai S, Ozawa K. Regulatory approval pathways for anticancer drugs in Japan, the EU and the US. Int J Hematol. 2016;104:73-84.
・Nagai S, et al. Evolving Japanese regulations on companion diagnostics. Nat Biotechnol. 2016;34:141-144.
・Salgado R, Solit DB, Rimm DL, Bogaerts J, Canetta R, Lively T, Lyerly K, Span PN, Bateman-House A, Makady A, Bergmann L, Nagai S, et al.; IBCD-Faculty. Addressing the dichotomy between individual and societal approaches to personalised medicine in oncology. Eur J Cancer. 2019;114:128-136.
・Lyerly HK, Ren J, Canetta R, Kim GH, Nagai S, et al. Global Development of Anticancer Therapies for Rare Cancers, Pediatric Cancers, and Molecular Subtypes of Common Cancers. J Glob Oncol. 2018;4:1-11.
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ES10.03 - China National Medical Products Administration (Formerly CFDA) (Now Available) (ID 3207)
13:30 - 15:00 | Presenting Author(s): Tony Mok
- Abstract
- Presentation
Abstract not provided
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ES10.04 - European Medicines Agency (Now Available) (ID 3208)
13:30 - 15:00 | Presenting Author(s): Jorge Camarero
- Abstract
- Presentation
Abstract
Oncology Drugs Approval: Challenges and Opportunities
In recent years, the development of new drugs in the oncology field has notably increased. This growth in oncology clinical trials appears to be mainly associated with the increasing knowledge in pathophysiology and molecular medicine in oncology. Targeted therapies have been approved, overall, on the basis of its ability to prolong progression free survival and/or life expectancy of patients. In addition, immunotherapy has arisen as a turning point in the treatment of cancer, opening a new era and setting up a milestone in the current armamentarium. However, the regulatory decision making process behind some of the approvals for these products have proven difficult and lead to important uncertainties still to be addressed. Such unanswered questions relate, among others, to the target population, subgroups of patients partially covered by authorized indications and limitations on important aspects such as duration and combination of treatments. Likewise, this increase in new molecules development poses a remarkable pressure on regulators, clinicians and payers, who albeit from different perspectives, face the very same problem of how to ensure (timely) access to patients of new authorized products. From a regulatory perspective, randomized clinical trials remain the gold standard for adequate assessment of both efficacy and safety. Nevertheless, conducting single arm studies is becoming a commonly approach for companies to speed up regulatory approval in those situations where there is an unmet medical need. The latter cast important doubts on when, where and how this strategy can be accepted.
Last but not least, new clinical trials designs and the proposal of using Real Word Evidence/Real World Data to complement non-compelling clinical development, are creating a new parading when it comes to making a decision upon the benefit-risk balance
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ES10.05 - Brazilian Health Regulatory Agency - Agência Nacional de Vigilância Sanitária (Now Available) (ID 3209)
13:30 - 15:00 | Presenting Author(s): Carlos Gil Ferreira
- Abstract
- Presentation
Abstract
Brazil, the largest country in South America, has become the second largest pharmaceutical market in the emerging world. The Brazilian Health Surveillance Agency (Agencia Nacional de Vigilancia Sanitaria - ANVISA) was created in 1999 with the primary goal to protect and promote public health surveillance over products and services in Brazil. Its hallmarks are administrative independence, financial autonomy, and the stability of its directors. Within the federal public regulatory structure, the agency is linked to the Ministry of Health [1].
Despite major advances in the regulatory process in Brazil, it is important to highlight that a major delay in cancer drugs approval over the last decade has had a negative impact on patient access to novel medications in Brazil. According to Barrios et al., [2] well-established and adequately functional drug approval legislation is indispensable to guarantee a country’s population health. Any malfunctions or delay in such a crucial process have serious consequences. As an example, the drug Crizotinib (Xalcori®Pfizer, NY, USA), which had its approval denied by ANVISA in June 2014 may be seen as a landmark. Assuming different premises, Barrios et al. [2] calculated 1.367 years of life lost over 34 months due to lack of access to Crizotinib between August 2011 (FDA approval) to June 2014 (refusal by ANVISA). Of note, Crizotinib was not approved in Brazil until Feb 2016, what may have added additional 804 years of life lost to final numbers due to this delay. Other example of unexplained delay in drug approval in lenalidomide. The gap between the drug approval in the US and Brazil was 12 years.
Regarding drugs that do require a companion diagnostic, the situation may become more complicated since, unlike the US Food and Drug Administration, no clear mechanism is in place with ANVISA for the simultaneous linking of most companion diagnostic tests with their respective targeted therapeutic drug [3].
In trying to understand the reasons behind this delayed drug approval process, methodological, cultural, political and ideologic reasons may account. At odds with other regulatory agencies such the FDA that allow conditioned approval based on non randomized data for drugs addressing unmet medical needs. For many years ANVISA authorities mandated randomized phase 3 data for a definitive approval, since no conditioned approval was allowed. In this context, having a specific oncology area or committee, such as the FDA Oncology Drug Advisory Committee [4], may be crucial. Fast track approval, breakthrough designation, companion diagnostics, different surrogate endpoints, integration of real world evidence (RWE) into the regulatory process are very specific topics from the oncology field and do require to be analyzed under the perspective of cancer specialists. From a political, cultural and ideologic perspective, althoughit is notorious that Brazil has invested substantially in expanding access to health care for all of its citizens, the country has, essentially, two clear distinct and dissimilar health systems [3]. The public system allows drugs to become commercially available through processes that are different from those in place in the private health-care system. Although difficult to measure those disparities and difficulties to reimburse expensive drugs in the public system, may have influenced the delayed process during the last decade.
Over the last decade, delays at ANVISA’s approval process have been considered the only reason for the inequitable access to oncology care between the USA and Brazil. Yet, this may be a biased conclusion and a more comprehensive analysis in needed. By analyzinga basket of twenty-three oncology products approved by ANVISA after 2002 Bustamante et al. [5] identified that on average there was a difference of 8.6 months (449 X 186 days). However on average, a delay in the manufacturers’ submission for regulatory approval of 1.1 years (393 days between Brazil and the USA) was also identified.
More recently, a trend toward improvements in the drug approval process has been identified (ex. Osimertinib and Durvalumab). Osimertinib was firstly approved by ANVISA in 2017 as a second line treatment in patients who did not respond well to the initial drug. With the new determination, in 2018 ANVISA approved its use as a first therapy to treat locally advanced non-small cell lung cancer. Durvalumab was approved by ANVISA in 2017. Nevertheless there is clear room for a continuous improvement. Increase in the number of ANVISA technicians, continuous training and collaboration with academic institutions and other regulatory agencies elsewhere are mandatory. Close scientific collaboration and open and transparent dialogue between ANVISA and pharmaceutical companies are required. In sum, if we are to have a continuous improvement in the oncology drug approval process, all the stakeholders (ANVISA, drug manufactures, patient advocacy, players at the private and public health systems) must act together.
References
1. Ba KH andSassi AB. ANVISA: an introduction to a new regulatory agency with many challenges. AAPS Open2018; 12 Dec 2018; 4:9.
2. Barrios PM, Debiasi M, Lopes G, Barrios CH. P1.51: Impact of Regulatory Delays in Drug Approval: Mortality and Morbidity Due to With Lack of Access to Crizotinib in Brazil: Track: Supportive Care and Others. IASLC 7th Latin American Conference on Lung Cancer, 25-27 August 2016 • Panama City, Panama; Volume 11, Issue 10, Page S215.
3. Ferreira CG, Achatz MI, Ashton-Prolla P, Begnami MD, Marchini FK, Stefani SD. Brazilian health-care policy for targeted oncology therapies and companion diagnostic testing. Lancet Oncol. 2016 Aug;17(8):e363-e370.
4. Vaccari L.A. The Role of the Oncology Drug Advisory Committee in the FDA Review Process for Oncologic Products. In: Teicher B.A., Andrews P.A. (eds) Anticancer Drug Development Guide. Cancer Drug Discovery and Development. Humana Press, Totowa, NJ, 2004.
5. Martin de Bustamante M, Martin de Bustamante M, Duttagupta S, Beckerman R, Smith NJ, Roitberg F, Lopes G. Regulatory approval for oncology products in brazil: a comparison between the FDA and Anvisa approval timelines. Value in Health 18 (2015) a805–a881. Abstract PCN60.
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Author of
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JCSE01 - Joint IASLC-CSCO-CAALC Session (ID 63)
- Event: WCLC 2019
- Type: Joint IASLC-CSCO-CAALC Session
- Track:
- Presentations: 1
- Moderators:Chunxue Bai, Tony Mok, Yi-Long Wu, Qing Zhou, Nan Wu
- Coordinates: 9/07/2019, 07:00 - 11:15, Toronto (1985)
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JCSE01.26 - PD-1 Inhibitor Plus Chemotherapy as 2nd/Subsequent Line Setting Demonstrate Superior Efficacy over PD-1 Inhibitor Alone in Pts of Advanced NSCLC (ID 3863)
07:00 - 11:15 | Author(s): Caicun Zhou
- Abstract
Abstract
Background
PD-1/PD-L1 inhibitors have become standard of care as the 2nd-line setting and also approved as 1st line setting when combined with doublet chemotherapy in patients with advanced NSCLC. This study aims to compare the efficacy of PD-1 inhibitor plus chemotherapy with PD-1 inhibitor alone as 2nd/subsequent lines setting in patients with advanced NSCLC
Methods
Patients who received PD-1 inhibitor monotherapy or PD-1 inhibitor plus chemotherapy as 2nd/subsequent lines setting in Shanghai Pulmonary Hospital, Tongji University were retrospectively collected. Detailed clinicopathologic characteristics and therapeutic outcomes were analysis.
Results
From January 2016 to February 2019, 148 patients who meet the criteria were included. Among them, 116 were in PD-1 inhibitor monotherapy group and 32 were in PD-1 inhibitor plus chemotherapy group. Chemotherapy regimens were pemetrexed(n=9), docetaxel(n=2), nab-paclitaxel(n=18) and gemcitabine(n=3). The baseline characteristics such as age, gender, smoking status, histology, PD-1 mono-antibodies, line of therapy were similar in the 2 groups. Combination group showed a favorable ORR (28.1% vs. 13.8%, p=0.055) and a significantly longer PFS(median 4.9 vs 2.5 months, p=0.005) compared with ICI monotherapy. Overall survial (OS) data was immature in the cutoff date of follow up. In the subgroup of 96 patients (monotherapy group n=69/ Combination group n=27) who were included as 2nd line setting, PD-1 inhibitor plus chemotherapy had significantly higher ORR(ORR:33.3% vs 18.8%, p=0.129) and longer PFS(median PFS: 4.9 vs 2.9 months, p=0.041).
Conclusion
PD-1 inhibitor plus chemotherapy as 2nd/subsequent lines setting demonstrated superior efficacy over PD-1 inhibitor alone in patients with advanced NSCLC.
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MA11 - Immunotherapy in Special Populations and Predictive Markers (ID 135)
- Event: WCLC 2019
- Type: Mini Oral Session
- Track: Immuno-oncology
- Presentations: 1
- Now Available
- Moderators:Frank Griesinger, Lecia Sequist
- Coordinates: 9/09/2019, 14:00 - 15:30, Hilton Head (1978)
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MA11.02 - KEYNOTE-042 China Study: First-Line Pembrolizumab vs Chemotherapy in Chinese Patients with Advanced NSCLC with PD-L1 TPS ≥1% (Now Available) (ID 1772)
14:00 - 15:30 | Author(s): Caicun Zhou
- Abstract
- Presentation
Background
In the global, open-label KEYNOTE-042 study (NCT02220894), pembrolizumab significantly improved OS vs chemotherapy in PD-L1–positive locally advanced/metastatic NSCLC without targetable EGFR/ALK aberrations (HRs: TPS ≥50%, 0.69; ≥20%, 0.77; and ≥1%, 0.81). We present the very first results for Chinese patients enrolled in the KEYNOTE-042 global and China extension (NCT03850444) studies.
Method
The global and extension studies were designed identically. Patients were randomized 1:1 (stratified by ECOG PS 0/1, squamous/nonsquamous histology, and TPS ≥50%/1‒49%) to up to 35 cycles of pembrolizumab 200 mg Q3W or up to 6 cycles of paclitaxel/pemetrexed + carboplatin with optional pemetrexed maintenance (nonsquamous only). Primary endpoints were OS in patients with PD-L1 TPS ≥50%, ≥20%, and ≥1%. No alpha was allocated to the China extension analysis. Overall, ~350 patients from China will be enrolled including 140 patients with TPS ≥50%, to determine the OS effect of pembrolizumab and consistency across outcomes in Chinese patients.
Result
As of September 4, 2018, 262 Chinese patients with PD-L1–positive (TPS ≥1%) NSCLC were enrolled (global, n=92; China extension, n=170) and randomized to pembrolizumab (n=128) or chemotherapy (n=134). 146 patients (55.7%) had PD-L1 TPS ≥50%; 204 (77.9%) had PD-L1 TPS ≥20%. After median (range) follow-up of 11.3 (0.1‒23.2) months, 32 patients (25.0%) were still receiving pembrolizumab and 6 (4.8%) were receiving pemetrexed maintenance. Pembrolizumab improved OS vs chemotherapy in patients with PD-L1 TPS ≥50%, ≥20%, and ≥1% (Table). Among patients who received ≥1 dose of pembrolizumab (n=128) or chemotherapy (n=125), grade 3–5 drug-related AEs occurred in 17% vs 68%, respectively.
ConclusionOverall Survival
n
Median (95% CI), mo
HR (95% CI)
PD-L1 TPS ≥50%
Pembrolizumab
72
20.0 (15.5–NR)
0.62 (0.38–1.00)
Chemotherapy
74
14.0 (10.0–17.9)
PD-L1 TPS ≥20%
Pembrolizumab
101
20.0 (17.4–NR)
0.62 (0.41–0.95)
Chemotherapy
103
13.7 (10.1–17.9)
PD-L1 TPS ≥1%
Pembrolizumab
128
20.0 (17.4–NR)
0.65 (0.45–0.94)
Chemotherapy
134
13.7 (10.1–17.9)
PD-L1 TPS 1–49%a
Pembrolizumab
56
19.9 (11.9–NR)
0.69 (0.40–1.20)
Chemotherapy
60
10.7 (8.3–20.9)
NR, not reached. aExploratory analysis.
Pembrolizumab monotherapy improved OS with a favorable safety profile vs platinum-based chemotherapy as first-line therapy in Chinese patients with locally advanced/metastatic NSCLC without sensitizing EGFR/ALK aberrations and a PD-L1 TPS ≥1%. Findings are consistent with the global study primary endpoints, supporting first-line use of pembrolizumab for PD-L1–expressing advanced/metastatic NSCLC in China.
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P1.14 - Targeted Therapy (ID 182)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Targeted Therapy
- Presentations: 1
- Moderators:
- Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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P1.14-62 - Afatinib in EGFR TKI-Naïve Patients with EGFR Mutation-Positive NSCLC: Combined Analysis of Two Single-Arm Phase IIIb Studies (ID 1338)
09:45 - 18:00 | Author(s): Caicun Zhou
- Abstract
Background
First-line afatinib significantly improved progression-free survival (PFS) compared with platinum-doublet chemotherapy in patients with EGFR mutation-positive (EGFRm+; including uncommon mutations) NSCLC in two Phase III studies (LUX-Lung 3: median 11.1 vs 6.9 months, hazard ratio [HR]=0.58; p=0.001; LUX-Lung 6: 11.0 vs 5.6 months, HR=0.28; p<0.0001). First-line afatinib also significantly improved PFS compared with gefitinib in the Phase IIb LUX-Lung 7 study (11.0 vs 10.9 months, HR=0.73; p=0.017). However, some patients still receive chemotherapy as a first-line treatment choice in clinical practice. Here, we report a combined analysis of outcomes from two large Phase IIIb studies of afatinib in EGFR TKI-naïve patients treated in a setting similar to real-world practice.
Method
In both studies, EGFR TKI-naïve, including chemotherapy-pretreated, patients with locally advanced or metastatic EGFRm+ NSCLC received 40 mg/day afatinib until progressive disease or lack of tolerability (dose reduction was permitted [minimum: 20 mg/day]). Study 1 enrolled patients across eight European countries, and Russia, Israel and Australia; Study 2 enrolled patients from centres in China, Hong Kong, India, Singapore, and Taiwan. Interim (Study 1; data cut-off: 30 April 2018) and final (Study 2; data cut-off: 06 July 2018) data were used for this combined analysis of time to symptomatic progression (TTSP), PFS, objective response, and safety.
Result
A total of 1020 patients were treated with afatinib (female: 59%; Asian/White/other: 54%/46%/<1%; median age [range]: 61 years [25–89]; ECOG PS 0/1/2: 26%/69%/5%; common/uncommon EGFR mutations: 82%/18%; treatment line 1st/2nd/≥3rd: 69%/23%/8%; presence of brain metastases: 18%). Overall, median TTSP was 14.6 months (95% confidence interval [CI]: 13.8–15.8 months); median PFS was 12.9 months (95% CI: 11.6–13.7 months). Objective response rate was 52.7%. Adverse events (AEs; all grade/grade ≥3) occurred in 1012/556 (99%/55%) patients; serious AEs were reported in 366 patients (36%). The most common grade ≥3 AEs were diarrhoea (14%) and rash (9%). Any-cause AEs leading to dose reduction were reported in 412 (40%) patients. Treatment discontinuation due to afatinib-related AEs occurred in 54 patients (5%).
Conclusion
In this combined analysis of two large, prospective ‘real-world’ afatinib studies in EGFR TKI-naïve patient populations, which included patients treated with afatinib in later lines, patients with ECOG PS 2, patients with brain metastases, and patients with uncommon mutations, safety data were consistent with previous results seen in the LUX-Lung 3, 6, and 7 studies. Efficacy findings are also encouraging, with a median TTSP of 14.6 months.
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P2.01 - Advanced NSCLC (ID 159)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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P2.01-99 - A Phase IIIb Open-Label Study of Afatinib in EGFR TKI-Naïve Patients with EGFR Mutation-Positive NSCLC: Final Analysis (ID 1671)
10:15 - 18:15 | Author(s): Caicun Zhou
- Abstract
Background
The safety and efficacy of afatinib, an orally administered irreversible EGFR TKI, have been demonstrated in patients with EGFR mutation-positive (EGFRm+) NSCLC in several Phase III clinical trials. However, prospective evidence supporting the clinical benefit of afatinib in the real-world setting is limited. Here, we report final data from a Phase IIIb open-label, multicenter trial evaluating safety and efficacy of afatinib in EGFR TKI-naïve Asian patients with locally advanced/metastatic EGFRm+ NSCLC, in a setting similar to real-world practice.
Method
EGFR TKI-naïve patients with locally advanced/metastatic EGFRm+ NSCLC were recruited from 34 sites in China, Hong Kong, India, Singapore, and Taiwan. Patients received 40 mg/day afatinib. Dose reduction to minimum 20 mg/day was permitted. Treatment continued until lack of clinical benefit as determined by the investigator. The primary and secondary safety endpoints were number of patients with serious adverse events (SAEs), and number of patients with drug-related AEs, respectively. The secondary efficacy endpoint was time to symptomatic progression (TTSP). Further endpoints included progression free survival (PFS), objective response, and duration of disease control.
Result
In total, 541 patients received afatinib. Baseline characteristics were representative of patients with EGFRm+ NSCLC (median age, 59 years; female, 52.9%; never smoked, 69.3%; EGFR mutations, common [Del19/L858R]/uncommon: 88.2% [48.2%/40.5%]/11.8%; ECOG performance status 0/1, 18.3%/79.7%; brain metastases, 19%). SAEs were reported in 164 patients (30.3%). 34 patients (6.3%) had drug-related SAEs, most commonly (grouped terms): diarrhea (1.8%), stomatitis (0.7%), and vomiting (0.7%). Drug-related AEs (DRAEs) of any grade were reported in 528 patients (97.6%). AEs leading to dose reduction occurred in 154 patients (28.5%); TRAEs leading to treatment discontinuation were reported in 17 patients (3.1%). Three patients experienced DRAEs leading to death (decreased appetite, dyspnea, and respiratory failure). Median TTSP was 14.0 months (95% confidence interval [CI]: 12.9, 15.9) and median PFS was 12.1 months (95% CI: 11.0, 13.6). Objective responses were reported in 312 patients (57.7%) by week 52; the median duration of response was 12.2 months (95% CI: 11.0, 13.5). 483 patients (89.3%) achieved disease control of median duration 13.6 months (95% CI: 12.1, 14.4).
Conclusion
Safety data for afatinib in this patient population were consistent with previously reported data, with no new safety signals. AEs were manageable and did not lead to discontinuation in most patients. This study also demonstrated the efficacy and clinical benefit of afatinib in Asian patients with locally advanced or metastatic EGFRm+ NSCLC in a near real-world setting.
