LILAC Study Research Articles

Trofinetide for the treatment of Rett syndrome: Results from the open-label extension LILAC study

Trofinetide was approved for the treatment of Rett syndrome based on the results of the phase 3, randomized, placebo-controlled, 12-week LAVENDER study. Rett syndrome is a chronic disorder requiring long-term treatment. We report the efficacy and safety results of LILAC, a 40-week, open-label extension study of LAVENDER. Females with Rett syndrome aged 5-21 years received open-label treatment with trofinetide for 40weeks. The primary endpoint was long-term safety of trofinetide; secondary endpoints included the change from baseline at week 40 in the Rett Syndrome Behaviour Questionnaire score and the Clinical Global Impression-Improvement score at week 40. Overall, 154 participants were enrolled and treated with trofinetide in LILAC. The most common adverse events in LILAC were diarrhea (74.7%), vomiting (28.6%), and COVID-19 (11.0%). Diarrhea wasthe most common adverse event leading to treatment withdrawal (21.4%). The Rett Syndrome Behaviour Questionnaire mean score (standard error) improvement from the LAVENDER baseline to week 40 in LILAC was -7.3 (1.62) and -7.0 (1.61) for participants treated with trofinetide and placebo in LAVENDER, respectively. Mean Clinical Global Impression-Improvement scores (standard error) at week 40 rated from the LILAC baseline were 3.1 (0.11) and 3.2 (0.14) for participants treated with trofinetide and placebo in LAVENDER, respectively. Treatment with trofinetide for ≤40weeks continued to improve symptoms of Rett syndrome. Trofinetide had a similar safety profile in LILAC as in LAVENDER. The study was supported by Acadia Pharmaceuticals Inc. (San Diego, CA, USA). This trial was registered at ClinicalTrials.gov (NCT04279314).

P.045 Trofinetide for the treatment of Rett syndrome: long-term safety and efficacy results from the open-label LILAC and LILAC-2 studies

Background: Trofinetide significantly improved core symptoms of Rett syndrome (RTT) with an acceptable safety profile in LAVENDER. Here, we report the safety and efficacy results of LILAC and LILAC-2, open-label extension studies of LAVENDER. Methods: Females with RTT, aged 5–21 years, received twice-daily, oral trofinetide in LILAC for 40 weeks. Participants who completed LAVENDER and LILAC continued trofinetide in LILAC-2, a 32-month extension study. Safety assessments included the incidence of adverse events (AEs). Efficacy endpoints included the Rett Syndrome Behaviour Questionnaire (RSBQ) and the Clinical Global Impression–Improvement (CGI-I) scale. Results: Overall, 154 patients were enrolled in LILAC. The most common AEs were diarrhea (74.7%) and vomiting (28.6%). The mean (standard error [SE]) change from the LAVENDER baseline to Week 40 in the LILAC study in RSBQ was -7.3 (1.62) and -7.0 (1.61) for participants treated with trofinetide and placebo in LAVENDER, respectively. Mean (SE) CGI-I scores compared with the LILAC baseline at Week 40 were 3.1 (0.11) and 3.2 (0.14) for patients treated with trofinetide and placebo in LAVENDER, respectively. Similar safety and efficacy trends were observed in LILAC-2. Conclusions: Trofinetide continued to improve symptoms of RTT in LILAC and LILAC-2 with a safety profile consistent with LAVENDER.

Litifilimab (BIIB059), a promising investigational drug for cutaneous lupus erythematosus

ABSTRACT Introduction There are no U.S. Food and Drug Administration (FDA) approved therapies for cutaneous lupus erythematosus (CLE). Litifilimab is a monoclonal antibody against BDCA2, a plasmacytoid dendritic cell-specific antigen, currently under investigation for systemic lupus erythematosus (SLE) and CLE. The LILAC study, published in the New England Journal of Medicine, is a phase II randomized controlled trial for CLE which demonstrated superiority of Litifilimab over placebo using a skin directed outcome measure. Areas covered This review identifies challenges that have hindered the development of any approved treatments for CLE, recent SLE trials that include skin disease data, and the pharmacological properties of litifilimab. We review the clinical efficacy and safety of litifilimab for both SLE and CLE in the phase I and II clinical trials. This review aims to highlight the need for more CLE-specific clinical trials and examine the potential of litifilimab as the first FDA approved therapy for CLE. (Clinical trial registration: www.clinicaltrials.gov identifier is NCT02847598.) Expert opinion Litifilimab demonstrated efficacy in a randomized phase II clinical trial as a standalone CLE trial using validated skin-specific outcome measures, making it the first successful clinical trial for a CLE targeted therapy. If approved, litifilimab will be a pivotal change in the landscape of CLE management especially for severe and refractory disease.

31341 BIIB059 reduces disease activity over 16 weeks in active cutaneous lupus erythematosus (CLE): Results from part B of phase 2 LILAC study

Part B of the phase 2 LILAC (NCT02847598) study demonstrated at week 16 the efficacy of BIIB059 50, 150, and 450 mg versus placebo (CLASI-50 response [450 mg; P = .024]) subcutaneously administered every 4 weeks (with 1 additional dose at week 2) in CLE participants with active SCLE and/or chronic CLE lesions. In these exploratory analyses, we evaluated the proportion of participants with a 20% (CLASI-20 response) or 70% (CLASI-70 response) improvement in CLASI-A score over 16 weeks. Among 132 participants, 26, 25, 48, and 33 received BIIB059 50, 150, and 450 mg and placebo, respectively. For BIIB059 50, 150, and 450 mg versus placebo, the proportion of participants who achieved CLASI-20 response was 15.4%, 28.0%, and 33.3% versus 15.2% at week 2; 42.3%, 64.0%, and 56.3% versus 30.3% at week 4; 50.0%, 76.0%, and 52.1% versus 42.4% at week 8; 50.0%, 80.0%, and 56.3% versus 42.4% at week 12; and 46.2%, 72.0%, and 72.1% versus 43.8% at week 16. For the same treatment groups, the proportion of participants who achieved CLASI-70 response was 3.8%, 0, and 0 versus 0 at week 2; 3.8%, 12.0%, and 10.4% versus 0 at week 4; 19.2%, 24.0%, and 18.8% versus 6.1% at week 8; 19.2%, 24.0%, and 14.6% versus 6.1% at week 12; and 15.4%, 32.0%, and 27.9% versus 9.4% at week 16. A greater proportion of CLE participants treated with BIIB059 versus placebo had improvement in disease activity over time using different thresholds for CLASI-A response.

Correlates of common concerns in older cancer survivors of leukemia and lymphoma: Results from the WHI-LILAC study.

e24031 Background: Older survivors of leukemia and lymphoma often experience long-term and late effects of chemotherapy, worsened by aging-related conditions such as functional and cognitive impairment, which may be inadequately addressed. In this study, we described common concerns in older survivors of leukemia and lymphoma, and assessed demographic and clinical factors associated with these concerns. Methods: We utilized data from the WHI LILAC study that recruited post-menopausal women aged 50 and 79 years. Participants who were diagnosed with leukemia and lymphoma after enrollment in WHI and answered at least half of the questions on current concerns in LILAC were included (n = 420). Participants were asked about 14 areas of current concerns common in cancer survivorship and to rate each from 0 (no concern) to 2 (major concern), with total score ranging 0-28. Linear regression was used to assess demographic and clinical factors associated with the concern score, and logistic regression for factors associated with the three most common concerns, with backward variable selection methods. Results: Mean age at assessment was 81 years (range 69-99) and 73% had non-Hodgkin lymphomas. Median time since diagnosis was 8.8 years (range 2.5-20.8 years). Seventy-two percent reported any concern; median concern score among these survivors was 3.5 (Q1-Q3, 2-5) (Table). Factors significantly correlated with the concern score were sadness, pain, loneliness, worse quality of life (QoL), lower physical functioning, more comorbidities, and greater prior symptom count (all p < 0.05). Significant factors correlated with common concerns were: 1) Fatigue/sleep: leukemia diagnosis, greater prior symptom count, feeling sad or depressed, reported distress, lower physical functioning; 2) Physical functioning/activity: public health insurance, older age, greater prior symptom count, reported pain, worse QoL, higher BMI; 3) Memory/concentration: prior chemotherapy or radiation, loneliness, worse QoL, greater prior symptom count (all p < 0.05). Conclusions: Almost three-quarter of survivors of leukemia and lymphoma reported at least one concern, with common concerns being fatigue/sleep, physical functioning/activity, and memory/concentration. A multicomponent intervention is needed to address these common concerns in older cancer survivors.[Table: see text]

Use of another Driver or other form of Transport by People of an Advanced Age

Background: A comparable number of advanced aged New Zealand Maori and non-Maori are presently driven by someone else or use other forms of transport.Method: Everyday Interests and Activities – Transport subsection of the LiLAC study provided the question area for analysis. Enquiry focused on whether older people did use private car transport driven by someone else, were questioned who was their most regular driver, how often did someone else drive them in a typical week and what distance they drove in a typical journey, whether they had used other forms of transportation, if they had problems obtaining their groceries and did they provide transport in the form of car/assistance for others Methods of analysis included binomial logistic regression, chi-square test for association, ordinal logistic regression, Mann-Whitney U test and descriptive analysis.Results: Participants totaled 931 with 421 New Zealand Maori and 510 New Zealand Maori non-Maori.New Zealand Maori: A higher ratio of New Zealand Maori males were transported making use of their daughter. Most of such trips were made only once a week with more males travelling between 1.5-20.5 kilometres, while both males and females covered longer distances of 25.5-80+ kilometres. New Zealand Maori were not seen to have not made use of other forms of transport in the last twelve months and very rarely had any problem obtaining their groceries. New Zealand Maori females aided other members of the family, while New Zealand Maori males provided such a service to people outside of their family.New Zealand non-Maori: Similarly, New Zealand non-Maori males were also seen to have made greater use of private transport provided by their daughter. In comparison there was almost a 50:50 split between those New Zealand non-Maori females who did and those who did-not make use of such a service. Of those who did such a service was primarily provided by their spouse followed by their daughter. Like New Zealand Maori, non-Maori New Zealanders generally only made use of such transport once a week or not at all. Trips taken by either male and female New Zealand non-Maori was firstly between 1.5-8, and then between 8.2-20.5 kilometres. More New Zealand non-Maori males had use of other forms of transport; while again there was practically a 50:50 split between those females who did and those who did not. Like New Zealand Maori, New Zealand non-Maori male and female very rarely had any problem obtaining their groceries. Both New Zealand non-Maori males and females were seen to provide care/assistance for that outside of the family. Conclusion: Although as is often expected the majority both New Zealand Maori and New Zealand non-Maori representatives were seen to utilise family (daughters and spouse) for transportation. However, use of such a provision was generally restricted to only once a week and in assessing distance, consideration also needs to be made of respondent geographical location, especially in line with placement of main services. However, despite the use of such a transportation facility independent mobility remained with both rural and urban population groups. Future older generations will have experienced a closer relationship with motor vehicle use. Consequently, any transportation policy needs to be designed in line with sustaining the provision of goods, services, employment, social opportunities and membership of the community.

Driving and Advanced Age

Background: Advanced aged people continue to use their vehicles, utlising them for a wide variety of purposes. Within that age group female drivers from both New Zealand Maori and non-Maori are predominantly noticeable. Method: Following the first wave of the LiLAC Study the present study examined the results of the Transport and Nottingham Extended Activities of Daily Living sub-sections involving New Zealand Maori aged between 75-95 years and non-Maori participants only aged 85 years. Questions asked of the recipients involved whether they had ever driven, did the still drive, how often and how far they drove in a typical week; and why they drove. Analysis of the results were conducted using a scaled questionnaire, binomial logistic regression, chi-square tests for association, ordinal logistic regression and descriptive analysis.Results: Participant number totalled 931 with 421 New Zealand Maori and 510 New Zealand Maori non-Maori. New Zealand Maori: Nearly double the number of females had ever driven. Of those who do drive both male (73) and female (69) indicated that they did, although females also offered the service of driving to both family and non-family members. Females also presented 1.028 higher odds of having ever driven a car. However, as New Zealand Maori aged a reduction in having ever driven was shown in the results (0.688). Typical weekly use of the car by New Zealand Maori males was grouped (p-value = 0.063), whereas female Maori took the car out daily. Increase in age was found not to be associated with how often New Zealand Maori drove. The odds ratio of Maori males was greater than that of females (p-value = 0.463), similarly with age (p-value = 0.192). In comparison both male and female covered a wide distance, although most noticeable were ones made 1.5-25 kilometres.New Zealand non-Maori: New Zealand non-Maori like New Zealand Maori females were also in the majority as to the number having ever driven. Of those still driving a higher number of males (154) compared to female (136) non-Maori were shown to be still driving. However, unlike New Zealand Maori, none of the non-Maori indicated that they offered their driving services to someone else. Typical weekly driving scores between male and female were not statistically significant different (p = 0.201). Median driving distances for male and female were the same (3.00). A varied use of the car was apparent by both New Zealand Maori and non-Maori.Conclusion: Maintaining independence is of primary concern to both New Zealand Maori and non-Maori. To enable this population group to remain as a contributing part of their community further research is required into their decision making, the licensing procedure and surrounding support facilities.

Public Transport Use by People of Advanced Age

Background: Both New Zealand M?ori and non-Maori males were most notable in the number who did not make use of public transport in the last twelve months. Method: Transport subsection of the LiLAC study provided the question area for analysis. Enquiry focused on whether older people had travelled on public transport in the last twelve months, how often they made use of the service and why they did not employ such facility. Methods of analysis included binomial logistic regression, Mann-Whitney U test, regression analysis and descriptive analysis.Results: Participants totaled 931 with 421 New Zealand Maori and 510 New Zealand Maori non-Maori.New Zealand Maori: The greater majority of New Zealand Maori signified that they did not use public transport. Of those that did, it was the females either on their own or with some difficulty. Of those that had engaged the service, (83-88 years), it was only once a week. Reasons given for not using public transport comprised primarily revolved around personal choice and knowledge of possible facilities. Other reasons given included continued use of a car, again not wanting to, no available facilities, family, health and the use of other methods of transportation.New Zealand non-Maori: A significant number of male New Zealand non-Maori indicated that had not used the service in the last twelve months. Although of those that did, a comparable number of both male and female non-Maori had similarly either completed the journey on their own or with difficulty. When asked how often they used the service, the majority indicated that they did not. Reasons being routes either not going where respondents wanted or needed to go; and females expressing concern about accessible bus stops or were inconvenient to use. Conclusion: National and/or local government have the opportunity to make improvements in route design, scheduling and diversity in type of bus being made available with the present and future growth of the older population. Also, in line with future developments such authorities could similarly work in conjunction with other providers such as service groups like Lions and Rotary; Retired Serviceman/women Association, Workingmen’s Clubs, Age Concern, Driving Miss Daisy, private organisations, taxi firms, or the provision of Uber sharing, in considering the type and style of public transport being made available to the public.

Predictors of Physical Activity Among Older Breast Cancer Survivors: Findings From the WHI LILAC Study

We examined the factors associated with physical activity following cancer treatment among older breast cancer survivors from the WHI LILAC study. The majority of participants (n=3,710, mean age=78.8±5.9) were white (86%), and had in situ/localized breast cancer (79%). Women who received radiation therapy, were underweight/normal weight, had fewer reported cancer-related symptoms, no lymphedema, higher self-rated health, higher physical functioning, no pain, no depressive symptoms, and higher social support had significantly greater participation and duration of physical activity (all p<0.05). Women aged <75 who received radiation had longer duration of total minutes of physical activity (β=19.7, p<0.05), while women aged 75-85 who received radiation had shorter duration of total minutes of physical activity (β=-3.2, p<0.05). These results indicate that multiple health and social factors are associated with physical activity in this cohort. Interventions to facilitate physical activity among this group should consider body weight, symptom burden, comorbidity status, and social support.

27475 Efficacy of the BIIB059 monoclonal antibody against BDCA2 in active cutaneous lupus erythematosus (CLE): Subgroup analyses of participants with or without systemic LE (SLE) and with different levels of disease activity

CLE is an autoimmune disease occurring with or without systemic manifestations that significantly impairs health-related QoL. In the phase 2 LILAC (NCT02847598) study (part B), efficacy of BIIB059 50mg, 150mg, and 450mg vs placebo SC Q4W was demonstrated in participants with CLASI-A scores ≥8 and ≥1 subacute and/or chronic CLE lesions. In the subgroup analyses presented here, percentage changes from baseline in CLASI-A scores were analyzed in CLE participants with vs without concomitant SLE and in those with baseline CLASI-A<10 vs ≥10. The overall modified intent-to-treat population consisted of n = 33 (placebo), n = 26 (BIIB059 50mg), n = 25 (BIIB059 150mg), and n = 48 (BIIB059 450mg). The least squares (LS) mean differences from placebo (95%CI) in percentage change in CLASI-A at week 16 for participants with SLE were -31.01 (-61.61,-0.41; n = 11; BIIB059 50mg), -34.93 (-63.86,-6.00; n = 12; BIIB059 150mg), and -19.04 (-44.44,6.35; n = 20; BIIB059 450mg). For participants without SLE, they were -21.08 (-47.00,4.84; n = 15; BIIB059 50mg), -33.58 (-60.36,-6.79; n = 13; BIIB059 150mg), and -36.52 (-59.09,-13.95; n = 28; BIIB059 450mg). The LS mean differences from placebo (95%CI) in percentage change in CLASI-A at week 16 for participants with CLASI-A<10 were 25.38 (58.82,8.06; n = 6; BIIB059 50mg), 59.37 (97.19,21.55; n = 4; BIIB059 150mg), and 28.64 (59.67,2.39; n = 8; BIIB059 450mg). For CLASI-A≥10, they were 23.48 (47.00,0.05; n = 20; BIIB059 50mg), 28.08 (50.72,5.44; n = 21; BIIB059 150mg), and 26.21 (45.91,6.51; n = 40; BIIB059 450mg). The incidence of AEs in the overall study population was similar between the placebo and BIIB059 groups. Although the subgroup analyses are limited by small sample sizes and are not powered for statistical testing, BIIB059 efficacy was observed regardless of SLE presence or disease severity, consistent with the primary analysis in part B of the LILAC study.

POS0698 BIIB059 DEMONSTRATED A CONSISTENT THERAPEUTIC EFFECT ON SRI-4 RESPONSE ACROSS SUBGROUPS OF PARTICIPANTS WITH SYSTEMIC LUPUS ERYTHEMATOSUS IN THE LILAC PHASE 2 STUDY

Background:Type I interferons and other inflammatory mediators derived from plasmacytoid dendritic cells (pDCs) are implicated in systemic lupus erythematous (SLE) pathology. BIIB059 is a humanized monoclonal antibody that targets blood dendritic cell antigen 2 (BDCA2), a pDC-specific receptor. The binding of BIIB059 to BDCA2 leads to rapid internalization of BDCA2 from the surface of pDCs and subsequent inhibition of interferon, cytokine, and chemokine production. In Part A of the 2-part, phase 2 LILAC study (NCT02847598), BIIB059 significantly reduced SLE activity, as evidenced by reduced total active joint count (primary endpoint) and higher SLE Responder Index (SRI-4)1 response (a secondary endpoint) versus placebo.2Objectives:To evaluate SRI-4 response for BIIB059 versus placebo at Week 24 in SLE participant subgroups.Methods:Enrollment in LILAC Part A was open to adults fulfilling ≥ 4 of 11 revised 1997 ACR criteria for classification of SLE, with ≥ 4 tender and ≥ 4 swollen joints, active skin disease, and positive lupus antibodies. Participants were randomized to receive either BIIB059 450 mg or placebo subcutaneously every 4 weeks for 20 weeks (with an additional dose at Week 2). SRI-4 response at Week 24 was analyzed in subgroups, though analyses were limited by small sample sizes and were not powered for statistical testing.Results:In LILAC Part A, 64 and 56 participants were dosed with BIIB059 450 mg and placebo, respectively. At week 24, SRI-4 response rate was observed in favor of BIIB059 regardless of the baseline disease activity, such as SLEDAI-2K &lt;10 versus ≥10, presence of BILAG-2004 grade A or B arthritis, oral corticosteroid usage, positivity for anti-ds DNA autoantibody and/or complement status, with point estimates for least-squares mean differences as well as corresponding 95% CIs consistently favoring BIIB059 (Figure 1). The incidence of adverse events in the overall study population was similar between the placebo and BIIB059 groups.2Conclusion:BIIB059 treatment was associated with greater SRI-4 response rate, consistent among different subgroups of baseline disease activity as measured by SLEDAI-2K and BILAG-2004, glucocorticoid dosage, and serology. These findings provide additional evidence of the potential benefit of BIIB059 for the treatment of patients with active SLE.

A Secondary Analysis of the LILAC Study Regarding Cesarean Birth by Maternal Request in Women Living with HIV.

Background:Latin America has the highest regional average cesarean birth rates. One potential driver is cesarean birth by maternal request (CBMR).Methods:We analyzed of a large prospective cohort study of HIV-infected women in six Latin American countries.Results:Comparisons were made between women who chose CBMR (n = 38) and women with a medical indication for cesarean (n = 683). The only variable associated with CBMR was onset of labor (AOR 0.3 [0.1,0.9], p = 0.04).Conslusion:Spontaneous labor reduced the likelihood of a woman living with HIV to pursue CBMR in a large Latin American cohort.

Abstract OT1-03-04: The importance of central pathology pCR review in an international multicenter neoadjuvant study in HER2 positive early breast cancer - Results of the ABP 980 LILAC trial

Abstract Pathological complete response (pCR) after neoadjuvant therapy is an accepted surrogate endpoint for breast cancer registration trials and is a strong prognostic biomarker especially in high-risk tumor biology. The LILAC study, a comparative trial for the trastuzumab biosimilar ABP 980, was the first international multicenter neoadjuvant breast cancer trial using local and central pathology review for pCR. Here we report concordance between local and central review for the most commonly used pCR definitions. This study included 725 patients with early HER2-positive breast cancer, comparing neoadjuvant ABP 980 and trastuzumab reference product (RP) in combination with anthracycline and taxane-containing chemotherapy. Equivalence of both arms was defined at a significance level of 0.05 by comparing the 2-sided 90% confidence interval (CI) for the risk difference (RD) of pCR between ABP 980 and RP within a predefined margin (-13%, 13%) using definition 2 as described below. pCR was evaluated in local laboratories and in a central laboratory blinded to the local result. The purpose of the independent, central review was to reduce the inter-pathologist variability and provide a more consistent assessment. Central review was performed by 2 independent pathologists; in cases of discordance the specimen was reviewed and decided by a third pathologist (adjudicator). The pCR definition in the primary analysis was no invasive breast cancer in breast and axillary nodes, regardless of ductal carcinoma in situ (DCIS). No invasive tumor in the breast was pCR definition 1, no invasive breast cancer in breast and axillary nodes regardless of DCIS was pCR definition 2, and no invasive breast cancer in breast and axillary nodes and absence of DCIS was pCR definition 3. The RDs and CIs were evaluated for local and central pCR review for all 3 pCR definitions. The results of the neoadjuvant LILAC study have been reported previously, demonstrating no clinically meaningful differences between ABP 980 and RP in HER2-positive early breast cancer. Of the 696 subjects who underwent surgery and had specimens evaluable for pCR review by the local pathologists, 669 specimens were available for central review. Rates of pCR in the local review were 51.1% (ABP 980) and 45% (RP) for definition 1, 48% (ABP 980) and 40.5% (RP) for definition 2, and 37.7% (ABP 980) and 29.6% (RP) for definition 3. The corresponding pCR rates in the central review were 51.3% and 47.3% for definition 1, 47.8% and 41.8% for definition 2, and 29.9% and 26.1% for definition 3. The CI for RD was within the predefined margins for pCR definition 1 in local and central review, whereas it exceeded the prespecified margin in local review for pCR definitions 2 and 3. In the central review the CI was within the margin for the pCR definitions 2 and 3, with the difference between local and central pathology review 1.6% for pCR definition 2 and 4.4% for pCR definition 3, respectively. RDs (90% CI) for all 3 pCR definitions are shown in the Table. The LILAC study demonstrated that a central pathology review for pCR is feasible in a large, international, multicenter neoadjuvant breast cancer trial. Our results show that concordance between local and central pathology can decrease with increasing complexity of the pCR definition. Based on the results, it may be justified to include a central pathology review in neoadjuvant multicenter breast cancer trials with strict pCR definitions. Citation Format: Hanz-Christian Kolberg, Marco Colleoni, Georgia Savva Demetriou, Patricia Santi, Hans Tesch, Yasuhiro Fujiwara, Vladimir Hanes. The importance of central pathology pCR review in an international multicenter neoadjuvant study in HER2 positive early breast cancer - Results of the ABP 980 LILAC trial [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr OT1-03-04.

Cardiac Safety of the Trastuzumab Biosimilar ABP 980 in Women with HER2-Positive Early Breast Cancer in the Randomized, Double-Blind, Active-Controlled LILAC Study.

IntroductionAlthough the human epidermal growth factor receptor 2 (HER2) blocker trastuzumab is generally well tolerated, cardiotoxicity can be an important therapeutic limitation.ObjectiveIn this prespecified analysis, we compared the cardiac safety of the trastuzumab biosimilar ABP 980 (KANJINTI™) and the trastuzumab reference product (RP; Herceptin®) in the phase III LILAC study (ClinicalTrials.gov identifier NCT01901146).MethodsIn the neoadjuvant phase of LILAC, after run-in chemotherapy, 725 patients were randomized 1:1 to ABP 980 (n = 364) or trastuzumab RP (n = 361) plus paclitaxel (every 3 weeks [Q3W] or every week [QW]) for four cycles. After surgery, patients continued treatment Q3W for up to 1 year; ABP 980-treated patients continued ABP 980 (ABP 980/ABP 980; n = 364), and trastuzumab RP-treated patients either continued on the RP (trastuzumab RP/trastuzumab RP; n = 190) or switched to ABP 980 (trastuzumab RP/ABP 980; n = 171). Cardiac safety was monitored by computerized 12-lead electrocardiogram, and left ventricular ejection fraction (LVEF) was assessed by two-dimensional (2D) echocardiogram. LVEF decline was defined as LVEF value decrease from study baseline by ≥ 10 percentage points and to < 50%.ResultsOver the entire study, 22 (3.1%) patients had protocol-defined LVEF decline; no meaningful between-group differences were observed (ABP 980/ABP 980: 2.8%; trastuzumab RP/trastuzumab RP: 3.3%; trastuzumab RP/ABP 980: 3.5%). The incidence of cardiac adverse events was low and comparable in the treatment groups. One grade 3 cardiac failure event reported in the trastuzumab RP/ABP 980 arm, and another in the trastuzumab RP/trastuzumab RP arm, were coincident with LVEF decline. One patient discontinued the investigational product during the adjuvant phase because of cardiac failure.ConclusionThese prespecified analyses confirm the tolerability of ABP 980 and demonstrate clinical similarity of ABP 980 and trastuzumab RP with respect to cardiac safety. No new cardiac safety signals were observed whether patients were receiving ABP 980 or switched from the RP to ABP 980.

Totality of Scientific Evidence in the Development of ABP 980, a Biosimilar to Trastuzumab.

ABP 980 was developed as a biosimilar to trastuzumab, a monoclonal antibody targeting human epidermal growth factor receptor 2 (HER2), that is indicated for the treatment of HER2-positive metastatic breast cancer, early breast cancer (EBC), and metastatic gastric cancer. ABP 980 is approved in the United States, European Union, and Japan for all the indications of trastuzumab, based on the totality of evidence (TOE) gathered by the systematic step-wise accumulation of comparative analytical, preclinical, and clinical (pharmacokinetics [PK], efficacy, safety and immunogenicity) data for ABP 980 and trastuzumab reference product (RP). As a key first step of the ABP 980 biosimilar program, comprehensive analytical characterization of critical quality attributes established that ABP 980 is structurally and functionally similar to trastuzumab RP. Complementing these data, results of non-clinical pharmacology, toxicology, and toxicokinetic studies supported similarity between ABP 980 and trastuzumab RP. A randomized study in healthy subjects demonstrated clinical PK equivalence of ABP 980 relative to trastuzumab RP in these subjects. In the final clinical evaluation step, a randomized comparative study (LILAC) confirmed the lack of clinically meaningful differences between ABP 980 and trastuzumab RP in efficacy, safety, and immunogenicity in women with HER2-positive EBC in the neoadjuvant–adjuvant setting. Neoadjuvant EBC represented a sensitive homogenous population for biosimilar demonstrations, and the primary endpoint of pathologic complete response served as a sensitive surrogate endpoint. An important aspect of the LILAC study design is that it is the only study that evaluated the effect of switching from the trastuzumab RP to a trastuzumab biosimilar during the adjuvant phase. No new or unexpected safety signals emerged in the clinical evaluations, with the safety profile of ABP 980 consistent with that previously described for trastuzumab. Overall, the TOE data generated for ABP 980 support the conclusion that it is highly similar to trastuzumab RP, thus providing the scientific justification for extrapolation to all the approved indications of trastuzumab.

Cardiac safety of the trastuzumab biosimilar ABP 980 in women with HER2-positive early breast cancer in the LILAC study.

557 Background: Although trastuzumab is generally well-tolerated, cardiotoxicity is the main limitation in its use, leading to a severe heart failure in 2-4% of patients in adjuvant trials. In the phase 3 LILAC trial, trastuzumab biosimilar ABP 980 demonstrated similar efficacy, safety, and immunogenicity to trastuzumab reference product (RP) in women with HER2-positive early breast cancer. Here we report analyses comparing cardiac safety of ABP 980 and RP. Methods: In the neoadjuvant phase, all 725 patients received 4 cycles of chemotherapy with epirubicin + cyclophosphamide Q3W and were then randomized 1:1 to ABP 980 (n = 364) or RP (n = 361) with a loading dose of 8 mg/kg, then 6 mg/kg IV Q3W for 3 cycles plus paclitaxel Q3W (4 cycles) or QW (12 cycles). After surgery, patients received investigational product (IP) Q3W for up to 1 year; ABP 980-treated patients continued ABP 980, and RP-treated patients either continued RP (n = 190) or switched to ABP 980 (RP/ABP 980; n = 171). AEs were assessed every 3 weeks and cardiac safety every 3 months. Cardiac safety was monitored by computerized 12-lead ECG; LVEF was assessed by 2D ECHO. LVEF decline was defined as LVEF value decrease from study baseline by ≥10 percentage points and to &lt; 50%. Results: Treatment groups were well balanced with regard to IP disposition. Over the entire study, 22 (3.1%) patients had LVEF decline by ≥10 percentage points compared to baseline and to &lt; 50%; no meaningful between-group differences were observed (ABP 980:10/359 [2.8%], RP: 6/184 [3.3%], RP/ABP 980: 6/171 [3.5%]). The incidence of cardiac AEs was low and comparable in treatment groups. One grade 3 cardiac failure event was reported in the RP/ABP 980 arm; another in the RP arm was coincident with LVEF decline. No patient discontinued IP during adjuvant phase because of cardiac failure. Conclusions: These pre-specified analyses confirm the tolerability of ABP 980 and demonstrate clinical similarity of ABP 980 and RP with respect to cardiac safety. The incidence of LVEF decline was consistent with the known cardiac safety profile of the RP. No new cardiac safety signals were observed whether patients were on ABP 980 or switched from RP to ABP 980. Clinical trial information: NCT01901146.

ABP 980: A Trastuzumab Biosimilar.

ABP 980 (KANJINTI™) is a biosimilar of the reference anti-HER2 antibody trastuzumab. In the EU, ABP 980 is approved for use in all indications for which reference trastuzumab is approved, including HER2-positive early breast cancer, metastatic breast cancer and metastatic gastric cancer. ABP 980 has similar physicochemical and functional properties to those of reference trastuzumab, and the pharmacokinetic biosimilarity of the agents has been shown in healthy subjects. In the phase 3 LILAC study, ABP 980 demonstrated similar clinical efficacy (based on central laboratory review sensitivity analysis) and tolerability to that of reference trastuzumab in patients with HER2-positive early breast cancer. The tolerability, immunogenicity and safety profiles of ABP 980 were similar to those of reference trastuzumab, and a single switch from reference trastuzumab to ABP 980 had no impact on the immunogenicity or safety of ABP 980. The role of reference trastuzumab in the management of HER2-positive early breast cancer, metastatic breast cancer and metastatic gastric cancer is well established and ABP 980 provides an effective biosimilar alternative for patients requiring trastuzumab therapy.

Efficacy and safety of ABP 980 compared with reference trastuzumab in women with HER2-positive early breast cancer (LILAC study): a randomised, double-blind, phase 3 trial

ABP 980 (Amgen Inc, Thousand Oaks, CA, USA) is a biosimilar of trastuzumab, with analytical, functional, and pharmacokinetic similarities. We compared the clinical safety and efficacy of ABP 980 with that of trastuzumab in women with HER2-positive early breast cancer. We did a randomised, multicentre, double-blind, active-controlled equivalence trial at 97 study centres in 20 countries, mainly in Europe and South America. Eligible women were aged 18 years or older, had histologically confirmed HER2-positive invasive early breast cancer, an Eastern Cooperative Oncology Group performance status score of 0 or 1, and were planning to have surgical resection of the breast tumour with sentinel or axillary lymph node dissection and neoadjuvant chemotherapy. After four cycles of run-in anthracycline-based chemotherapy, patients were assigned 1:1 to receive ABP 980 or trastuzumab with a permuted block design (blocks of four) computer-generated randomisation schedule. Patients received neoadjuvant therapy with a loading dose (8 mg/kg) of ABP 980 or trastuzumab plus paclitaxel 175 mg/m2 in a 90 min intravenous infusion, followed by three cycles of 6 mg/kg intravenous ABP 980 or trastuzumab plus paclitaxel 175 mg/m2 every 3 weeks in 30 min intravenous infusions (or 80 mg/m2 paclitaxel once per week for 12 cycles if that was the local standard of care). Randomisation was stratified by T stage, node status, hormone receptor status, planned paclitaxel dosing schedule, and geographical region. Surgery was completed 3-7 weeks after the last dose of neoadjuvant treatment, after which adjuvant treatment with ABP 980 or trastuzumab was given every 3 weeks for up to 1 year after the first dose in the study. Patients had been randomly assigned at baseline to continue APB 980, continue trastuzumab, or switch from trastuzumab to APB 980 as their adjuvant treatment. The co-primary efficacy endpoints were risk difference and risk ratio (RR) of pathological complete response in breast tissue and axillary lymph nodes assessed at a local laboratory in all patients who were randomly assigned and received any amount of neoadjuvant investigational product and underwent surgery. We assessed safety in all patients who were randomly assigned and received any amount of investigational product. This trial is registered with ClinicalTrials.gov, number NCT01901146 and Eudra, number CT 2012-004319-29. Of 827 patients enrolled, 725 were randomly assigned to receive ABP 980 (n=364) or trastuzumab (n=361). The primary endpoint was assessable in 696 patients (358 who received ABP 980 and 338 who received trastuzumab). Pathological complete response was recorded in 172 (48%, 95% CI 43-53) of 358 patients in the ABP 980 group and 137 (41%, 35-46) of 338 in the trastuzumab group (risk difference 7·3%, 90% CI 1·2-13·4; RR 1·188, 90% CI 1·033-1·366), with the upper bounds of the CIs exceeding the predefined equivalence margins of 13% and 1·318, respectively. Pathological complete response in the central laboratory assessment was seen in 162 (48%) of 339 patients assigned to ABP 980 at baseline and 138 (42%) of 330 assigned to trastuzumab at baseline (risk difference 5·8%, 90% CI -0·5 to 12·0, and RR 1·142, 90% CI 0·993 to 1·312). Grade 3 or worse adverse events during the neoadjuvant phase occurred in 54 (15%) of 364 patients in the ABP 980 group and 51 (14%) of 361 patients in the trastuzumab group, of which the most frequent grade 3 or worse event of interest was neutropenia, occurring in 21 (6%) patients in both groups. In the adjuvant phase, grade 3 or worse adverse events occurred in 30 (9%) of 349 patients continuing ABP 980, 11 (6%) of 171 continuing trastuzumab, and 13 (8%) of 171 who switched from trastuzumab to ABP 980, the most frequent grade 3 or worse events of interest were infections and infestations (four [1%], two [1%], and two [1%]), neutropenia (three [1%], two [1%], and one [1%]), and infusion reactions (two [1%], two [1%], and three [2%]). Two patients died from adverse events judged to be unrelated to the investigational products: one died from pneumonia while receiving neoadjuvant ABP 980 and one died from septic shock while receiving adjuvant ABP 980 after trastuzumab. Although the lower bounds of the 90% CIs for RR and risk difference showed non-inferiority, the upper bounds exceeded the predefined equivalence margins when based on local laboratory review of tumour samples, meaning that non-superiority was non-conclusive. In our sensitivity analyses based on central laboratory evaluation of tumour samples, estimates for the two drugs were contained within the predefined equivalence margins, indicating similar efficacy. ABP 980 and trastuzumab had similar safety outcomes in both the neoadjuvant and adjuvant phases of the study. Amgen.

Efficacy analyses of central laboratory pCR results from the LILAC study comparing the biosimilar ABP 980 and trastuzumab.

583Background: The phase 3 LILAC Study compared ABP 980 with trastuzumab (TRAS) on pathologic complete response (pCR) in women with HER2+ early breast cancer. The primary efficacy results, based on...

Fear of recurrence among older breast, ovarian, endometrial, and colorectal cancer survivors: Findings from the WHI LILAC study.

To examine the prevalence of and factors associated with fear of recurrence (FCR) following treatment for breast, ovarian, endometrial, and colorectal cancer among older women. Participants were enrolled in the Women's Health Initiative Life and Longevity After Cancer study. Descriptive statistics and multivariate logistic regression models were used to assess the association of demographic, clinical, and quality of life variables with survivors' FCR, dichotomized as <14 (low) or ≥14 (high) using the Cancer Worry Scale. Out of the 4259 participants, 3124 (73.3%) were diagnosed with breast cancer, 559 (13.1%) with colorectal cancer, 493 (11.6%) with endometrial cancer, and 83 (2%) with ovarian cancer. There were no significant differences in FCR by cancer type (P=.75), with a mean scale score of 10.8±2.87 for all participants combined. Approximately 16% (n=679) were in the high FCR group. Multivariable analyses indicated that being younger at diagnosis, reporting a symptom score of ≥8, receipt of chemotherapy, and lower self-rated health were significantly associated with high FCR. Women who were widowed or never married were less likely to report high FCR. Fear of recurrence was experienced by a small but important proportion of older, long-term cancer survivors and is associated with multiple demographic and clinical variables. These results will better inform researchers and clinicians regarding the individuals who are at risk of FCR.