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Makoto Nishio
Moderator of
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GR 02 - Management of Immunotherapy-Related Adverse Events (ID 521)
- Event: WCLC 2017
- Type: Grand Rounds
- Track: Immunology and Immunotherapy
- Presentations: 8
- Moderators:Edward Brian Garon, Makoto Nishio
- Coordinates: 10/17/2017, 11:00 - 12:30, Main Hall
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GR 02.00 - Intro (ID 11065)
11:00 - 11:02 | Presenting Author(s): Makoto Nishio
- Abstract
Abstract not provided
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GR 02.01 - Case Study (ID 10951)
11:02 - 11:07 | Presenting Author(s): Edward Brian Garon
- Abstract
- Presentation
Abstract not provided
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GR 02.02 - Case Study (ID 10952)
11:07 - 11:12 | Presenting Author(s): Makoto Nishio
- Abstract
- Presentation
Abstract not provided
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GR 02.03 - Pathophysiology of Immunotherapy-related Toxicity (ID 7631)
11:12 - 11:27 | Presenting Author(s): Ji-Youn Han
- Abstract
- Presentation
Abstract:
Clinical development and approval of immune-checkpoint inhibitors have transformed the treatment of many types of tumors. In recent years, three anti-PD-1 or –PD-L1 antibodies have been approved for advanced NSCLC, including nivolumab, pembrolizumab, and atezolizumab. These antibodies have entered into the routine practice of treatment for patients with advanced NSCLC. In addition, all clinical trials, which compared the efficacy of anti-PD-1 or PD-L1 antibodies with chemotherapy, demonstrated that these antibodies are less toxic than chemotherapy (1-4). However, these immunomodulatory antibodies have led to the emergence of unusual autoimmune toxicities, also called immune-related adverse events (IrAEs). IrAEs management is challenging because they may concern many organ systems, including the skin, hepatic, gastrointestinal, endocrine, and pulmonary systems. Furthermore, given the recent success of immunotherapy, the incidence of immunotoxicity will likely continue to rise as these therapies become more widely used not only in advanced diseases but also in early stage diseases (5). Treatment-related toxicities have correlated with better response in some cases, and it is probable that serious adverse events from immune-mediated reaction will increase as immunotherapeutic approaches become more effective (6). Adding more complexity, the natural history of certain irAEs is unpredictable. The onset of clinical disease manifestation can vary from weeks to decades after the appearance of autoantibodies (7). Thus understanding irAEs is critical for early detection and appropriate management of patients. We will discuss the mechanisms that might be related with the induction of anutoimmunity from immunotherapy. References: Lancet. 2016; 387(10027):1540-50. N Engl J Med. 2015;373(2):123-35. N Engl J Med. 2015; 373(17):1627-39. Lancet. 2016;387(10030):1837-46. Eur J Cancer. 2016 ;54:139-48. Blood. 2011;118(3):499-509. Nat Med. 2017 ;23(5):540-547.
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GR 02.04 - Current Standard in Monitoring of Immunotherapy-related Toxicity (ID 7632)
11:27 - 11:42 | Presenting Author(s): Clarissa Mathias
- Abstract
- Presentation
Abstract:
Checkpoint protein inhibition is associated with on- and off-target, cell and metabolic toxic effects that need to be carefully monitored and managed during and after treatment[1]. Despite important clinical benefits, immunotherapy is associated with a unique spectrum of side effects termed immune-related adverse events (irAEs) or, occasionally, adverse events of special interest. IrAEs include dermatologic, gastrointestinal, hepatic, endocrine, and other less common inflammatory events. Most irAEs remain mild in intensity but approximately 10% of patients treated with immune checkpoint blockade agents will develop severe, sometimes life-threatening, grade 3–4 dysimmune toxicities. Before prescribing immune checkpoint blockade agents to patients, oncologists need to be aware of the toxicity spectrum and must identify potential risk factors that could favor the emergence of irAEs[2]. Patients should be informed that most of these irAEs are mild and reversible if detected early and specifically addressed. Therefore, patients should be educated about signs of organ inflammation that would require prompt referral such as diarrhea, blood or mucus in the stool, severe abdominal pain, fatigue, weight loss, nausea, vomiting, thirst or appetite increase, polyuria, extensive rash, severe pruritus, shortness of breath, coughing, headache, confusion, muscle weakness, numb-ness, arthralgia or swelling joints, myalgia, unexplained fever, hemorrhagic syndrome and severe loss of vision in one or both eyes. Any new symptom or deterioration of pre-existing symptoms must at least be monitored attentively and if necessary be explored to determine its etiology and rule out any dysimmune cause that could be worsened by immunotherapy continuation. Although early recognition and treatment improves symptoms and severity, a broad differential diagnosis should be entertained. It is recommended that all patients receiving these agents routinely have thyroid function studies, complete blood counts, and liver function and metabolic panels at each treatment and at intervals of 6 to 12 weeks for the first 6 months after finishing treatment. Adrenocorticotropic hormone, cortisol, and in men, testosterone should also be checked in patients who develop fatigue and nonspecific symptoms. Follow-up testing may need to increase in frequency based on individual response and adverse events that occur[3]. It is challenging to differentiate between infection, early pulmonary edema, alveolar hemorrhage, immune-mediated pneumonitis, immune-related tumor inflammation, and tumor progression (figure 1). Infections, thromboembolism, congestive heart failure, and COPD are among the many diagnoses to consider before committing patients to a long course of steroid therapy with additional consideration of prophylaxis for opportunistic (i.e., pneumocystis with or without fungal) infections. Pulmonary specialty consultation and consideration of bronchoscopic evaluation with lavage to assess for infections alongside biopsies of lung tissue can help narrow the diagnosis. IrAEs can develop at any time: at the beginning, under treatment and after immunotherapy termination. As shown with nivolumab, the majority of irAEs occur within the first 4 months[4]. On the basis of this median time to onset, irAEs could be classified as early (median time to onset <2 months) and late toxicities (median time to onset >2 months). Early toxicities include skin (5 weeks), gastrointestinal (7.3 weeks) and hepatic (7.7 weeks), whereas late toxicities include pulmonary (8.9 weeks), endocrine (10.4 weeks) and renal (15.1 weeks). However, clinicians should keep in mind that all toxicities can develop at any time since confidence interval may vary widely among organs: 0.1–57 weeks for skin; 0.1–37.6 weeks for gastrointestinal. Rarely, other irAEs may occur after week 24 with any checkpoint-blocking antibodies. In trials including maintenance ipilimumab, colitis has been seen 47 months from initiation of treatment[5]. Patients with prior autoimmune diseases or a history of viral hepatitis have been excluded from receiving ipilimumab on trials, but recent data suggest that the drug can be given safely to those patients. Nonetheless, extreme caution should be taken in treating patients with recent or ongoing autoimmune conditions, particularly any type of inflammatory bowel disease[6]. Management algorithms have been established for patients treated with immunotherapy, which may be useful in helping to manage irAEs but they are based upon clinical experience, since no prospective trials have been conducted to guide the treatment of irAEs. Resolution of irAEs usually follows a temporal pattern: 2 weeks for gastrointestinal, 4 weeks for hepatic, 6 weeks for skin, and 20 weeks for endocrine irAEs[7]. The key to successful management of checkpoint protein antibody toxicities is early diagnosis, high suspicion, excellent patient-provider communication, and rapid and aggressive use of corticosteroids and other immune suppressants for irAEs. Effective biomarkers to predict toxicity could be valuable in the development of these agents. Figure 1 FIGURE 1: CT scan of a patient with non-small cell lung cancer presenting with cough, dyspnea, and hypoxia on an immunotherapy drug. References: Fecher LA, et al: Ipilimumab and its toxicities: A multidisciplinary approach. Oncologist 18:733-743, 2013 Champiat S. et al., Management of immune checkpoint blockade dysimmune toxicities: a collaborative position paper Annals of Oncology Volume 27, No. 4, 559-74, 2016 Weber JS et. al. Toxicities of Immunotherapy for the Practitioner, J of Clin Oncol., volume 33, No 18, 2092-2099, 2015 Weber JS et al. Safety profile of nivolumab (NIVO) in patients (pts) with advanced melanoma (MEL): a pooled analysis. J Clin Oncol 2015; 33 (suppl): abstr 9018 Sarnaik AA et al: Extended dose ipilimumab with a peptide vaccine: Immune corre- lates associated with clinical benefit in patients with resected high-risk stage IIIc/IV melanoma. Clin Cancer Res 17:896-906, 2011 Hodi FS, et al: Ipilimumab plus sargramostim vs ipilimumab alone for treatment of metastatic melanoma: A randomized clinical trial. JAMA 312:1744-1753, 2014 Weber JS, et al. Management of immune-related adverse events and kinetics of response with ipilimumab. J Clin Oncol. 2012;30:2691-2697
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GR 02.05 - Practical Management of Immunotherapy-related Toxicity (ID 7633)
11:42 - 11:57 | Presenting Author(s): Scott N. Gettinger
- Abstract
- Presentation
Abstract not provided
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GR 02.06 - Who Should Not Receive Immunotherapy? (ID 7634)
11:57 - 12:12 | Presenting Author(s): Terufumi Kato
- Abstract
- Presentation
Abstract not provided
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GR 02.07 - Toxicity of Induction Immunotherapy Followed by Radiotherapy: How to Minimize It? (ID 7635)
12:12 - 12:27 | Presenting Author(s): Dirk K De Ruysscher
- Abstract
- Presentation
Abstract:
Checkpoint inhibitors have changed the outcome of patients with metastatic non-small cell lung cancer (NSCLC). Radiotherapy has consistently been shown to activate key elements of the immune system that are responsible for resistance for immune therapy. Radiation upregulates MHC-class I molecules that many cancer cells lack or only poorly express, tumor-associated antigens, provokes immunogenic cell death, activates dendritic cells, decreases regulatory T-cells (Tregs) in the tumor, broadens the T-cell repertoire and increases T-cell trafficking, amongst many other effects. Radiation may convert a completely or partly poorly or non-immunogenic tumor immunogenic. Radiotherapy in combination with different forms of immune therapy such as anti-PD-(L)1, anti-CTLA4,immunocytokines, dendritic cell vaccination and Toll-like receptor agonists improved consistently local tumor control and very interestingly, lead to better systemic tumor control (the “abscopal” effect) and the induction of specific anti-cancer immunity with a memory effect. At the time of writing, the most compelling data in human studies come from Shaverdian et al. (Lancet Oncol 2017). In 97 patients with advanced NSCLC treated on the phase 1 KEYNOTE-001 trial it was shown that patients having received prior radiotherapy, the six-month PFS rate was 54.3% vs. 21.4% among never irradiated patients. The median OS was 11.6 months and the six-month OS estimate was 75.3% among patients who previously received extra-cranial radiation therapy vs. a median OS of 5.3 months and a six-month OS estimate of 45.3% among patients who did not receive extra-cranial radiation therapy. Patients with prior thoracic radiotherapy had more overall pulmonary toxicity compared to never irradiated patients: 12.5% vs. 1.4%. Unfortunately, no dose-volume parameters such as the mean lung dose are available of these patients. The biggest concern of combining radiotherapy and immune treatment is indeed a higher incidence of pneumonitis. Many studies are investigating the combination of radiotherapy, chemotherapy and immune therapy in lung cancer, including the PACIFIC, the STIMULI and the NICOLAS studies. The results of these studies have not been reported at the time of writing, but none of the trials have been closed prematurely. Moreover, as radiotherapy is used to stimulate the immune system, classical concept in dose and volume will have to be investigated again. Less dose in a few fractions may suffice, and margins may be reduced, which in turn will lead to less side effects. When studied meticulously, radiotherapy and immune therapy may well turn out to be efficacious and with few side effects and additional costs.
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Author of
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GR 02 - Management of Immunotherapy-Related Adverse Events (ID 521)
- Event: WCLC 2017
- Type: Grand Rounds
- Track: Immunology and Immunotherapy
- Presentations: 2
- Moderators:Edward Brian Garon, Makoto Nishio
- Coordinates: 10/17/2017, 11:00 - 12:30, Main Hall
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GR 02.00 - Intro (ID 11065)
11:00 - 11:02 | Presenting Author(s): Makoto Nishio
- Abstract
Abstract not provided
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GR 02.02 - Case Study (ID 10952)
11:07 - 11:12 | Presenting Author(s): Makoto Nishio
- Abstract
- Presentation
Abstract not provided
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MA 12 - Circumventing EGFR Resistance (ID 665)
- Event: WCLC 2017
- Type: Mini Oral
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:Wan Ling Tan, Nobuyuki Yamamoto
- Coordinates: 10/17/2017, 11:00 - 12:30, F205 + F206 (Annex Hall)
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MA 12.02 - Phase I/II Study of S49076, a MET/AXL/FGFR Inhibitor, Combined with Gefitinib in NSCLC Patients Progressing on EGFR TKI (ID 7974)
11:05 - 11:10 | Author(s): Makoto Nishio
- Abstract
- Presentation
Background:
S49076 is a potent ATP-competitive TKI that targets MET, AXL and FGFR1/2/3 at clinically relevant doses. Preclinical data showed that combination of S49076 with 1[st] generation EGFR-TKI can overcome acquired resistance to EGFR inhibition in a NSCLC EGFR-mutated MET-amplified cell model. Here we report interim phase I data from NSCLC patients treated with S49076 in combination with gefitinib to overcome acquired non-EGFR-T790M-mediated resistance to EGFR TKI (1[st]/2[nd] generation).
Method:
This is a phase I dose-finding study of S49076 combination with a standard dose of gefitinib using a modified Bayesian Continual Reassessment Method with S49076 doses of 500 and 600mg. Both agents are administered orally once daily. The primary objective is to determine the safety profile of the combination and the recommended phase 2 dose (RP2D) based on safety assessments. Patients are selected according to tumor status; they carried an activating-EGFR mutation without secondary T790M mutation and with at least one of the following dysregulations: MET IHC3+, MET FISH 2+/3+, or AXL IHC 2+/3+.
Result:
In June 2017, molecular screening was performed in 48 EGFR/T790M-negative tumor samples to assess MET and AXL dysregulation. 17/48 met the molecular eligibility criteria: 12/17 with MET overexpression/amplification; 4/17 with both MET overexpression/amplification and AXL overexpression; and 1/17 with AXL overexpression. As regards S49076 dose levels, 4 patients were included at 500 mg and 4 at 600 mg. Five patients discontinued treatment: 4 disease progression and 1 consent withdrawal. The most frequent related AEs (≥2 patients) were asthenia (n=5), diarrhea, nausea and paronychia (n=4 each), ASAT/ALAT increase, anemia, and yellow skin (n=3 each), peripheral edema, stomatitis, blood creatinine increase, vomiting, hypoalbuminemia, and decreased appetite (n=2 each); most were grade 1-2. A DLT occurred in 1 patient at 600mg (grade 3 stomatitis). The other severe related AEs included grade 3 ALAT increase, asthenia, and neutrophil count decrease. Concomitant intake of gefitinib did not appear to modify the S49076 PK profile as compared to previous data. The best overall response rate were partial response (PR, 1/8), stable disease (SD, 6/8), and progressive disease (1/8), including 3 patients with PR/SD ≥6 months.
Conclusion:
According to preliminary data, the frequency of MET and AXL dysregulations is consistent with the literature. Combination of S49076 and gefitinib is well tolerated and safety data are consistent with the overall safety profile of each drug. The phase II part of this study will start once the RP2D is defined to evaluate the anti-tumour activity of the combination.
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MA 16 - Mediastinal, Tracheal and Esophageal Tumor: Multimodality Approaches (ID 675)
- Event: WCLC 2017
- Type: Mini Oral
- Track: Thymic Malignancies/Esophageal Cancer/Other Thoracic Malignancies
- Presentations: 1
- Moderators:K. Shibuya, Francoise Mornex
- Coordinates: 10/17/2017, 15:45 - 17:30, Room 313 + 314
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MA 16.04 - Phase II Trial of S-1 Treatment as Palliative-Intent Chemotherapy for Previously Treated Advanced Thymic Carcinoma (ID 8627)
16:00 - 16:05 | Author(s): Makoto Nishio
- Abstract
- Presentation
Background:
Thymic carcinoma (TC) is a rare cancer with minimal evidence of survival with palliative-intent chemotherapy. Sunitinib and everolimus monotherapies have been proposed as active molecular-targeted approaches based on phase II (Ph II) trials, and S-1, an oral fluoropyrimidine, has been described in the NCCN guideline as an active cytotoxic agent for refractory TC based on a case series. Therefore, we conducted a Ph II trial to study the result of S-1 treatment in patients with refractory TC.
Method:
In this Ph II study performed at three cancer centers in Tokyo, we aimed to enroll 26 TC patients previously treated with platinum-based chemotherapy. The patients received S-1 orally twice daily at a dose of 40–60 mg/m2 for 4 weeks, followed by 2 weeks off until progressive disease or unacceptable toxicities. S-1 was used off-label. The primary end-point was determining the objective response rate, and secondary endpoints were progression-free survival (PFS), overall survival (OS), and toxicities.
Result:
Twenty-six patients (10 males) were recruited between November 2013 and May 2016. The median age was 63 (27–74) years. Among the 26 patients, 23 had squamous cell carcinoma histology and 10 had an ECOG performance status of 0. Additionally, one patient showed complete response and seven patients showed partial responses, resulting in a 30.8% response rate (95% confidence interval [CI], 16.5–50.0) and a 65.4% disease control rate (95% CI, 46.2–80.6). After a median follow-up of 13.4 months, the median PFS was 4.3 months (95% CI, 2.3–7.6 months) and median OS was 23.4 months (95% CI, 12.8–not reached). Treatment-related adverse events (AEs) of grade ≥3 included neutropenia (12%), skin rash (8%), elevated ALT, decreased WBC count, and fatigue (4%). No treatment-related death was observed. However, treatment was discontinued in three patients (12%) because of AEs.
Conclusion:
S-1 for refractory TC confirmed clinical activity with good tolerability. Clinical trial identification: UMIN000010736
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MA 17 - Locally Advanced NSCLC (ID 671)
- Event: WCLC 2017
- Type: Mini Oral
- Track: Locally Advanced NSCLC
- Presentations: 1
- Moderators:S. Jheon, Georgios Stamatis
- Coordinates: 10/17/2017, 15:45 - 17:30, F203 + F204 (Annex Hall)
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MA 17.06 - Safety Data from Randomized Phase II Study of CDDP+S-1 vs CDDP+PEM Combined with TRT for Locally Advanced Non-Squamous NSCLC (ID 8296)
16:20 - 16:25 | Author(s): Makoto Nishio
- Abstract
- Presentation
Background:
Both cisplatin (CDDP)+S-1 and CDDP+pemetrexed (PEM) can be given at full systemic doses with thoracic radiotherapy (TRT) in locally advanced non-small cell lung cancer (NSCLC), and CDDP+PEM is one of the standard chemotherapy regimens in patients with advanced non-squamous (non-sq) NSCLC. This multicenter, randomized, open-label, phase II study (SPECTRA) compared the efficacy and safety of the two above-mentioned promising regimens combined with TRT in patients with unresectable locally advanced non-sq NSCLC.
Method:
Patients were randomly assigned to receive CDDP+S-1 (CDDP 60mg/m2, d1, and S-1 80mg/m2, d1-14, q4w, up to 4 cycles) or CDDP+PEM (CDDP 75mg/m2, d1, and PEM 500mg/m2, d1, q3w, up to 4 cycles) combined with TRT 60Gy in 30 fractions. The primary endpoint was 2-year progression-free survival (PFS) rate. If the 2-year PFS rate is assumed to be 25% in the inferior therapy group and 15% higher in the superior therapy group of this study, the sample size needed for selection of the optimum treatment group at a probability of approximately 95% will be 51 cases/group with the Simon’s selection design. The sample size was set at 100 patients.
Result:
Between Jan 2013 and Oct 2016, 102 patients were enrolled in this study from 9 institutions in Japan. All 102 patients were eligible and assessable, of whom 52 were assigned to CDDP+S-1 and 50 to CDDP+PEM. Baseline characteristics were similar (CDDP+S-1/CDDP+PEM): median age (range) 64.5 (39-73)/63.5 (32-74) years; women, n=17 (33%)/n=17 (34%); stage IIIB, n=21 (40%)/n=20 (40%); ECOG PS of 1, n=14 (27%)/n=14 (28%); never smoker, n=12 (23%)/n=12 (24%); and adenocarcinoma, n=47(90%)/n=45(90%). Completion rate of TRT (60Gy) and chemotherapy (4 cycles) was 92%/98% and 73%/86%, respectively. Response rate was 60%/64%. Grade 3 or higher toxicities included febrile neutropenia (12%/2%), anorexia (8%/16%), diarrhea (8%/0%), esophagitis (6%/8%), pneumonia (4%/4%), neutropenia (38%/52%), anemia (8%/12%), thrombocytopenia (4%/6%), and hyponatremia (12%/12%). Grade 1 radiation pneumonitis was observed in 8 (15%)/2 (4%) patients on the basis of the data collected 30 days or less after the discontinuation of protocol treatment. No treatment-related death was observed. The data on PFS and overall survival are immature.
Conclusion:
Response rate was similar between the two arms. Toxicities were tolerable and manageable in both arms; however febrile neutropenia was more frequently observed in the CDDP+S-1 arm. We will present the updated safety data of this study at the conference. Survival data will be analyzed in late 2018.
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OA 05 - Next Generation TKI (ID 657)
- Event: WCLC 2017
- Type: Oral
- Track: Advanced NSCLC
- Presentations: 2
- Moderators:James Chih-Hsin Yang, Fiona Blackhall
- Coordinates: 10/16/2017, 15:45 - 17:30, Room 301 + 302
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OA 05.03 - Clinical Activity of ASP8273 in Asian Non-Small Cell Lung Cancer Patients with EGFR Activating and T790M Mutations (ID 7889)
16:05 - 16:15 | Author(s): Makoto Nishio
- Abstract
- Presentation
Background:
Epidermal growth factor receptor (EGFR) activating mutations confer sensitivity to tyrosine kinase inhibitor (TKI) treatment for non-small cell lung cancer (NSCLC) and occur in ~50% of East Asian patients with NSCLC. While initial TKI treatment can be effective, acquired resistance inevitably develops with a secondary mutation (T790M). ASP8273 is a highly specific, irreversible, once-daily, oral, EGFR TKI which inhibits both activating (eg, exon 19 deletions, L858R) and resistance (eg T790M) mutations.
Method:
This dose-escalation/dose-expansion study (NCT02192697) was conducted in two phases. In Phase 1, adult Japanese patients (≥20 yr) with NSCLC previously treated with ≥1 EGFR TKI were enrolled and received escalating ASP8273 doses (25–600mg) to assess safety/tolerability as well as to determine maximum tolerated dose (MTD) and/or recommended phase 2 dose (RP2D). In phase 2, adult T790M-positive NSCLC patients in Japan, Korea, and Taiwan were enrolled to further define the ASP8273 safety/tolerability profile at RP2D and determine antitumor activity (assessed using RECIST v1.1). Antitumor activity in phase 2 was evaluated according to Simon’s 2-stage design (uninteresting response=0.3, desired response=0.5, α=0.05, β=0.1). If ≥9 of 24 ASP8273-treated patients achieved a desired response in the first stage, then 39 additional patients would be enrolled. If ≥ 25 of the 63 total patients achieved response, ASP8273 would be considered to have antitumor effects.
Result:
A total of 123 patients (n=47 phase 1; n=76 phase 2) were enrolled. In both phases, more women were enrolled. The median age was 65 years in phase 1 and 63 years in phase 2. Based on phase 1 findings, MTD and RP2D were 400mg and 300mg, respectively. As 27 of the 63 patients treated with ASP8273 300mg in the first and second stages combined achieved a clinical response (based on independent central review), ASP8273 was determined to have antitumor activity (ORR=42.9%; 95% CI: 30.5–56.0). The ORR at week 24 in all patients in the full analysis set was 42.1% (n=32/76; 95% CI: 30.9, 54.0). The median duration of PFS (central review) was 8.1 months (95%CI: 5.6,--). The most commonly reported treatment-emergent AEs (TEAE) in phase 2 were diarrhea (n=50/76), nausea (n=31/76), increased alanine aminotransferase (n=27/76), decreased appetite and vomiting (n=26/76 each), and hyponatremia (n=25/76). Drug-related TEAEs were reported in 93.4% (n=71/76) of patients, the most common of which was diarrhea (n=43/76).
Conclusion:
ASP8273 was generally well tolerated and demonstrated antitumor activity in Asian patients with both EGFR activating and T790M mutations.
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OA 05.08 - Final Result of Phase I/II Study (AF-001JP) of Alectinib, a Selective CNS-Active ALK Inhibitor, in ALK+ NSCLC Patients (Pts) (ID 9732)
17:00 - 17:10 | Presenting Author(s): Makoto Nishio
- Abstract
- Presentation
Background:
Alectinib (ALC) is a selective, CNS-active ALK tyrosine kinase inhibitor. In two Phase 3 studies (J-ALEX and ALEX), ALC proved superior efficacy and tolerability compared to crizotinib (CRZ). Here we report the final efficacy and safety results of the 46 pts enrolled in the phase II part of study AF-001JP with a longer follow-up period than that observed in J-ALEX and ALEX studies.
Method:
ALC 300 mg b.i.d was given to ALK+ NSCLC pts who were ALK inhibitor-naive and had disease progression after at least one line of chemotherapy to investigate the efficacy and safety until the investigator confirmed no further clinical benefits.
Result:
This study was completed in December 2016. The median treatment duration was 46.1 months (range: 1-62). 20 of 46 pts were on treatment with alectinib at the study termination. Progressive disease (PD) was confirmed in 20 pts (43%). Median PFS was not reached and 4-year PFS rate was 52% (95% CI: 36-66). 14 of 46 pts had CNS metastasis at baseline. Median PFS was 38 months (95% CI: 9-NE) in pts with CNS metastases and was not reached in pts without CNS metastases. Four pts had CNS progression and the 4-year cumulative incidence rate of CNS progression was 9.5%. Median OS was not reached and the 4-year OS rate was 70% (95% CI: 54-81). Safety profile was similar to that reported previously and there were no treatment-related Grade 4 or 5 adverse events for this long administration period.
Conclusion:
Regardless of CNS metastases at baseline, ALC have demonstrated excellent efficacy in ALK+ NSCLC pts without prior ALK inhibitor treatment. ALC was well tolerated over a prolonged administration period.
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P1.03 - Chemotherapy/Targeted Therapy (ID 689)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Chemotherapy/Targeted Therapy
- Presentations: 1
- Moderators:
- Coordinates: 10/16/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P1.03-005 - Phase 2 Study of Ceritinib in Patients with ALK+ NSCLC with Prior Alectinib Treatment in Japan: ASCEND-9 (ID 8417)
09:30 - 09:30 | Author(s): Makoto Nishio
- Abstract
Background:
ALK inhibitors are a standard of care for ALK-positive metastatic NSCLC and several ALK inhibitors are currently available. Alectinib is one of the recommended therapies as 1[st] line treatment for ALK-positive metastatic NSCLC in Japan based on robust progression-free survival (PFS) prolongation and favorable safety profile. However, even with treatment with alectinib, these cancers eventually progress after acquiring resistance against alectinib. Therefore, which drug should be chosen after alectinib is relevant clinical question. Recently, ceritinib, which is a highly selective oral ALK inhibitor, has demonstrated superior activity compared to chemotherapy in the 1[st] line setting for patients with ALK-positive metastatic NSCLC (ASCEND-4, Soria et al. Lancet 2017). It also showed clinically meaningful benefit in patients who failed to prior ALK inhibitor treatment including alectinib (Nishio et al. J Thorac Oncol 2015). In this study, we tried to evaluate efficacy and safety of ceritinib in ALK-positive metastatic NSCLC patients who progressed on alectinib treatment.
Method:
ASCEND-9 (NCT02450903) is a single-arm, open-label, multicenter, phase 2 study of ceritinib 750 mg/day (fasted) in adult patients with ALK+ (Vysis ALK Break Apart FISH Probe kit test), stage IIIB/IV NSCLC previously treated with alectinib and had subsequent disease progression. Other key inclusion criteria are ≥ 1 measurable lesion per RECIST 1.1 and WHO PS 0-1. Patients must have received previous treatment with alectinib, but prior crizotinib and/or up to 1 chemotherapy regimen are allowed. Patients with asymptomatic CNS metastases are eligible. Ceritinib may be continued beyond RECIST-defined PD. Primary endpoint is investigator assessed-overall response rate (ORR) per RECIST 1.1. Secondary endpoints include disease control rate (DCR), time to response (TTR), duration of response (DOR), PFS and safety. Biomarkers are evaluated for exploratory purpose.
Result:
Twenty patients were enrolled at 10 centers in Japan from Aug 2015 to Feb 2017. At present, the study is underway, and the results including ORR, DCR, TTR, DOR, PFS, safety and exploratory biomarker data will be presented at the 2017 WCLC.
Conclusion:
Section not applicable.
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P2.04 - Clinical Design, Statistics and Clinical Trials (ID 705)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Clinical Design, Statistics and Clinical Trials
- Presentations: 1
- Moderators:
- Coordinates: 10/17/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P2.04-005 - GEOMETRY Mono-1: Phase II, Multicenter Study of MET Inhibitor Capmatinib (INC280) in EGFR Wt, MET-Dysregulated Advanced NSCLC (ID 8961)
09:30 - 09:30 | Author(s): Makoto Nishio
- Abstract
Background:
Amplification of MET leading to oncogenic signaling occurs in 3‒5% of newly diagnosed EGFR wild type (wt) non-small cell lung cancer (NSCLC) cases with decreasing incidence at higher levels of amplification. Mutations in MET leading to exon 14 deletion (METΔ[ex14]) also occur in 2–4% of adenocarcinoma and 1–2% of other NSCLC subsets. Capmatinib (INC280) is a potent and selective MET inhibitor that has shown strong evidence of antitumor activity in a phase I study in patients with EGFR wt advanced NSCLC harboring MET amplification and METΔ[ex14].
Method:
This phase II, multicenter study (NCT02414139) was designed to confirm the clinical activity of capmatinib in patients with advanced NSCLC by MET amplification and METΔ[ex14] status. Eligible patients (≥18 years of age, Eastern Cooperative Oncology Group Performance Status 0–1) must have ALK-negative, EGFR wt, stage IIIB/IV NSCLC (any histology). Centrally assessed MET amplification (gene copy number [GCN]) and mutation status is used to assign patients to one of the below cohorts: Pretreated with 1–2 prior systemic lines of therapy for advanced setting (cohorts 1–4): 1a: MET amplification GCN ≥10 (n=69) 1b: MET amplification GCN ≥6 and <10 (n=69) 2: MET amplification GCN ≥4 and <6 (n=69) 3: MET amplification GCN <4 (n=69) 4: METΔ[ex14] mutation regardless of MET GCN (n=69) Treatment naïve (cohorts 5a and 5b): 5a: MET amplification GCN ≥10 and no METΔ[ex14] mutation (n=27) 5b: METΔ[ex14] mutation regardless of MET GCN (n=27) Capmatinib 400 mg tablets are orally administered twice daily on a continuous dosing schedule 12 hours apart. Primary and key secondary endpoints are overall response rate (ORR) and duration of response (DOR), respectively (blinded independent review assessment). Other secondary endpoints include investigator-assessed ORR, DOR, time to response, disease control rate, progression-free survival (independent and investigator assessment), safety, and pharmacokinetics. Enrollment is ongoing in 25 countries. Cohorts 1b, 2, and 3 are now closed to enrollment; cohorts 1a and 4 continue to enroll patients who have received 1–2 prior lines of therapy in the advanced setting, and cohorts 5a and 5b are open for enrollment of treatment-naïve patients. Responses have been seen in both MET-amplified and MET-mutated patients irrespective of the line of therapy.
Result:
Section not applicable
Conclusion:
Section not applicable
