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H. Wakelee
Moderator of
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ED15 - Thymic Malignancies: Update on Treatment (ID 285)
- Event: WCLC 2016
- Type: Education Session
- Track: Mesothelioma/Thymic Malignancies/Esophageal Cancer/Other Thoracic Malignancies
- Presentations: 4
- Moderators:H. Wakelee, P.E. Van Schil
- Coordinates: 12/07/2016, 14:30 - 15:50, Hall C1
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ED15.01 - Biology of Thymic Epithelial Tumors (ID 6506)
14:30 - 14:50 | Author(s): G. Giaccone
- Abstract
- Presentation
Abstract not provided
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ED15.02 - Chemotherapy and Targeted Therapies of Thymic Malignancies (ID 6507)
15:25 - 15:45 | Author(s): N. Girard, C. Merveilleux Du Vignaux
- Abstract
- Presentation
Abstract:
Thymic malignancies represent a heterogeneous group of rare thoracic cancers. The histopathological classification distinguishes thymomas from thymic carcinomas. Thymomas are further subdivided into different types (so-called A, AB, B1, B2, and B3) based upon the atypia of tumor cells, the relative proportion of the associated non-tumoral lymphocytic component, and resemblance to the normal thymic architecture. Thymic carcinomas are similar to their extra-thymic counterpart, the most frequent subtype being squamous cell carcinoma. The management of thymic epithelial tumours is a paradigm of multidisciplinary collaboration. The treatment strategy is primarily based on the resectability of the tumour. If complete resection is deemed not to be achievable upfront based on imaging studies, what is the case in Masaoka-Koga stage III/IVA tumors (classified as stage IIIA/IIIB/IVA in the 2015 IASLC-ITMIG TNM proposed system), after a biopsy is performed, primary/induction chemotherapy is administered, part of curative-intent sequential strategy integrating subsequent surgery or radiotherapy. Cases not eligible for local treatment receive definitive chemotherapy. Primary/induction chemotherapy is then standardin non-resectable advanced thymic epithelial tumors. Cisplatin-based combination regimens should be administered; combinations of cisplatin, adriamycin, and cyclophosphamide, and cisplatin and etoposide are the most usually used. Primary chemoradiotherapy with platin and etoposide is an option, especially for thymic carcinomas. Usually 2-4 cycles are administered before imaging is performed to reassess resectability of the tumor. Surgery should be offered to patients for whom complete resection is thought to be ultimately achievable; extended resection may be required. Hyperthermic intrapleural chemotherapy, as well as extra-pleural pneumonectomy may be discussed in case of stage IVA tumor. Postoperative radiotherapy is usually delivered. When the patient is not deemed to be a surgical candidate - either because R0 resection is not thought to be achievable, or because of poor performance status or co-existent medical condition, definitive radiotherapy is recommended part of a sequential chemoradiotherapy strategy. Combination with chemotherapy (including cisplatin, etoposide chemotherapy and a total dose of radiation of 60 Gy) may be considered as well. Chemotherapy should be offered as the single modality treatment in advanced, non-resectable, non-irradiable or metastatic (stage IVB) thymic epithelial tumor to improve tumor-related symptoms the aim is to improve tumor-related symptoms through obtention of tumor response, while prolonged survival is uncertain. Cisplatin-based combination regimen should be administered. No randomized studies have been conducted, and it is unclear which regimens are best; multi-agent combination regimens and anthracycline-based regimens appear to have improved response rates compared to others, especially the etoposide, ifosfamide and cisplatin combination. Combinations of cisplatin, adriamycin, and cyclophosphamide is preferred. Combination of carboplatin and paclitaxel is an option for thymic carcinoma. Surgery or radiotherapy is possible in rare and selected cases with unknown survival benefit. Recurrences of thymic epithelial tumors should be managed according to the same strategy as newly diagnosed tumors. Complete resection of recurrent lesions represents a major predictor of favorable outcome, and surgery is then recommended in case of resectable lesion. In non-resectable recurrences, several consecutive lines of chemotherapy may be administered when the patient presents with tumor progression. The re-administration of a previously effective regimen has to be considered, especially in case of previous response, late occurring recurrence, and for anthracyclins, a patient in a good medical condition and not having received cumulative doses precluding the safe delivery of at least 3 additional cycles. Preferred regimens for second-line treatment include carboplatin plus paclitaxel, and platin plus etoposide; capecitabine plus gemcitabine is an option. These regimens were evaluated in dedicated phase II trials. Options for subsequent lines include pemetrexed, oral etoposide. In patients with octreoscan-positive thymoma, not eligible to receive additional chemotherapy, octreotide alone or with prednisone may represent a valuable option. The use of targeted agents may be done in an off-label setting in advanced thymic malignancies. While KIT is overexpressed in 80% of thymic carcinomas, KIT gene mutations are found only in 9% of cases, consisting of mutations observed in other malignancies (V560del, L576P) or mutations unique to thymic carcinomas (H697Y, D820E). Responses and possibly prolonged survival was reported with the use KIT inhibitors - imatinib, sunitinib, or sorafenib - , mostly in single-case observations. Non-pretreated reported KIT mutants are not uniformly sensitive to imatinib, based on the clinical and/or the preclinical evidence in thymic carcinoma and/or other KIT-mutant malignancies. KIT sequencing (exons 9-17) is an option for refractory thymic carcinomas in the setting of possible access to off-label use of such inhibitors. KIT inhibitors also potently inhibiting other kinases, including Vascular Endothelial Growth Factor Receptors and Platelet-Derived Growth Factor Receptors activated in thymic malignancies. A phase II trial recently demonstrated the efficacy of sunitinib in terms of response and disease control rate in thymic epithelial tumors, including thymic carcinomas (ORR 26%; DCR: 91%) and, to a lesser extent, thymomas (ORR:6%; DCR:81%). Sunitinib may then represent an option as second-line treatment for thymic carcinomas, independantly from KIT status. There is no clinical data reporting on antitumor efficacy of other antiangiogenic drugs. mTOR is emerging as a potential target in thymic epithelial tumors, following tumor responses observed in phase I trials. Everolimus (10 mg daily) was evaluated in thymic epithelial tumors in a recently reported phase II trial reporting on a 22% response rate, as well as a 93% disease control rate. Everolimus may then represent an option for refractory tumors. Several trials assessing the efficacy of PD-1 checkpoint inhibitors are currently ongoing. A phase II study of pembrolizumab, a fully humanized IgG4 Ab that targets the PD-1 receptor, was recently reported; the study has accrued 30 patients. Four serious autoimmune disorders developed. Out of 30 patients evaluable for response so far the response rate is 24%. The off-label use of checkpoint inhibitors is currently not recommended. Overall, a dramatic improvement in our knowledge of the management of thymic tumors has occurred in the last few years. This improvement has primarily resulted from an increased interest in these rare tumors at some dedicated centers, and from the development of international efforts that succeed in putting together large-volume, top-quality centers all over the world, for databases, translational research, and clinical trials.
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ED15.03 - Surgery of Thymic Malignancies (ID 6508)
14:50 - 15:10 | Author(s): M. Okumura
- Abstract
Abstract:
Thymic epithelial tumors Thymic epithelial tumors are the most common malignancy among mediastinal tumors according to Japanese thoracic surgery survey (1). Surgical resection is generally the treatment of choice for thymic epithelial tumors. Thymic epithelial tumors are classified into thymoma, thymic carcinoma (TC), and thymic neuroendocrine carcinoma (TNEC). Retrospective surgical database of Japanese Association for Research of the Thymus (JART) revealed that recurrence free 10-year survival after macroscopic complete resection was 88% in thymoma, 51% in TC, and 11% in TNEC. Thymomas are further classified mainly into 5 pathological subtypes, WHO type A, AB, B1, B2 and B3. Pathological subtype of thymoma has been shown to reflect the oncological behaviors, and post-operative recurrence rate increases in this order. JART database study revealed that nearly 3 quarters of thymoma surgical cases have Masaoka stage I or II disease. Pleural dissemination is often encountered either before or after resection in thymoma while hematogenous or lymphatic spread seldom occurs. On the other hand, TC is often associated with metastasis to distant organs as well as nodal involvement in the mediastinum and cervical region. Approximately 3 quarters of surgically treated TC have Masaoka Stage III or IV disease in surgical cases. While most thymomas are treated by surgical resection, a considerable portion of TC are judged unresectable at initial presentation. TNEC often has nodal involvement. Initial resection is indicated when clinical diagnosis is a thymic epithelial tumor with Masaoka stage I or II. The standard procedure is extended thymectomy through median sternotomy even for tumors with Masaoka stage I or II disease because of the possibility of post-thymectomy myasthenia gravis, intrathymic metastasis and multiple foci of tumor. JART database study, however, revealed that recurrence rate in thymoma with T1N0M0 by UICC was not significantly different between two procedures, thymothymomectomy (1.4%) and thymomectomy (2.8%) (p = 0.192) (2). Furtheremore, systematic dissection of mediastinal lymph nodes is not supposed essential in thymoma because incidence of nodal involvement is negligible. Advancement in video-assisted thoracic surgery (VATS) has prompted endoscopic operation also for thymoma, and currently, partial resection of the thymus by VATS seems accepted for less-invasive thymoma when myasthenia gravis is not associated, but careful observation by annual examination by CT scan is recommended after partial thymectomy. Highly invasive thymomas should be treated by preoperative induction chemotherapy to reduce the tumor size. Pathological diagnosis by biopsy is required before chemotherapy to differentiate between invasive thymoma and TC. Resection of the pericardium, lung, great vessels, and thoracic wall is sometimes required. JART database study revealed that invasion of the thoracic wall was the independent factor of recurrence after complete resection. (3) Even subtotal resection sometimes results in long-term survival. If complete resection is not achieved, radiotherapy is supposed to control the remaining tumor. Surgery for thymoma with pleural or intrapericardial dissemination can be indicated. JART database study revealed that the number of the disseminated lesions is a prognostic factor and that patients with less than 10 lesions had better survival. (4) Operative procedure varies from partial pleurectomy to extrapleural pneumonectomy with resection of the primary lesion. The recommended procedure depends on the spread of disseminations. Although intrapericardial implantation is commonly thought to be hard to resect, resection can be achieved in some cases because thymomas usually do not invade into the heart muscle severely. Preoperative chemotherapy is supposed to enable complete resection of intrapericardial implantations through reduction of the tumor volume. Most of the hematogenous metastases of thymoma occur in the lung probably because the neoplastic cells can directly enter the blood stream through thymic veins. Surgical treatment for thymomas with lung metastasis is feasible, but indication of surgery for thymoma with extrathoracic distant metastasis should be determined carefully. Recurrence often occurs on the pleural surface followed by the lung metastasis. Surgical resection of the recurrent lesions in the intrathoracic cavity is generally thought to contribute to survival. (5) Preoperative induction therapy is almost mandatory in highly invasive TC and poorly-differentiated NEC. Concurrent chemoradiotherapy is effective in reducing the tumor size. Resection and reconstruction of even the ascending aorta under cardiopulmonary bypass can be attempted. Systematic mediastinal and cervical lymph node dissection is recommended because of high incidence of nodal involvement. Malignant germ cell tumors (GCT) Malignant GCT is a highly aggressive neoplasm arising in young males. Chemotherapy is recommended without pathological diagnosis when serum tumor marker is extraordinarily elevated. In case of non-seminomatous GCT, complete resection of the tumor after normalization of tumor marker value by chemotherapy should be achieved, or otherwise, tumor recurrence is highly possible. Resection and reconstruction of the great vessels under cardiopulmonary bypass is often necessary. Liposarcoma Mediatinal liposarcoma is a rare neoplasms and sometimes appears as a huge tumor. This neoplasm is supposed to be resistant to chemotherapy, and complete surgical resection is required. Local recurrence occurs frequently because obtaining safe surgical margin is difficult. Radiotherapy could be a treatment of choice for recurrent tumors. Lymphoid malignancies Role of surgery is limited. Surgical biopsy is sometimes required when ML is suspected by imaging and high value of serum sIL-2 receptor. When tumor remains after chemotherapy, surgical resection is sometimes indicated. Low-grade malignancy including MALT and Castleman’s disease can be exceptionally treated by initial surgery. References Committee for Scientific Affairs, The Japanese Association for Thoracic Surgery. Thoracic and cardiovascular surgery in Japan during 2013: Annual report by The Japanese Association for Thoracic Surgery. Gen Thorac Cardiovasc Surg. 2015 ;63:670-701. Nakagawa K, et al. Is thymomectomy alone Appropriate for stage I (T1N0M0) thymoma? Results of a propensity-score analysis. Ann Thorac Surg. 2016;101:520-6. Yamada Y, et al. Surgical outcomes of patients with stage III thymoma in the Japanese nation-wide database. Ann Thorac Surg 2015;100:961–7. Okuda K, et al. Thymoma Patients With Pleural Dissemination: Nationwide Retrospective Study of 136 Cases in Japan. Ann Thorac Surg 2014;97:1743–9. Mizuno T, et al. Surgical management of recurrent thymic epithelial tumors. A retrospective analysis based on the Japanese nationwide database. J Thorac Oncol. 2015;10:199–205.
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ED15.04 - Radiation of Thymic Malignancies (ID 6510)
15:10 - 15:25 | Author(s): A. Rimner
- Abstract
- Presentation
Abstract:
Radiation therapy (RT) plays an important role in the multimodality management of thymic malignancies. It can be employed in the neoadjuvant, adjuvant, definitive or palliative setting. Adjuvant RT is the most extensively studied setting for RT in thymic malignancies. After complete resection there is likely no role for adjuvant RT for patients with stage I thymomas, a possible role for patients with stage II thymomas, and likely a survival benefit in patients with stage III and IV thymomas. Several recent large database and population-based studies have detected a survival benefit for advanced thymomas, while the results for stage II thymomas have been mixed. For thymic carcinomas the impact of adjuvant RT appears more significant. Several large database and population-based studies have consistently reported a survival benefit with adjuvant RT for thymic carcinoma across various disease stages. For incompletely resected thymic tumors there is a stronger rationale for adjuvant RT based on emerging data and general oncologic principles. Neoadjuvant RT has been mostly explored in thymic carcinoma and demonstrated high response and operability rates. Definitive RT is an excellent treatment option for patients with unresectable thymic malignancies. While most thymic tumors are resectable, a subset of patients is technically or medically inoperable, due to invasion of critical structures or comorbidities. In general, thymic malignancies are radiosensitive, allowing for long-term local control rates. Palliative RT should be considered even in the recurrent or metastatic setting. Image-guided hypofractioned ablative RT may be used for oligometastatic disease as an alternative to surgical resection and has been shown to be a highly effective treatment modality with >90% long-term local control rates and minimal morbidity. Conventional palliative RT is an important modality to improve quality of life by alleviating pain, treating SVC syndrome, airway compression and other symptoms. Modern radiation therapy techniques such as 3D conformal radiation therapy or intensity-modulated radiation therapy should be used to minimize morbidity from treatment. Proton therapy may have advantages in certain clinical scenarios and is currently under investigation.
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Author of
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ED08 - Early-Stage NSCLC: State-of-the-Art Treatment and Perspectives (ID 276)
- Event: WCLC 2016
- Type: Education Session
- Track: Early Stage NSCLC
- Presentations: 1
- Moderators:T. Le Chevalier, M. Tsuboi
- Coordinates: 12/06/2016, 14:30 - 15:45, Hall C2
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ED08.04 - Perspectives of Targeted Therapies and Immunotherapy in Completely Resected NSCLC (ID 6472)
15:30 - 15:45 | Author(s): H. Wakelee
- Abstract
- Presentation
Abstract:
Perspectives of Targeted Therapies and Immunotherapy in Completely Resected NSCLC - Heather Wakelee, USA The use of four cycles of cisplatin-based adjuvant chemotherapy is now the standard of care for patients with resected stage II and IIIA NSCLC and is commonly used for patients with larger (at least 4 cm in size) stage IB tumors. The survival benefit with adjuvant chemotherapy though is limited with meta-analyses revealing a 4-5% absolute survival benefit at 5 years for patients receiving adjuvant cisplatin-based chemotherapy.[1,2]Some recent attempts to improve outcomes with the addition of other agents to cisplatin doublets (or as longer term therapy) have been disappointing. The addition of bevacizumab to chemotherapy in the ECOG-ACRIN E1505 adjuvant trial failed to show a benefit in disease free survival (DFS) or overall survival (OS).[3] The use of the MAGE-A3 vaccine in the MAGRIT trial was similarly negative.[4] With knowledge about molecular drivers of NSCLC and targeted treatment options in advanced disease, multiple studies are either completed or underway to study molecularly targeted agents in earlier stages of lung cancer, particularly with epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs). In metastatic NSCLC the EGFR TKIs produce superior response and progression free survival (PFS) compared with platinum doublet chemotherapy in treatment naïve patients with tumors with activating EGFR mutations (EGFRmut).[5,6]Similar outcomes with significant response and PFS improvements with the anaplastic lymphoma kinase (ALK) inhibitor crizotinib compared to chemotherapy have been reported in patients with tumors harboring translocations of ALK.[7] Encouraging data from retrospective and non-randomized trials looking at adjuvant EGFR TKI use led to randomized trials. Earlier trials that did not select based on EGFRmut status were negative, but more recent trials have been more encouraging. The phase III RADIANT trial selected patients with resected early stage NSCLC for EGFR expression by IHC/FISH, but not by EGFR mutation status, and randomized them to adjuvant erlotinib or placebo. [8] The primary end point was DFS in the full data set, with secondary analyses focused on patients with tumors harboring del19 or L858R EGFR mutations. No differences were found in DFS or OS based on treatment arm for the nearly 1000 patients who were enrolled. In the EGFRmut subset (N=161) DFS did favor erlotinib (HR 0.61, 95% CI = 0.384-0.981, p = 0.0391), but this was not considered statistically significant, as the primary endpoint of the trial was negative. The overall survival results, while still immature, were not in favor of the erlotinib arm, even in the EGFRmut subset. The conclusion from this study is that adjuvant EGFR TKI therapy requires further investigation and should not be considered a standard treatment option at this time. Multiple ongoing trials are exploring adjuvant EGFR TKI (and adjuvant ALK TKI) therapy for resected early stage NSCLC patients with tumors harboring the appropriate molecular marker.(Table 1) The ongoing trials are looking not only at whether or not an OS benefit can be obtained with adjuvant molecularly targeted therapy but also duration of therapy and the potential to use EGFR TKIs instead of chemotherapy in selected patients. The largest United States study is the NCI National Clinical Trials Network (NCTN) ALCHEMIST trial. The study is open to patients with resected early stage (IB-IIIA) NSCLC who are screened for EGFR activating mutations and ALK translocations. Patients with tumors harboring EGFR mutations or ALK translocations enter the appropriate sub-study and, after completion of all planned adjuvant chemotherapy or radiation therapy, are randomized to targeted TKI therapy or placebo for 2 years. Both sub-studies will enroll approximately 400 patients (410 EGFR; 378 ALK) and are powered for an OS endpoint. Patients without actionable mutations can enroll on the ANVIL sub-study looking at adjuvant nivolumab, a PD-1 targeted agent.(Table 1) Globally most targeted therapy adjuvant trials are being conducted in Asia, particularly China and Japan. ADJUVANT (C-TONG 1104) trial in China and IMPACT WJOG6410L in Japan are phase III trials for patients with resected stage II-IIIA EGFRmut NSCLC comparing gefitinib to cisplatin/vinorelbine using DFS as the primary endpoint.(Table 1) Other trials outlined in Table 1 are exploring variations on this theme using gefitinib or icotinib and either after or instead of adjuvant chemotherapy. The PD-1 inhibitors nivolumab and pembrolizumab are approved for the second line treatment of advanced stage NSCLC and will likely be utilized in first-line in the near future.[9-11] Based on their promise in advanced stage NSCLC, multiple trials with PD-1 and PD-L1 agents are ongoing. Most studies are for patients who have completed adjuvant chemotherapy (though some allow chemotherapy naïve patients) and they predominantly randomize patients to approximately 1 year of PD-1 or PD-L1 inhibitor therapy. Most include testing for PD-L1 expression, but do not exclude patients with low tumor levels of PD-L1. Many are placebo controlled.(Table 1) Chemotherapy has helped improve outcomes but continued investigations with novel approaches will be necessary to continue to improve cure rates for patients with resected early stage NSCLC. The use of molecularly targeted agents for patients with tumors containing EGFRmut or ALK translocations are promising with validation studies ongoing and the hope of immunotherapy is being investigated as well in multiple global trials. Table 1. Ongoing Phase III Targeted and Immunotherapy Adjuvant Trials
All EGFR studies include stage II-IIIA All PD-1/PD-L1 studies open to IB (4cm) – IIIA after adjuvant chemotherapy N: Number of estimated enrollment DFS: disease-free survival; OS: overall survival *EGFR deletion 19 or exon 21 L858R mutation only ALK^ : Positive for ALK translocation by FISH &- regardless of PD-L1 status US NCI NCTN: United States National Cancer Institute, National Clinical Trials Network References: 1. Pignon JP, Tribodet H, Scagliotti GV, et al: Lung Adjuvant Cisplatin Evaluation: A Pooled Analysis by the LACE Collaborative Group. J Clin Oncol, 2008 2. Group NM-aC, Arriagada R, Auperin A, et al: Adjuvant chemotherapy, with or without postoperative radiotherapy, in operable non-small-cell lung cancer: two meta-analyses of individual patient data. Lancet 375:1267-77, 2010 3. Wakelee HA, Dahlberg SE, Keller SM, et al: Randomized phase III trial of adjuvant chemotherapy with or without bevacizumab in resected non-small cell lung cancer (NSCLC): Results of E1505. Journal of Thoracic Oncology Proceedings WCLC 2015:Abstr: Plen04.03, 2015 4. Vansteenkiste JF, Cho BC, Vanakesa T, et al: Efficacy of the MAGE-A3 cancer immunotherapeutic as adjuvant therapy in patients with resected MAGE-A3-positive non-small-cell lung cancer (MAGRIT): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol 17:822-835, 2016 5. Mok TS, Wu YL, Thongprasert S, et al: Gefitinib or Carboplatin-Paclitaxel in Pulmonary Adenocarcinoma. N Engl J Med, 2009 6. Sequist LV, Yang JC, Yamamoto N, et al: Phase III Study of Afatinib or Cisplatin Plus Pemetrexed in Patients With Metastatic Lung Adenocarcinoma With EGFR Mutations. J Clin Oncol, 2013 7. Solomon BJ, Mok T, Kim DW, et al: First-line crizotinib versus chemotherapy in ALK-positive lung cancer. N Engl J Med 371:2167-77, 2014 8. Kelly K, Altorki NK, Eberhardt WE, et al: Adjuvant Erlotinib Versus Placebo in Patients With Stage IB-IIIA Non-Small-Cell Lung Cancer (RADIANT): A Randomized, Double-Blind, Phase III Trial. J Clin Oncol 33:4007-14, 2015 9. Brahmer J, Reckamp KL, Baas P, et al: Nivolumab versus Docetaxel in Advanced Squamous-Cell Non-Small-Cell Lung Cancer. N Engl J Med 373:123-35, 2015 10. Borghaei H, Paz-Ares L, Horn L, et al: Nivolumab versus Docetaxel in Advanced Nonsquamous Non-Small-Cell Lung Cancer. N Engl J Med 373:1627-39, 2015 11. Herbst RS, Baas P, Kim DW, et al: Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomised controlled trial. Lancet 387:1540-50, 2016Trial Description Primary Endpoint(s) C-TONG 1104 NCT01405079 *gefitinib vs. cisplatin/vinorelbine 3-year DFS GASTO1002 NCT01996098 *Chemo then icotinib vs obs 5-year DFS BD-IC-IV-59 NCT02125240 *Chemo then icotinib vs. placebo 2-year DFS WJOG6401L IMPACT *Gefitinib vs. cisplatin/vinorelbine 5-year DFS ALCHEMIST A081105/E4512 *Erlotinib vs. placebo: ALK^ crizotinib vs placebo OS ALCHEMIST/ANVIL &EGFR/ALK wildtype; US NCI NCTN, Nivolumab vs obs OS/DFS Impower010 Restricted to PD-L1+ Global, Atezolizumab vs. placebo DFS MEDI4736 &Global, MEDI4736 vs placebo DFS Keynote-091 &ETOP/EORTC, Pembrolizumab vs placebo DFS
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ISS10 - Industry Supported Symposium: Novel Treatment Strategies for ALK+ NSCLC: From Evidence to Practice – Novartis Oncology (ID 443)
- Event: WCLC 2016
- Type: Industry Supported Symposium
- Track:
- Presentations: 2
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ISS10.02 - ALK+ NSCLC: Not Your Typical Patients (ID 6993)
12:50 - 13:05 | Author(s): H. Wakelee
- Abstract
Abstract not provided
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ISS10.05 - Panel Discussion: Challenges in Sequencing Therapy for Your ALK+ NSCLC Patients (ID 6996)
13:30 - 14:00 | Author(s): H. Wakelee
- Abstract
Abstract not provided
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MA08 - Treatment Monitoring in Advanced NSCLC (ID 386)
- Event: WCLC 2016
- Type: Mini Oral Session
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:R. Perez-Soler, T. Reungwetwattana
- Coordinates: 12/06/2016, 11:00 - 12:30, Lehar 3-4
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MA08.01 - A Highly Sensitive Next-Generation Sequencing Platform for Detection of NSCLC EGFR T790M Mutation in Urine and Plasma (ID 4637)
11:00 - 11:06 | Author(s): H. Wakelee
- Abstract
- Presentation
Background:
Non-invasive genotyping of NSCLC patients by circulating tumor (ct)DNA is a promising alternative to tissue biopsies. However, ctDNA EGFR analysis remains challenging in patients with intrathoracic disease, with a reported 26-57% T790M mutation detection rate in plasma (Karlovich et al., Clin Cancer Res 2016; Wakelee et al., ASCO 2016). We investigated whether a mutation enrichment NGS could improve mutation detection in plasma and urine from TIGER-X, a phase 1/2 study of rociletinib in patients with EGFR mutation-positive advanced NSCLC.
Methods:
The therascreen (Qiagen) or cobas (Roche) EGFR test was used for EGFR T790M analysis in tumor biopsies. Urine and plasma were analyzed by trovera mutation enrichment NGS assay (Trovagene).
Results:
Of 174 matched tissue, plasma and urine specimens, 145 (83.3%) were T790M+ by central tissue testing, 142 (81.6%) were T790M+ by plasma, and 139 (79.9%) were T790M+ by urine. Urine and plasma combined identified 165 cases (94.8%) as T790M+. Of 25 cases positive by ctDNA but negative/inadequate by tissue, 16 were double-positive in plasma and urine, unlikely to be false positive (Figure 1). T790M detection rate was higher for extrathoracic (n=119) vs intrathoracic (n=55) disease in plasma (87.4% vs 69.1%, p=0.006) but not urine (81.5% vs 76.4%, p=0.42). Combination of urine and plasma identified T790M in 92.7% of intrathoracic and 95.8% of extrathoracic cases (p=0.47). In T790M+ patients, objective response rate was similar whether T790M mutation was identified by tissue, plasma or urine: 37.4%, 33.1% and 36.6%, respectively. 4 of 9 patients T790M+ by urine but negative by tissue responded, and 2 of 8 patients T790M+ by plasma but negative by tissue responded.
Conclusion:
Mutation enrichment NGS testing by urine and plasma combined identified 94.8% of T790M+ cases. Combination of urine and plasma may be considered before tissue testing in EGFR TKI resistant NSCLC, including patients without extrathoracic metastases. Figure 1
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MA16 - Novel Strategies in Targeted Therapy (ID 407)
- Event: WCLC 2016
- Type: Mini Oral Session
- Track: Chemotherapy/Targeted Therapy/Immunotherapy
- Presentations: 1
- Moderators:G. Purkalne, J. Von Pawel
- Coordinates: 12/07/2016, 14:20 - 15:50, Strauss 2
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MA16.03 - Global RET Registry (GLORY): Activity of RET-Directed Targeted Therapies in RET-Rearranged Lung Cancers (ID 4325)
14:26 - 14:32 | Author(s): H. Wakelee
- Abstract
- Presentation
Background:
GLORY is a global registry of patients with RET-rearranged non-small cell lung cancer (NSCLC). In order to complement ongoing prospective studies, the registry’s goal is to provide data on the efficacy of RET-directed targeted therapies administered outside the context of a clinical trial. We previously reported results from our first interim analysis (Gautschi, ASCO 2016). Following additional accrual into the registry, updated results are presented here, with a focus on an expanded efficacy analysis of various RET inhibitors.
Methods:
A global, multicenter network of thoracic oncologists identified patients with pathologically-confirmed NSCLC harboring a RET rearrangement. Molecular profiling was performed locally via RT-PCR, FISH, or next-generation sequencing. Anonymized data including clinical, pathologic, and molecular features were collected centrally and analyzed by an independent statistician. Response to RET tyrosine kinase inhibition (TKI) administered off-protocol was determined by RECIST1.1 (data cutoff date: April 15, 2016). In the subgroup of patients who received RET TKI therapy, the objectives were to determine overall response rate (ORR, primary objective), progression-free survival (PFS), and overall survival (OS).
Results:
165 patients with RET-rearranged NSCLC from 29 centers in Europe, Asia, and the USA were accrued. The median age was 61 years (range 28-89 years). The majority of patients were female (52%), never smokers (63%), with lung adenocarcinomas (98%) and advanced disease (91%). The most frequent metastasic sites were lymph nodes (82%), bone (51%) and lung (32%). KIF5B-RET was the most commonly identified fusion (70%). 53 patients received at least one RET-TKI outside of a clinical protocol, including cabozantinib (21), vandetanib (11), sunitinib (10), sorafenib (2), alectinib (2), lenvatinib (2), nintedanib (2), ponatinib (2) and regorafenib (1). In patients who were evaluable for response (n=50), the ORR was 37% for cabozantinib, 18% for vandetanib, and 22% for sunitinib. Median PFS was 3.6, 2.9, and 2.2 months and median OS was 4.9, 10.2, and 6.8 months for cabozantinib, vandetanib, and sunitinib, respectively. Responses were also observed with nintedanib and lenvatinib. Among patients who received more than one TKI (n=10), 3 partial responses were achieved after prior treatment with a different TKI.
Conclusion:
RET inhibitors are active in individual patients with RET-rearranged NSCLC, however, novel therapeutic approaches are warranted with the hope of improving current clinical outcomes. GLORY remains the largest dataset of patients with RET-rearranged NSCLC, and continues to accrue patients.
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MA17 - Genetic Drivers (ID 409)
- Event: WCLC 2016
- Type: Mini Oral Session
- Track: Biology/Pathology
- Presentations: 1
- Moderators:M. Satouchi, G.R. Simon
- Coordinates: 12/07/2016, 14:20 - 15:50, Lehar 1-2
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MA17.07 - Circulating Tumor DNA Detects Minimal Residual Disease and Predicts Outcome in Localized Lung Cancer (ID 5388)
15:02 - 15:08 | Author(s): H. Wakelee
- Abstract
Background:
CT imaging is standard-of-care for surveillance following definitive lung cancer therapy but is complicated by difficulties in distinguishing recurrence from treatment-related fibrosis and inability to detect microscopic disease. CAPP-Seq is a novel blood-based assay that uses next-generating sequencing to quantitate circulating tumor DNA (ctDNA). We performed a prospective study to compare disease surveillance by CAPP-Seq to CT imaging after definitive treatment for localized lung cancer.
Methods:
We prospectively enrolled 34 patients treated definitively for non-metastatic primary lung cancer at Stanford University between June 2010 and September 2015. Our cohort included 22 (64.7%) patients with stage III, 6 (17.6%) patients with stage II and 6 (17.6%) patients with stage I disease. All patients received pre-treatment evaluation by thoracic CT and PET/CT scans as well as ctDNA quantitation by CAPP-Seq. Twenty-one (61.8%) patients were treated with conventionally fractionated radiotherapy, 8 (23.5%) with hypofractionated radiotherapy, 3 (8.8%) with surgery, and 2 (5.9%) with both surgery and radiotherapy. Twenty-five (73.5%) patients received platinum-based doublet chemotherapy. Following treatment completion, patients underwent disease surveillance by CT scans and CAPP-Seq every 3-6 months. CT scans were evaluated using RECIST v1.1. CAPP-Seq was performed at each time point as previously described (Newman et al, Nature Medicine 2015 and Nature Biotechnology 2016).
Results:
A total of 222 scans and 107 plasma samples were analyzed. Median follow-up time was 21.1 months and median overall survival was 30.0 months. Eighteen (52.9%) patients progressed based on RECIST criteria and CAPP-Seq detected ctDNA at or before the time of RECIST progression in all patients (18 of 18; 100%) with a lead-time of 121 +/- 39 days (mean +/- SEM). For 13 of 16 (81.3%) evaluable patients who progressed, ctDNA was detected at the first time-point after completion of all treatment (median 2 months post treatment), indicating detection of minimal residual disease. Two-year overall survival for patients with detectable post-treatment ctDNA was 25.3% versus 92.9% for those with no detectable post-treatment ctDNA (p=0.0003, HR=6.8, 95% CI=2.6-17.9). This difference remained significant in multivariate models controlling for stage, age, sex, and tumor volume (P=0.01).
Conclusion:
We found that noninvasive ctDNA profiling appears to be useful for evaluating response to lung cancer treatment. Quantitation of ctDNA allowed identification of minimal residual disease, which was strongly associated with outcome. These results suggest that ctDNA assessment after definitive intent treatment could potentially be used to guide risk-adapted treatment strategies for localized lung cancer.
Information from this presentation has been removed upon request of the author.
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OA04 - Epidemiology and Prevention of Lung Cancer (ID 370)
- Event: WCLC 2016
- Type: Oral Session
- Track: Epidemiology/Tobacco Control and Cessation/Prevention
- Presentations: 1
- Moderators:L. Petruželka, S. Shastri
- Coordinates: 12/05/2016, 11:00 - 12:30, Schubert 4
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OA04.02 - Smoking Behavior in Patients with Early Stage Non-Small Cell Lung Cancer: A Report from ECOG-ACRIN 1505 Trial (ID 5385)
11:10 - 11:20 | Author(s): H. Wakelee
- Abstract
- Presentation
Background:
Approximately 85% of lung cancer is related to cigarette smoking. Smoking cessation has been reported to benefit patients even after the diagnosis of lung cancer. We studied the smoking behavior of patients with lung cancer in a phase 3 study for early stage lung cancer.
Methods:
The ECOG-ACRIN 1505 study enrolled patients with stages IB, II and IIIA non-small cell lung cancer (NSCLC) after they had undergone surgical resection. It was designed to evaluate whether the addition of bevacizumab would improve survival relative to cisplatin-based chemotherapy alone. Studying the correlation between smoking status and outcome was a secondary endpoint. Patients completed a questionnaire about their smoking habits at baseline, 3, 6, 9 and 12 months after study entry.
Results:
Out of 1501 patients enrolled, 99%, 90%, 85%, 82% and 80% responded to the questionnaire at baseline, 3, 6, 9 and 12 months respectively. Nearly 90% reported having smoking during their lifetime. At study entry, 12% reported ongoing smoking. The median age patients started smoking was 17 years and the median age at which they quit smoking was 55 years. The median number of cigarettes smoked per day was 20. Approximately 4% smoked cigars (median number 2/day). Of the 40% that reported smoking after the diagnosis of lung cancer, only 15% reported smoking at 12 months. At 12 months after study entry, among those who continued to smoke, 79% reported smoking fewer cigarettes/day, whereas 11% smoked more cigarettes. When asked about the number of cigarettes smoked at 12 mos, 63% reported smoking fewer than 10 cigarettes/day. The incidence of grades 3-5 toxicity was 76% in smokers versus 69% in non-smokers (p=0.06). There were no differences in dose reductions for chemotherapy (P=0.55) or bevacizumab (P=0.90) between smokers and non-smokers. The median number of chemotherapy cycles were nearly identical for smokers and never-smokers. The disease-free survival (DFS) and OS for smokers relative to never-smokers were 0.97 (P=0.83) and 1.54 (P=0.01) respectively.
Conclusion:
This is the first comprehensive, prospective report of smoking habits of patients with lung cancer. There were a high rate of smoking cessation and reduction in number of cigarettes smoked, that was maintained at 12m after study entry. Toxicity and DFS did not differ significantly between smokers and never-smokers, though overall survival was more favorable with the never-smokers. Study was coordinated by ECOG-ACRIN (Robert L. Comis, M.D., Chair) and supported in part by Public Health Service Grants CA180820, CA180888, CA180821, & CA180863.
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P2.03b - Poster Session with Presenters Present (ID 465)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 12/06/2016, 14:30 - 15:45, Hall B (Poster Area)
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P2.03b-012 - A Phase II Study of Etirinotecan Pegol (NKTR-102) in Patients with Refractory Brain Metastases and Advanced Lung Cancer (ID 4345)
14:30 - 14:30 | Author(s): H. Wakelee
- Abstract
Background:
Up to 40% of lung cancer patients develop brain metastases. As brain metastases often progress following radiotherapy, chemotherapeutics with central nervous system (CNS) activity are needed. Etirinotecan pegol (NKTR-102) is a PEG-conjugate prodrug of irinotecan, resulting in a half-life of 37 days and accumulation in tumors with permeable vasculature. This phase II trial evaluated the CNS activity of etirinotecan pegol in patients with lung cancer and refractory brain metastases.
Methods:
Patients with lung cancer and brain metastases were eligible who had received prior systemic therapy and prior brain-directed neurosurgery, radiation/radiosurgery, or refused whole brain radiotherapy (WBRT). Measurable brain metastases were defined as one >= 10 mm; or one 5-9 mm with others >= 3 mm, totaling >= 10 mm. Etirinotecan pegol was administered at 145 mg/m2 IV every 3 weeks. Response (modified RECIST 1.1) was assessed with brain MRI and systemic CT every 6 weeks. The primary endpoint was a 25% or greater 12-week CNS disease control rate (CNS-DCR; defined as unconfirmed response or stable disease with systemic non-progression) in a non-small cell lung cancer (NSCLC) cohort. Another exploratory cohort enrolled small cell lung cancer (SCLC) patients.
Results:
In the NSCLC cohort, twelve patients were enrolled, all with adenocarcinoma. Genomic alterations included six (50%) with EGFR mutation, and one each with HER2, KRAS, ROS1, and NRAS. Patients received a median of 2.5 prior systemic treatments. Two (17%) patients had prior neurosurgery, ten patients (83%) had irradiation - 3 WBRT, 9 radiosurgery. Common related toxicities were nausea and diarrhea (each in 50%), vomiting (22%) and blurred vision (22%). One patient died after developing diarrhea and dehydration. CNS responses lasting 24, 8, and 6 weeks were observed in 25% (3/12) - all EGFR mutation positive. The 6-week CNS-DCR was 50% (6/12), but 12-week CNS-DCR was 17% (2/12). Median progression-free survival was 11.4 weeks (95% CI 5.3-11.7) and median overall survival from study entry was 29.6 weeks (95% CI 22.3-38.2). In the SCLC cohort, two patients were enrolled. One patient with prior PCI had CNS response at 5 weeks but died of neutropenic infection; one who refused prior WBRT had CNS progression at 6 weeks.
Conclusion:
Radiographic responses of brain metastases were observed in patients following administration of etirinotecan pegol, but the study did not meet the primary endpoint because the 12-week CNS-DCR was 17%. Further study of etirinotecan pegol is ongoing in patients with breast cancer and brain metastases.
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P2.06 - Poster Session with Presenters Present (ID 467)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Scientific Co-Operation/Research Groups (Clinical Trials in Progress should be submitted in this category)
- Presentations: 1
- Moderators:
- Coordinates: 12/06/2016, 14:30 - 15:45, Hall B (Poster Area)
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P2.06-004 - A Phase 1b Study of Erlotinib and Momelotinib for EGFR TKI Naïve EGFR Mutated Metastatic Non-Small Cell Lung Cancer (ID 4778)
14:30 - 14:30 | Author(s): H. Wakelee
- Abstract
Background:
Momelotinib (MMB) is a selective ATP-competitive small-molecule inhibitor of Janus kinases (JAK) 1 and 2. The JAK signal transduction pathway is hyperactivated in patients with epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC). Erlotinib, a tyrosine kinase inhibitor (TKI), is a standard of care treatment for EFGR-mutated NSCLC. However, patients eventually develop resistance to single agent EGFR TKI and thus this combination trial was designed. The primary objective of this phase 1b study (NCT02206763) was to determine the maximum tolerated dose and safety of MMB in combination with erlotinib. Other objectives included pharmacokinetics (PK), pharmacodynamics (PD), and preliminary efficacy.
Methods:
Eligible patients had metastatic EGFR-mutated NSCLC (exon 19 deletion or exon 21 [L858R] substitution). Oral erlotinib 150 mg was administered once daily. MMB was dose escalated in a standard 3+3 design as follows: MMB 100 mg once daily (Dose Level [DL] 1), 200 mg once daily (DL2A), and 100 mg twice daily (DL2B). Dose limiting toxicities (DLTs) were evaluated in the first 28 days. Plasma samples for PK/PD analyses were serially collected up to 24 hours postdose.
Results:
Eleven patients enrolled: 3 in DL1, 3 in DL2A, and 5 in DL2B. Seven were female and median age was 55 years. DLTs of grade 3 diarrhea (n=1) and grade 4 neutropenia (n=1) without fever were seen at DL2B, and trial enrollment was halted. Decreased neutrophil count was recorded in 4 additional patients (grade 1-3; only one grade 3). The most common treatment-emergent adverse events were diarrhea and fatigue, each reported by 7 patients. One patient reported grade 1 peripheral neuropathy (sensory). No deaths were reported. Mean MMB systemic exposure was dose proportional between DL1 and DL2A, and comparable between DL2A and DL2B (200 mg total daily dose). MMB did not affect erlotinib PK. Mean blood pSTAT3 was maximally decreased by 34.9% at 1 hour postdose and was not dose dependent. As observed for MMB in myelofibrosis, inflammatory cytokines such as CRP, IL-10 and IL-12/-23p40 were reduced, whereas IL-8 was increased. The overall response rate was 54.5% (n=6; all partial responses).
Conclusion:
MMB administered in combination with erlotinib had more toxicity than expected at DL2B, including one grade 4 neutropenia. However, grade 2-3 neutropenia without fever was seen in 2 additional patients. The response rate was similar to previous reports with erlotinib, but it is too early in the study to provide progression-free survival with this treatment combination.
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P3.02a - Poster Session with Presenters Present (ID 470)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 12/07/2016, 14:30 - 15:45, Hall B (Poster Area)
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P3.02a-001 - Response and Plasma Genotyping from Phase I/II Trial of Ensartinib (X-396) in Patients (Pts) with ALK+ NSCLC (ID 6090)
14:30 - 14:30 | Author(s): H. Wakelee
- Abstract
Background:
Ensartinib (X-396) is a novel, potent anaplastic lymphoma kinase (ALK) small molecule tyrosine kinase inhibitor (TKI) with additional activity against MET, ABL, Axl, EPHA2, LTK, ROS1 and SLK. We report data on the ALK TKI-naïve and crizotinib (C)-resistant NSCLC pts treated with ensartinib. Clinical trial information: NCT01625234
Methods:
In this multicenter expansion study, pts with ALK+ NSCLC were treated with ensartinib 225 mg daily on a 28-day schedule. Pts had measurable disease, ECOG PS 0-1, and adequate organ function. Untreated brain metastases (CNS) and leptomeningeal disease were allowed. Next Generation Sequencing (NGS) was performed on plasma samples collected at baseline and on study and compared with central tissue results (FISH/IHC). All pts were assessed for response to therapy using RECIST 1.1 and for adverse events (AEs) using CTCAE version 4.03.
Results:
80 pts (51% female) have been enrolled. Median age 54 (20-79) years, 64% ECOG PS 1. Of 40 ALK+ NSCLC pts evaluable for response; partial response (PR) was achieved in 23 pts (58%) and stable disease (SD) in 8 pts (20%). In the C-naïve pts (n = 8), PRs were observed in 7 pts (88%). In the 22 pts with prior C but no other ALK TKI, 14 pts (64%) achieved PR and 6 (27%) SD. In the 10 pts who had received two or more prior ALK TKIs, there was 2 PR, 2 SD (40% DCR). CNS responses (50% PR) have been observed in both C-naïve and C-resistant pts. Plasma and tissue genotyping were available on 27 pts (26 ALK+ and 1 ALK-). ALK was detected in plasma in 16 pts, all of whom had a response to therapy. 2 pts with PD were tissue +ve and plasma -ve. 9 plasma samples were unevaluable. Serial sequencing demonstrated a decrease in ALK in pts responding and an increase at the time of progression. The most common drug-related AEs (≥ 20% of pts) included rash (53%), nausea (32%), vomiting (26%), fatigue (23%), and pruritus (21%). Most AEs were Grade (G) 1-2. The G3 treatment-related AEs were rash (8 pts), fatigue (2 pts), pruritus (2 pts), edema (2 pts), decreased appetite (1 pt), nausea (1pt), and vomiting (1pt).
Conclusion:
Ensartinib is well-tolerated with response in both C-naïve and C-resistant ALK+ NSCLC pts, as well as pts with CNS disease. Plasma sequencing appears to be promising to select pts for therapy and monitor for response and development of acquired resistance.
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P3.02b - Poster Session with Presenters Present (ID 494)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 12/07/2016, 14:30 - 15:45, Hall B (Poster Area)
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P3.02b-115 - Clinical Activity of Osimertinib in EGFR Mutation Positive Non Small Cell Lung Cancer (NSCLC) Patients (Pts) Previously Treated with Rociletinib (ID 4893)
14:30 - 14:30 | Author(s): H. Wakelee
- Abstract
Background:
Both osimertinib and rociletinib were developed to target the EGFR resistance mutation T790M. Sequist, et al reported clinical activity with osimertinib in 9 pts previously treated with rociletinib[1]. We conducted a retrospective analysis at 8 institutions of pts treated with rociletinib, who discontinued the drug due to disease progression or intolerable toxicity and subsequently received osimertinib.
Methods:
We identified pts treated with rociletinib followed by osimertinib, as part of osimertinib's US expanded access program or via commercial supply. Clinical characteristics and outcomes were assessed. Frequency of clinical and radiologic assessments on osimertinib was at the discretion of the treating physician. For this retrospective review, reverse KM method was used to calculate the median follow-up; KM method was used for time-to-event endpoints.
Results:
45 pts were included in this analysis. Median age at the start of osimertinib was 66 years (43-86) and 71% were female. 28 pts had exon 19 deletions and 16 had L858R. Median duration of therapy on front line EGFR TKI was 18 months (5-54). Median starting dose of rociletinib was 625 mg bid (range 500-1000). The response rate (RR) and disease control rate (DCR; Response+Stable Disease) with rociletinib were 38% and 91%; median duration of rociletinib therapy was 6.2 months. 32 (71%) pts discontinued rociletinib for disease progression. 23 (51%) pts received other therapies (1-4) before starting osimertinib. 25 (56%) pts were known to have brain metastases at osimertinib initiation. RR and DCR with osimertinib were 33% and 82%. DCR in the brain was 88%. With a median follow-up of 7.1 months, median duration of osimertinib therapy in all patients was 8 months (95%CI- 6.6-NR; 64% censored). The 1-year overall survival (OS) rate on osimertinib was 70% (54%-91%). In the 32 pts who discontinued rociletinib due to progression, DCR with osimertinib was 75% and median duration of therapy was 7.8 months (4.6-NR). Neither duration of,or response to rociletinib treatment, nor interval between the two the drugs was associated with duration of osimertinib or OS after osimertinib using a Cox model adjusted for age and sex.
Conclusion:
Osimertinib can provide clinical benefit in EGFR mutation positive NSCLC patients previously treated with rociletinib. The clinical activity of osimertinib in these patients may be related to more potent inhibition of T790M mutation or ability to overcome resistance to rociletinib. Reference- 1. Sequist, et al. JAMA Oncology 2016
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P3.02c - Poster Session with Presenters Present (ID 472)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 12/07/2016, 14:30 - 15:45, Hall B (Poster Area)
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P3.02c-050 - IMpower010: Phase III Study of Atezolizumab vs BSC after Adjuvant Chemotherapy in Patients with Completely Resected NSCLC (ID 6098)
14:30 - 14:30 | Author(s): H. Wakelee
- Abstract
Background:
Early-stage non-small cell lung cancer (NSCLC) is treated surgically, but 30%-70% of patients experience post-resection recurrence and succumb to disease. Adjuvant chemotherapy is the standard of care for fully resected NSCLC (stages IB [tumors ≥4 cm]-IIIA), and although cisplatin-based chemotherapy provides some benefit, the 5-year absolute survival benefit is ≈5%, underscoring the unmet need. Atezolizumab is an anti-PD-L1 monoclonal antibody that inhibits PD-L1 from binding to its receptors PD-1 and B7.1, thereby restoring anti-tumor immune response. Atezolizumab monotherapy has demonstrated promising efficacy and tolerable safety in patients with previously-treated advanced NSCLC, with a survival benefit observed across all PD-L1 expression levels. Given the need to improve survival for patients with early-stage NSCLC, IMpower010 (NCT02486718), a global Phase III randomized, open-label trial, has been initiated to compare the efficacy and safety of atezolizumab with best supportive care (BSC), following adjuvant cisplatin-based chemotherapy in patients with resected stage IB (tumors ≥4 cm)-IIIA NSCLC.
Methods:
Eligibility criteria include complete tumor resection 4-12 weeks prior to enrollment for pathologic stage IB (tumors ≥4 cm)–IIIA NSCLC. Patients must have adequately recovered from surgery, be eligible to receive cisplatin-based adjuvant chemotherapy and have an ECOG PS 0-1. Exclusion criteria include the presence of other malignancies, use of hormonal cancer or radiation therapy within 5 years, prior chemotherapy, autoimmune disease or exposure to prior immunotherapy. Approximately 1127 patients, regardless of PD-L1 expression status, will be enrolled. Eligible patients will receive up to four 21-day cycles of cisplatin-based chemotherapy (cisplatin [75 mg/m[2] IV, day 1] + either vinorelbine [30 mg/m[2] IV days 1, 8], docetaxel [75 mg/m[2] IV day 1] or gemcitabine [1250 mg/m[2] IV days 1, 8], or pemetrexed [500 mg/m[2] IV day 1; non-squamous NSCLC only]). Adjuvant radiation therapy is not permitted. Following adjuvant treatment, eligible patients will be randomized 1:1 to receive atezolizumab (1200 mg q3w, 16 cycles) or BSC. Stratification factors will include sex, histology (squamous vs non-squamous), extent of disease (stage IB vs II vs IIIA) and PD-L1 expression by IHC (TC, tumor cell; IC, tumor-infiltrating immune cell; TC2/3 [≥5% expressing PD-L1] and any IC vs TC0/1 [<5%] and IC2/3 [≥5%] vs TC0/1and IC0/1 [<5%]). The primary endpoint is disease-free survival, and secondary endpoints include overall survival and safety. Exploratory endpoints include PD-L1 status, immune and tumor related biomarkers before, during and after treatment with atezolizumab and at radiographic disease occurrence or confirmation of new primary NSCLC.
Results:
Section not applicable
Conclusion:
Section not applicable
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SC14 - Immunotherapy of NSCLC (ID 338)
- Event: WCLC 2016
- Type: Science Session
- Track: Chemotherapy/Targeted Therapy/Immunotherapy
- Presentations: 1
- Moderators:N. Rizvi, C. Zielinski
- Coordinates: 12/06/2016, 11:00 - 12:30, Hall C2
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SC14.04 - The CD47 Macrophage Checkpoint as a New Immunotherapy Target (ID 6656)
11:55 - 12:10 | Author(s): H. Wakelee
- Abstract
- Presentation
Abstract:
Background: Hu5F9-G4 is a humanized monoclonal antibody that targets CD47, blocking its anti-phagocytic “don’t eat me” signal through macrophage receptor SIRPα, leading to tumor phagocytosis. CD47 is overexpressed on human cancers and also on red blood cells (RBCs). In primate toxicology studies, Hu5F9-G4 caused a transient anemia that was improved with a single lower Priming Dose allowing higher Maintenance Doses. Materials and Methods: Relapsed/refractory solid tumors and lymphomas were included. This dose escalation study included: Part A, to determine the Priming Dose and Part B, to determine the Maintenance Dose. The maximum tolerated dose (MTD) in part A was used for the single Priming Dose in part B (Hu5F9-G4 dosed weekly). The primary objective is to determine safety and secondary objectives are to determine PK and PD. Preliminary data reported from data cutoff of July 22, 2016.Results: 25 patients have enrolled. Part A included 0.1 (N=1), 0.3 (N=2), 1 (N=6), and 3 (N=2) mg/kg. There were 2 dose-limiting toxicities (DLTs) in Part A at the 3 mg/kg dose: grade (G) 3 abdominal pain and G3 hemagglutination (H) (protocol-specific scale of G1 H on peripheral blood smear (PBS) and G2 headache). 1 mg/kg was selected as the Priming Dose, with no >G2 anemia. Pharmacodynamic studies show almost 100% RBC receptor occupancy at the Priming Dose. Treatment-related adverse event (TRAE) in Part A included: anemia (3 G1, 3 G2), hyperbilirubinemia (3 G1, 2 G2; unconjugated), headache (6 G1, 1 G2), H on PBS (8 G1), and nausea (3 G1). Part B included 3 (N = 4), 10 (N = 3), and 20 mg/kg (N=6, ongoing). There have been no DLTs in 3 patients on 10 mg/kg, and one DLT (headache with hemagglutination) in 6 patients at the 20 mg/kg maintenance dose (ongoing). Most toxicities were was associated with the initial single Priming Dose and were completely reversible. TRAE in Part B at 3 mg/kg included: anemia (2 G1, 2 G2), hyperbilirubinemia (1 G1, 1 G3), headache (3 G1), H on PBS (1 G1), retinal toxicity (G2 protocol-specific scale, asymptomatic). TRAE at 10 mg/kg included: anemia (3 G1), headache (2 G1), and nausea (1 G1). Two patients with adenoid cystic carcinoma in Part A had stable disease for 16 and 8 months. In Part B, 2 of 3 patients have had prolonged stable disease at 10 mg/kg for 8+ months (follicular thyroid cancer) and 7+ months (myoepithelioma of the head and neck). Evaluation of subjects in the 20 mg/kg cohort is ongoing. Conclusions: Hu5F9-G4 is well tolerated at 10 mg/kg weekly, with 1 mg/kg Priming Dose. Part B with a Maintenance Dose of 20 mg/kg is ongoing. Acknowledgements: Stanford Clinical and Translational Research Unit; California Institute for Regenerative Medicine; Forty Seven, Inc.Trial Registration: NCT02216409References: 1. Willingham SB, et al. The CD47-signal regulatory protein alpha (SIRPa) interaction is a therapeutic target for human solid tumors. Proc Natl Acad Sci U S A. 2012 Apr 24;109(17):6662-7. 2. Liu J t al. Pre-Clinical Development of a Humanized Anti-CD47 Antibody with Anti-Cancer Therapeutic Potential. PLoS One. 2015 Sep 21;10(9):e0137345. References 1. Willingham SB, Volkmer JP, Gentles AJ, Sahoo D, Dalerba P, Mitra SS, Wang J, Contreras-Trujillo H, Martin R, Cohen JD, Lovelace P, Scheeren FA, Chao MP, Weiskopf K, Tang C, Volkmer AK, Naik TJ, Storm TA, Mosley AR, Edris B, Schmid SM, Sun CK, Chua MS, Murillo O, Rajendran P, Cha AC, Chin RK, Kim D, Adorno M, Raveh T, Tseng D, Jaiswal S, Enger PØ, Steinberg GK, Li G, So SK, Majeti R, Harsh GR, van de Rijn M, Teng NN, Sunwoo JB, Alizadeh AA, Clarke MF, Weissman IL. The CD47-signal regulatory protein alpha (SIRPa) interaction is a therapeutic target for human solid tumors. Proc Natl Acad Sci U S A. 2012 Apr 24;109(17):6662-7. 2. Liu J, Wang L, Zhao F, Tseng S, Narayanan C, Shura L, Willingham S, Howard M, Prohaska S, Volkmer J, Chao M, Weissman IL, Majeti R. Pre-Clinical Development of a Humanized Anti-CD47 Antibody with Anti-Cancer Therapeutic Potential. PLoS One. 2015 Sep 21;10(9):e0137345.Figure: CD47 is a myeloid-specific immune checkpoint. Figure 1Figure 2
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