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K. Kelly
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GR 04 - Problems in Advanced Metastatic Disease (ID 18)
- Event: WCLC 2015
- Type: Grand Rounds
- Track: Treatment of Advanced Diseases - NSCLC
- Presentations: 4
- Moderators:K. Kelly, R. Pirker
- Coordinates: 9/09/2015, 14:15 - 15:45, 702+704+706
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GR04.01 - Case of a Patient with EGFR Mutation Positive Disease and Two Small Brain Metastases (ID 1844)
14:20 - 14:40 | Author(s): C. Faivre-Finn
- Abstract
- Presentation
Abstract:
Non-small-cell lung cancer (NSCLC) is the leading cause of brain metastases. The development of brain metastases in this group of patients represents an important public health issue, as 20-40% of NSCLC patients present with or will develop brain metastasis during the course of their treatment. The prognosis of NSCLC patients with brain metastases is generally extremely poor and brain metastases have a major impact on quality of life. The incidence of brain metastases has been increasing over time as a consequence of better neuroimaging modalities and also prolonged survival in the locally advanced and metastatic setting with improved therapies. This is particularly relevant in the group of patients with somatic aberrations within driver oncogenes, such as epidermal growth factor receptor (EGFR) as targeted therapy using tyrosine kinase inhibitors (TKIs) are producing high response rates and progression free survival. Patients with EGFR mutations therefore represent a population at higher risk of brain metastases than the overall NSCLC population, with a risk of developing intra-cranial disease as the first site of progression in approximately 20-30%, and a lifetime risk >50%. Of note, brain metastases in this group of patients present more and more in the context of well controlled systemic disease and are more likely to be treatable than in the historic paradigm where brain metastases developed in concert with progressive multi-organ metastatic disease.Furthermore, there is a suggestion that the prognosis of EGFR mutated patients and brain metastases is better compared to wild type . In the context of stable thoracic and systemic disease treatment options for oligometastatic brain disease include; surgery, stereotactic radiotherapy, whole brain radiotherapy, and systemic treatments. Surgery can play an important role in patients with brain metastases and particularly patients with mass effect from a large symptomatic lesion. Randomised controlled trials with single brain metastases have demonstrated that the addition of surgery to WBRT improves survival. Stereotactic radiosurgery (SRS) is increasingly used as the sole treatment rather than as a ‘booster therapy’ in addition to WBRT to improve local control. Typically, SRS is reserved for patients with controlled extracranial disease and life expectancy >6 months, 1 to 4 brain metastases less than 3cm in maximum diameter. Treatment with EGFR TKIs is generally considered in patients with EGFR mutations but the evidence to support the optimal sequencing with local therapies is limited. In my talk I will discuss the following points: • Risk of developing brain metastases in EGFR mutated NSCLC • Prognostic factors (including EGFR mutation) • The role of local treatment (SRS, WBRT and neurosurgery) • The role of prophylactic cranial irradiation • The role of systemic treatment • Future directions
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GR04.02 - Leptomeningeal Carcinomatosis (ID 1845)
14:40 - 15:00 | Author(s): R. Soo
- Abstract
- Presentation
Abstract:
Leptomeningeal disease is a severe neurologic complication that can be seen in up to 5% of patients with cancer and it is more commonly seen in patients with lymphoma, breast cancer, melanoma and lung cancer. It usually presents in approximately 70% patients with metastatic and progressive disease but may also be the first manifestation of cancer in 10% of cases. With improved diagnostic methods and longer survival of patients with advanced stage non-small cell lung cancer (NSCLC), the incidence of leptomeningeal disease has increased. The diagnosis of leptomeningeal disease is usually established by cytological examination of the cerebrospinal fluid (CSF) or by characteristic changes seen on gadolinium enhanced magnetic resonance imaging (MRI). Furthermore MRI provides anatomic information that may be useful in identifying sites for local radiotherapy treatment. Prognosis is generally poor, especially in patients with poor performance status, multiple, serious or major neurological deficits, bulky CNS disease, and CSF block. Factors associated with a better prognosis include good performance status, absence of major neurological deficits, minimal systemic disease, absence of CSF block and the availability of reasonable systemic therapies. Management principles include early diagnosis and achieving systemic control with the aim of preserving or improving neurological status, improving quality of life and prolonging survival, taking into account the burden of systemic disease, intracranial metastasis and the expected prognosis. Currently there is no standard treatment for leptomeningeal disease in patients with NSCLC and options include intra-thecal chemotherapy, systemic chemotherapy, molecular targeted therapy, and radiotherapy. Although the benefit of intra-thecal chemotherapy has not been proven in randomized controlled studies, it is commonly used as it provides local therapy with minimum systemic toxicity and high drug concentrations can be achieved. It has been noted that intra-thecal chemotherapy is ineffective for bulky meningeal disease as intra-CSF agents can only penetrate 2-3mm into such lesions. Retrospective studies in patients with NSCLC harboring sensitizing mutations in the epidermal growth factor receptor (EGFR) gene or rearrangement in anaplastic lymphoma kinase (ALK) gene suggest EGFR or ALK tyrosine kinase inhibitors is an attractive treatment option. Radiotherapy is used to in the treatment of bulky disease and in patients with CSF flow abnormalities. Radiotherapy is also indicated in symptomatic sites and also in the treatment of cauda equine syndrome and cranial neuropathies. Craniospinal irradiation is rarely administered, as it is associated with significant systemic toxicities and leucoencephalopathy. Several case examples will be presented and the clinical presentation, diagnostic assessment and management will be discussed. The role of molecular targeted agents such as the EGFR and ALK tyrosine kinase inhibitors will also be reviewed. The development of novel systemic agents especially molecular targeted agents with improved CNS penetration and anti-tumor activity is urgently required.
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GR04.03 - Systemic Treatment with Organ Failure (ID 1846)
15:00 - 15:20 | Author(s): P. Wheatley-Price
- Abstract
- Presentation
Abstract:
For patients with lung cancer, choices of systemic therapy are informed by clinical research. These guide the patient and clinician as to the gold standard options when facing their disease. However many patients seen day to day in the clinic are not eligible for clinical trials due to one factor or another, and therefore the applicability of standard of care options has a less solid evidence base. In a recent analysis of 528 newly diagnosed stage 4 NSCLC patients seen in consultation by medical oncologists, only 55% received systemic treatment [1]. Further, when simple and limited generic clinical trial inclusion criteria were applied to these patients, only 27% would have been ‘trial eligible’ [2]. In a review of selected recent practice changing chemotherapy, targeted therapy and immunotherapy trials, patients with significant renal impairment, hepatic impairment or cardiac impairment would have been excluded [3-6]. Therefore how should clinicians and patients approach making decisions about systemic therapy in the presence of organ failure, given the lack of available evidence? This abstract seeks to provide guidance on a reasonable approach to patients with lung cancer and organ failure. These issues should be discussed in a multi-disciplinary format, with specific interaction with specialists related to the particular organ failure (nephrology, hepatology, cardiology etc.), in addition to a specialist oncology pharmacist if the decision is made to proceed with therapy. Patients should be fully informed regarding relative benefits and harms from therapy, the consequences of declining therapy, and that proceeding with treatment will almost certainly not be based on level one evidence. Consideration should be given to early palliative care specialist input, and advance care planning. Understanding the cause and prognosis of the organ failure is self-evidently important. This abstract restricts discussion to patients with pre-existing organ failure, rather than organ failure secondary to the malignancy. In a recent review of clinical indicators of 6-month mortality in advanced non-cancer illnesses, Salpeter and colleagues evaluated heart failure, dementia, geriatric failure-to-thrive syndrome, hepatic cirrhosis, chronic obstructive pulmonary disease and end-stage renal disease. This list represented approximately 70% of the non-cancer diagnoses on admission to hospice [7]. Clearly not all patients with these conditions die within 6 months, and the authors identified common and disease specific prognostic indicators, including poor PS, malnutrition, comorbid illness and organ dysfunction. In the cancer clinic, the clinician must understand the natural course of the organ failure pathology. For patients with liver, kidney or heart failure who may be waiting for organ transplantation, the diagnosis of lung cancer makes them ineligible for the transplant program. Regarding prognosis of advanced organ failure, the United States Renal Data System (USRDS) Annual Report for patients receiving hemodialysis for end-stage renal disease, describes 3-year survival as 52%, and 61% for patients receiving peritoneal dialysis. The risk of death is particularly high in the first year of hemodialysis, with rates reported up to 25%. The Canadian Organ Replacement Register Annual Report describes a 5-year survival for patients on dialysis of approximately 43% (www.cihi.ca/corr ). For patients with end-stage heart failure, the 1-year survival is approximately 50% [8], which is not dramatically different to patients with stage 4 NSCLC receiving 1[st] line chemotherapy. The prognosis of patients with liver cirrhosis is variable, depending on severity, etiology and the presence or absence of complications. The MELD score (Model for End-Stage Liver Disease) is used to assess the severity of chronic liver disease [9], as an alternative to the Child-Pugh scoring system. Salpeter et al reported patients with decompensated liver failure (the presence of complications of cirrhosis) may have a median survival <6 months if associated with high MELD scores. An understanding of competing morbidities therefore clearly plays an important role in understanding the role systemic therapy plays in lung cancer. In assessing the need for adjuvant chemotherapy in patients with early stage disease, for patients with organ failure it is highly likely that any benefit from chemotherapy (approximately 5%) will be outweighed by the competing risks of the comorbid condition. After assessing patients with lung cancer, in the multi-disciplinary context and taking into account the issues discussed, the decision may still be to proceed with therapy. This should be on the understanding of the relative lack of data, and then a choice of regimen based on an understanding of the drug metabolism, with appropriate dose adjustments after dialogue with an oncology pharmacist. Table 1 outlines common lung cancer drugs and their route of elimination, and recommendations on use in renal or hepatic impairment. For patients receiving dialysis, there is variation in advice as to timing of adminstration relative to dialysis. This information and tabular information is taken from product monographs and selected references [10,11]. Data on efficacy for these drugs in these scenarios is largely limited to case reports. In conclusion, lung cancer patients with organ failure represent a population excluded from clinical trials and with a limited evidence base. The competing morbidity and mortality significantly mitigate against potential benefits from anti-cancer systemic therapy. The newer generations of targeted therapies and immunotherapies may be easier to deliver, but again limited data exists. Clinicians should discuss these cases in a multi-disciplinary environment, and early intervention from palliative care specialists may be particularly appropriate.
References : 1. Brule S, Al-Baimani K, Jonker H, et al: Palliative chemotherapy (CT) for advanced non-small cell lung cancer (NSCLC): Investigating disparities between patients who are treated versus those who are not. J Clin Oncol 33, 2015 2. Al-Baimani K, Jonker H, Zhang T, et al: Are clinical trial eligibility criteria an accurate reflection of a real world population of advanced lung cancer patients, World Conference on Lung Cancer. Denver, 2015, pp Abstract 1398 3. Gettinger SN, Horn L, Gandhi L, et al: Overall Survival and Long-Term Safety of Nivolumab (Anti-Programmed Death 1 Antibody, BMS-936558, ONO-4538) in Patients With Previously Treated Advanced Non-Small-Cell Lung Cancer. J Clin Oncol 33:2004-12 4. Mok TS, Wu YL, Thongprasert S, et al: Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N Engl J Med 361:947-57, 2009 5. Schiller JH, Harrington D, Belani CP, et al: Comparison of four chemotherapy regimens for advanced non-small-cell lung cancer. N Engl J Med 346:92-8, 2002 6. Shaw AT, Kim DW, Nakagawa K, et al: Crizotinib versus chemotherapy in advanced ALK-positive lung cancer. N Engl J Med 368:2385-94 7. Salpeter SR, Luo EJ, Malter DS, et al: Systematic review of noncancer presentations with a median survival of 6 months or less. Am J Med 125:512 e1-6 8. Friedrich EB, Bohm M: Management of end stage heart failure. Heart 93:626-31, 2007 9. Kamath PS, Kim WR: The model for end-stage liver disease (MELD). Hepatology 45:797-805, 2007 10. Janus N, Thariat J, Boulanger H, et al: Proposal for dosage adjustment and timing of chemotherapy in hemodialyzed patients. Ann Oncol 21:1395-403 11. Brandes JC, Grossman SA, Ahmad H: Alteration of pemetrexed excretion in the presence of acute renal failure and effusions: presentation of a case and review of the literature. Cancer Invest 24:283-7, 2006Drug Elimination Liver Renal Cisplatin Renal N/A ↓ depending on CrCl Caboplatin Renal N/A Calvert Formula Docetaxel Liver Adjust N/A Pemetrexed Renal Caution in severe dysfunction avoid if CrCl <45 Paclitaxel Liver Adjust N/A Gemcitabine Urine (inactive) Adjust by Bilirubin Caution Vinorelbine Liver Adjust by Bilirubin N/A Gefitinib Liver Caution Caution if CrCl <20 Erlotinib Liver Caution N/A Afatinib Liver Caution Caution if CrCl <30 Crizotinib Liver Adjust Caution if CrCl <30 Ceritnib Liver Adjust Caution if CrCl <30 Bevacizumab Reticulo-endothelial system Not involved Not involved Nivolumab Biochemical degradation No effect in mild impairment no effect if CrCl>/=15
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GR04.04 - A Case of Recurrent Clotting in Lung Cancer Despite Initial Anticoagulation (ID 1847)
15:20 - 15:40 | Author(s): R. Rosovsky
- Abstract
- Presentation
Abstract not provided
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MINI 14 - Pre-Clinical Therapy (ID 119)
- Event: WCLC 2015
- Type: Mini Oral
- Track: Biology, Pathology, and Molecular Testing
- Presentations: 1
- Moderators:L. Fernandez-Cuesta, A.F. Gazdar
- Coordinates: 9/08/2015, 10:45 - 12:15, Mile High Ballroom 2c-3c
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MINI14.01 - EGFR-Mutated PDX in NSCLC: Molecular Fidelity and Correlation of PDX and Patient Response to EGFR Inhibition (ID 2191)
10:45 - 10:50 | Author(s): K. Kelly
- Abstract
- Presentation
Background:
Inevitable emergence of resistance to tyrosine kinase inhibitor (TKI) therapy in EGFR-mutated NSCLC warrants development of pro-active therapeutic strategies to delay or circumvent this evolution. To model such approaches, we are employing a clinically and genomically annotated patient derived xenotransplant (PDX) resource designed to duplicate relevant known mechanisms of resistance to TKI therapy. This analysis examines molecular fidelity and correlates response between patient and PDX in EGFR-mutant NSCLC.
Methods:
Six EGFR-mutated NSCLC, 1 EGFR-TKI naïve and 5 after progressive disease on erlotinib, were implanted subcutaneously into the flank of NOD.Cg-Prkdc[scid] Il2rg[tm1Wjl]/SzJ (NSG) mice as previously described (DR Gandara, Clin Lung Cancer 2015). Models were considered established when PDX growth was confirmed in passage 1 (P1); tumor growth studies were conducted in P3-P5. The donor patient tumor (PT) and the resultant PDX were analyzed for driver mutations (Response Genetics Inc., and Illumina TSCAP), copy number variants (CNV) and global RNA expression (Affymetrix arrays). Informed consent was obtained from all patients. EGFR-mutant PDX treatments included: erlotinib, afatinib, cetuximab, and afatinib+cetuximab. Patient response was graded by RECIST 1.1 and measured in PDX by tumor shrinkage from pre-treatment baseline. In select models, pharmacodynamic studies (kinase arrays; immunoblotting) were also performed.
Results:
The EGFR mutation subtypes identified in the donor PT were preserved in all PDX models (4 EGFR E19del and 2 EGFR L858R). Corresponding putative mechanisms of resistance were identical in both PT and PDX in 3 cases: EGFR T790M (2 of 5) and MET amplification (1 of 5). Of 5 post-erlotinib progression PDX models, 3 had progressive disease (PD) and 2 had transient tumor shrinkage to erlotinib. The PDX derived from an erlotinib-naïve patient (EGFR E19del) demonstrated sustained tumor shrinkage to erlotinib. Patient-PDX treatment correlations were possible in 3 post erlotinib-progression models. Two of these patients received afatinib-cetuximab: 1 with partial response (PR) and 1 with PD. The two models corresponding to these patients, when treated with afatinib-cetuximab, underwent complete regression of tumor (CR) and PD, respectively. Pharmacodynamic assessment of the responding model at 24h showed near complete diminishment of pEGFR following afatinib-cetuximab, concomitant with decreased pHer2, pERK, pAKT and p38. Erlotinib showed transient inhibition on signaling in this model at 6h, returning to baseline by 24h. In contrast, the non-responding model showed minimal effects on target inhibition and signal transduction following treatment with any EGFR inhibitor.
Conclusion:
Genomic fidelity was preserved in EGFR-mutant PDX, including putative mechanisms of resistance in the post-erlotinib progression models. The majority (3/5) of the EGFR-mutant PDXs created after erlotinib resistance demonstrated PD. In the other post-erlotinib progression models transient tumor shrinkage was noted, which may reflect PDX passaging in the absence of selective pressure of EGFR-inhibition or pharmacokinetic considerations. Overall, the PDX response to treatment reflected the corresponding patient’s clinical course. Pharmacodynamic studies of select models informed PDX response to treatment.
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ORAL 17 - EGFR Mutant Lung Cancer (ID 116)
- Event: WCLC 2015
- Type: Oral Session
- Track: Treatment of Advanced Diseases - NSCLC
- Presentations: 1
- Moderators:P. Meldgaard, E. Felip
- Coordinates: 9/08/2015, 10:45 - 12:15, Four Seasons Ballroom F3+F4
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ORAL17.06 - Phase I/II Study of INC280 plus Erlotinib in Patients with MET Expressing Adenocarcinoma of the Lung (ID 1064)
11:39 - 11:50 | Author(s): K. Kelly
- Abstract
- Presentation
Background:
MET dysregulation is one mechanism responsible for EGFR-TKI (epidermal growth factor receptor-tyrosine kinase inhibitor) resistance in patients (pts) with EGFR mutated lung cancer. INC280 is a potent oral small molecular inhibitor of the c-MET kinase. We conducted a phase I/II study of INC280 plus erlotinib to determine the maximum tolerated dose (MTD), dose limiting toxicity (DLT), pharmacokinetics (PK) and antitumor activity of this combination. Tumor analysis of the EGFR and MET pathways was exploratory.
Methods:
Using a 3 + 3, dose escalation design, INC280 was increased over 5 dose levels (DL) from 100 - 600 mg po bid. Daily erlotinib was given at 100 mg in DL1 and 150 mg in DL 2- 6. DL 6 is a transition cohort from INC280 capsules (600 mg) to tablets (400 mg). Both agents were given for 28 days (1 cycle). Key eligibility included: lung adenocarcinoma with MET expression by a CLIA certified lab, age > 18, ECOG PS of < 2, acceptable organ function, and > 1 systemic therapy for advanced disease.
Results:
18 pts were treated on 6 dose levels. Pt characteristics: median age 59 (range 52-78), M/F (7/11), ECOG 0-1/2 (16/2), MET expression by IHC/FISH/RT-PCR/NGS (6/2/9/1), EGFR mutated tumors (9) and previously treated with erlotinib (12). 17 patients completed at least 1 cycle. One DLT (grade 3 neutropenia) occurred in DL 5 (Table 1). Common drug-related adverse events (AE) of any grade were rash (50%) and diarrhea (45%), fatigue (39%), anorexia and nausea (28% each) and increased alkaline phosphatase, hypoalbuminemia and paronychia (22% each). Drug-related grade 3/4 AE were anorexia, increased amylase or lipase and neutropenia (all 6%). PK analysis revealed that INC280 exhibited a linear PK and no interaction with erlotinib. Of the 17 evaluable patients, 3 (18%) patients had partial responses, 10 (59%) had stable disease, 3 of whom had a minor response (10-29% decrease in target lesion) (Table 1). Eight pts have received treatment for >3 months. Figure 1
Conclusion:
In patients with MET-expressing lung adenocarcinoma, INC280 plus erlotinib is feasible, tolerable and demonstrates anti-tumor activity. The recommended phase 2 doses are INC280 400 mg (tablets) bid plus erlotinib 150 mg daily. Three expansion cohorts have been initiated: 1 - EGFR mutated tumors refractory to an EGFR-TKI, 2 - EGFR-TKI naïve in the first line setting and 3 - WT EGFR that are EGFR-TKI naïve as second or third line therapy. Updated trial results from the expansion cohorts will be presented. NCT01911507
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ORAL 31 - PD1 Axis Inhibition (ID 143)
- Event: WCLC 2015
- Type: Oral Session
- Track: Treatment of Advanced Diseases - NSCLC
- Presentations: 1
- Moderators:J. Weiss, B. Luey
- Coordinates: 9/09/2015, 16:45 - 18:15, Four Seasons Ballroom F1+F2
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ORAL31.04 - Discussant for ORAL31.01, ORAL31.02, ORAL31.03 (ID 3367)
17:18 - 17:28 | Author(s): K. Kelly
- Abstract
- Presentation
Abstract not provided
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ORAL 38 - Liquid Biopsies (ID 147)
- Event: WCLC 2015
- Type: Oral Session
- Track: Biology, Pathology, and Molecular Testing
- Presentations: 1
- Moderators:M.S. Tsao, J. Wang
- Coordinates: 9/09/2015, 16:45 - 18:15, Mile High Ballroom 2a-3b
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ORAL38.06 - Identification of Actionable Tumor Alterations in Circulating Cell-Free Tumor DNA (cf DNA) Using Digital Sequencing from NSCLC Patients (ID 1706)
17:39 - 17:50 | Author(s): K. Kelly
- Abstract
- Presentation
Background:
To fully implement precision therapy in lung cancer, transition to a re-biopsy policy will be required at baseline and at progression after each line of therapy. The molecular testing paradigm is shifting toward next generation sequencing (NGS). As tissues are limited and repeat invasive biopsy introduces cost and risk, novel technologies sensitive and specific enough for multiplexed assessment in cell-free DNA (cfDNA) isolated from patient blood would represent a significant advance. Preliminary experience from investigators suggest a high degree of correlation between repeat tumor biopsy and plasma NGS. Here, we present the Guardant Health (GH) digital sequencing approach in a consecutive series of NSCLC cases.
Methods:
225 consecutive blood specimens from NSCLC patients, collected February–March 2015, were evaluated for cfDNA tumor alterations by digital sequencing using the GH panel of 68 genes. The test includes all reported fusion partners for ALK, RET, ROS1, and NTRK1 and cfDNA amplification for 16 genes. The mutant allele fraction (MAF) was calculated relative to WT in cfDNA. The test is sensitive to a single fragment of mutated cfDNA in a 10 ml blood sample and analytic specificity is >99.9999%.
Results:
Canonical EGFR activating mutations were detected in 20 cases (14 E19del, 3 L858R, 2 E20ins, 1 G719A). EGFR T790M co-occurred in 7 cases (6 E19del, 1 L858R), with EGFR amplification observed in 6 of the 20. Median age for patients with EGFR mut+ was 62.5; 18 female(90%), compared to nonEGFR-mutant cases. Four cases had driver fusions (2EML4-ALK, 2 KIF5B-RET) and five cases harbored an ERBB2 E20ins. KRAScodon 12/13 mutations were detected in 23 patients, while 3 harbored mutations in HRAS(Q61L) and NRAS(Q61L, G13R), and 6 had BRAF mutations (4 V600E, 2 G466X). All putative drivers were mutually exclusive. Mutations in signal transduction factors with confirmed gain-of-function activity included AKT1(E17K), MEK1(K57N, C121S), PIK3CA(E542K, E545K x2, H1047L, M1043V, R93W) and JAK2(V617F x2); truncating or missense mutations (>3% MAF) were observed in NF1 (6 cases), PTEN(1 case), SMAD4(4 cases) and STK11(4 cases). TP53 mutations were detected in 116/225 (51%). Evidence of gene amplification was seen in 32 cases, with 11 harboring multiple events. By function, amp events were observed for G1 cell cycle factors:11, RTKs: 17, MYC: 2; and signal transduction: 21. MAF ranged from 0.06% to 83.4% (av 5.1%; median: 9.8%), reflecting clinical and biologic diversity of patients. In a clinical subset at UC Davis, 27 patients were evaluated and alterations were detected in 18 (66.7%). Actionable findings were identified in 14 (77.8%) including 2 with EGFRL858R, 1 with EGFR E19del, and 1 interesting case with EGFR E19del at 45% MAF, EGFR amplification, and an emerging EGFR T790M clone at 0.54% MAF.
Conclusion:
In a series of NSCLC cases, high-sensitivity, high-specificity cfDNA analysis demonstrated the ability to identify somatic tumor alterations, including clinically actionable predictors, in a majority of patients via a simple blood draw, suggesting that this approach can be used for guiding therapeutic decision-making when repeat biopsy is high risk or not possible. Assuming validation, plasma cfDNA analysis may supplant invasive tumor biopsy in the near future.
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P1.01 - Poster Session/ Treatment of Advanced Diseases – NSCLC (ID 206)
- Event: WCLC 2015
- Type: Poster
- Track: Treatment of Advanced Diseases - NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 9/07/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
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P1.01-077 - First-Line Nivolumab + Nab-Paclitaxel + Carboplatin (C) in Advanced NSCLC (ID 1565)
09:30 - 09:30 | Author(s): K. Kelly
- Abstract
Background:
Nivolumab, an anti-PD-1 inhibitor, has demonstrated anti-tumor activity in several solid tumors and is approved for unresectable/metastatic melanoma and disease progression following ipilimumab, and if BRAF V600 mutation positive, a BRAF inhibitor; and for metastatic squamous NSCLC in patients with progression on/after platinum-based chemotherapy. Combining a taxane, which can act as a cytotoxic and an immunomodulator, with an immune checkpoint inhibitor has demonstrated improved outcomes over chemotherapy alone in NSCLC. First-line nivolumab and solvent-based paclitaxel plus C (sb-P/C) resulted in a 43% overall response rate and a median progression-free survival of 31 weeks in an interim analyses from a phase I trial in patients with advanced NSCLC (Antonia et al. Presented at ASCO 2014 [Abstract 8113]). nab-Paclitaxel (nab-P) based therapy has demonstrated improved efficacy over standard treatment in pancreatic and breast cancers, and nab-P plus carboplatin (nab-P/C) significantly improved the primary endpoint (ORR) vs sb-P/C in a phase III trial of patients with advanced NSCLC (Socinski et al. J Clin Oncol. 2012;30:2055-2062) and does not requires immunosuppressive premedication. This phase I, open-label, 6-arm, multicenter trial, will evaluate safety of nivolumab with nab-P in 3 cancer types: advanced NSCLC (+ C), advanced pancreatic cancer (± gemcitabine), and metastatic breast cancer; 2 arms in each disease. The study design for the NSCLC portion is described below.
Methods:
Eligibility criteria include histologically/cytologically confirmed stage IIIB/IV NSCLC, no prior chemotherapy for metastatic disease, prior adjuvant chemotherapy allowed providing completion >12 months before study entry, ECOG PS 0-1, adequate organ function, and preexisting peripheral neuropathy grade <2. NSCLC patients will be treated in 2 arms: 4 cycles of nab-P 100 mg/m[2] on days 1, 8, and 15 plus C AUC 6 on day 1 of a 21 day cycle with nivolumab 5 mg/kg on day 15 starting at cycle 1 or the same nab-P/C regimen with nivolumab 5 mg/kg on day 15 starting at cycle 3. In both arms, nivolumab monotherapy will begin at cycle 5. Part 1 will assess the dose-limiting toxicities (DLTs) of the nivolumab dose with nab-P/C (≈ 6 patients/arm). If deemed safe, the treatment arms may be expanded using the recommended part 2 dose with an additional ≈ 14 patients/arm (total of 20 nivolumab-treated patients/arm) to further assess safety and tolerability as well as anti-tumor activity. Patients will be allowed to continue nivolumab treatment beyond RECIST 1.1 disease progression (physician discretion). ClinicalTrials.gov number NCT02309177. Figure 1 .
Results:
Not applicable
Conclusion:
Not applicable
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P1.02 - Poster Session/ Treatment of Localized Disease – NSCLC (ID 209)
- Event: WCLC 2015
- Type: Poster
- Track: Treatment of Localized Disease - NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 9/07/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
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P1.02-036 - Peripheral Blood Immunophenotype Changes Following Thoracic Stereotactic Ablative Radiotherapy (ID 2282)
09:30 - 09:30 | Author(s): K. Kelly
- Abstract
Background:
Stereotactic ablative radiotherapy (SAR) is a standard therapy for early stage, medically inoperable non-small cell lung cancer (NSCLC) and select metastatic tumors. Strategies combining SAR and immune checkpoint inhibitors are of great interest in potentially augmenting anti-tumor immune response, and prospective trials evaluating SAR/immunotherapy combinations are underway. However, the systemic immune response profile following SAR is poorly defined. Better understanding of the systemic immune response following SAR should allow optimization of SAR/immunotherapy protocols. We performed pre and 1 week post-SAR immune profiling on patients undergoing lung SAR, focusing on central memory T-cells which have been implicated as important mediators of systemic anti-tumor immune responses.
Methods:
Patients are actively accruing to an IRB approved protocol examining systemic immunophenotype changes following SAR for early stage (T1-2N0) NSCLC or metastatic lesions to the lung. Patients underwent collection of 30 cc blood by venipuncture immediately prior to and at 1 week post-SAR to a median dose of 50 Gy (range: 50-54 Gy) over 5 fractions (range: 3-5 fractions). Immunophenotyping of peripheral blood mononuclear cells (pbmc’s) was performed using flow cytometric analysis. Central Memory T-cells were defined as CD62L+ and CD45RA- subsets of CD4+ or CD8+ T-cells. Changes pre-treatment to post-treatment were compared across the cohort using a paired T-test.
Results:
To date eleven NSCLC patients have accrued, and evaluable pre- and post-SAR specimens are available for six, all with early stage NSCLC (T1=4, T2=2, synchronous primaries =1). At one week post-SAR increases in systemic central memory CD4+ T-cells were observed in 4/6 patients and increases in systemic central memory CD8+ T-cells were observed in 3/6 patients with substantial (up to 10-fold) increases observed in some patients. Across the cohort the percent of circulating memory CD4+ T-cells increased from 1.9% pre-SAR to 3.1% post-SAR (p=0.06, Figure 1) and the percent of circulating memory CD8+ T-cells increased from 0.3% pre-SAR to 0.5% post-SAR (p=0.34, Figure 1).
Conclusion:
Our preliminary data in a limited patient cohort suggest lung SAR may induce systemic upregulation of circulating central memory T-cells which may be important mediators of the anti-tumor immune response. As more patients accrue, additional post-treatment time points are evaluated, and further analyses including cytokine/chemokine signatures are performed, we aim to better define systemic immunophenotype changes induced by lung SAR, assess how these changes relate to treatment toxicity and efficacy, and whether they can predict which patients will most likely benefit from the addition of immunotherapy to SAR. Figure 1
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P1.07 - Poster Session/ Small Cell Lung Cancer (ID 221)
- Event: WCLC 2015
- Type: Poster
- Track: Small Cell Lung Cancer
- Presentations: 1
- Moderators:
- Coordinates: 9/07/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
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P1.07-014 - Predictors of Survival in Small Cell Lung Cancer (SCLC) Patients (pts) < 50 Years of Age: Results from the California Cancer Registry (CCR) (ID 2416)
09:30 - 09:30 | Author(s): K. Kelly
- Abstract
Background:
SCLC is an often lethal disease that commonly occurs in older individuals with a history of heavy tobacco use. Limited epidemiologic and outcomes data are available for young SCLC pts (< 50 years of age). We analyzed the CCR to explore the clinical variables related to cause specific survival (CSS) of young pts.
Methods:
SCLC pts diagnosed between 1998-2012 were included. Primary outcome was CSS. Hazard ratios (HR) for CSS were calculated using Cox Proportional Hazards (PH) models for all ages & for pts <50 years, adjusted for baseline variables: age, gender, stage, race, year of diagnosis, treatment, socioeconomic status (SES), and location (urban vs. rural).
Results:
We identified 22,863 SCLC pts, of which 975 were <50 years of age (4.2%). Demographics for pts <50 years: Males-51%; White-71%; Stage IV-60%; Chemotherapy-79%; Urban location-92%; high SES-28%. Fewer pts < 50 years were diagnosed in later years: from 40% in ‘98-’02 to 24% in ‘08-‘12. Results of multivariate Cox PH models are shown. (HR=Hazard Ratio).Select Variables All pts Pts<50 years of age HR P-value HR P-value Age at diagnosis (vs. ≥50yrs) 0.82 <0.0001 N/A N/A Female sex (vs.Male) 0.91 <0.0001 0.81 0.0045 Race (vs.White) Asian 0.84 <0.0001 0.57 0.0075 Year of Dx (vs.'88-'02) 2003-'07 0.96 0.0096 0.95 0.5562 2008-'11 0.94 0.0017 0.89 0.2796 Stage (vs.I) Stage II 1.22 0.0111 1.20 0.7255 Stage III 1.80 <0.0001 1.81 0.0282 Stage IV 2.93 <0.0001 3.81 <0.0001 Treatment (vs.None) Surgery 0.43 <0.0001 0.37 0.004 Chemotherapy 0.44 <0.0001 0.49 <0.0001 Radiation 0.66 <0.0001 0.71 <0.0001 Rural (vs.Urban) 0.97 0.3042 0.75 0.0419 Low SES {vs.High SES(4,5)} 1.05 0.0011 1.04 0.6306
Conclusion:
Age < 50 years was an independent predictor of improved CSS (HR 0.82, p<0.0001). In younger pts, female sex (HR 0.81, p=0.0045), Asian race (HR 0.57, p=0.0075), and rural residence (HR 0.75, p=0.042) were associated with better CSS, among other variables. Analyses for relevant interactions within subgroups will be presented.
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P2.01 - Poster Session/ Treatment of Advanced Diseases – NSCLC (ID 207)
- Event: WCLC 2015
- Type: Poster
- Track: Treatment of Advanced Diseases - NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 9/08/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
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P2.01-085 - Abemaciclib in Combination with Single Agent Options in Stage IV NSCLC, a Phase 1b Study (ID 125)
09:30 - 09:30 | Author(s): K. Kelly
- Abstract
Background:
Abemaciclib, a cell cycle inhibitor selective for CDK4/6, demonstrated acceptable safety and early clinical activity in metastatic NSCLC, given orally as monotherapy on a continuous schedule. Combinations of abemaciclib showed greater activity compared with monotherapy in KRAS-mutant NSCLC preclinical models. Primary aim of study NCT02079636 was safety/tolerability of combination therapy with abemaciclib; secondary aims included pharmacokinetics and antitumor activity.
Methods:
In this open-label 3+3 dose-escalation study with expansion cohorts, eligibility included stage IV NSCLC, measurable or nonmeasurable disease (RECISTv1.1), ECOG PS ≤1, and 1-3 prior therapies. Abemaciclib was combined with pemetrexed (Part A, nonsquamous, 500 mg/m[2] IV day 1), gemcitabine (Part B, 1250 mg/m[2] IV days 1 and 8), ramucirumab (Part C, 10 mg/kg IV day 1, or 8 or 10 mg/kg IV days 1 and 8) (Q21), or LY3023414 (dual PI3K-mTOR inhibitor) (Part D, 100 mg, 150 mg or 200 mg orally Q12H). In escalation, patients were dosed continuously until progression with abemaciclib at 100 mg (Part D), 150 mg or 200 mg orally Q12H.
Results:
As of February 27, 2015, 70 patients (Parts A-C) received ≥1 dose; 15 patients at 150 mg and 55 patients (including all 39 patients in expansion) at 200 mg Q12H abemaciclib. The MTD was established at 200 mg Q12H abemaciclib for Parts A-C. See Table 1 for treatment-emergent adverse events (TEAEs). Stable disease was observed in 13/23 patients in Part A; 7 unknown, 4/24 patients in Part B; 10 unknown, and 7/23 patients in Part C; 12 unknown. In Parts A-C, 18/70 (26%) patients started ≥4 cycles (Part A=9, Part B=3, Part C=6). Three confirmed PRs were observed: Part B, 1 patient with squamous histology (unknown mutation status), Part C, 1 patient with nonsquamous histology (KRAS mutation positive; EGFR mutation negative), and 1 patient with squamous histology (unknown mutation status). Updated analyses will be presented including Part D and longer term follow-up for Parts A-C through approximately June 2015. Table 1. TEAEs related to treatment (≥20% in ≥1 part)% All grades (% Gr3/4) Part A (n=23) Part B (n=24) Part C (n=23) Diarrhea 65 (4) 50 (17) 52 (9) Fatigue 57 (9) 63 (8) 17 (4) Nausea 35 (0) 50 (4) 48 (9) Neutropenia 61 (61) 50 (33) 17 (4) Anemia 57 (26) 33 (17) 9 (0) Thrombocytopenia 39 (9) 38 (8) 17 (13) Decreased appetite 30 (0) 25 (0) 22 (0) Vomiting 9 (0) 21 (0) 35 (0) Blood creatinine increased 30 (0) 8 (0) 17 (4) Leukopenia 30 (22) 17 (8) 9 (4)
Conclusion:
Abemaciclib combined with single-agents with acceptable toxicity. Safety findings observed in Parts A and B are consistent with AEs expected when combining myelosuppressive compounds with abemaciclib, resulting in an increased myelosuppressive effect. In Part C, safety findings are consistent with those of single-agents. Tumor responses were observed in Parts B and C.
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P3.01 - Poster Session/ Treatment of Advanced Diseases – NSCLC (ID 208)
- Event: WCLC 2015
- Type: Poster
- Track: Treatment of Advanced Diseases - NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 9/09/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
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P3.01-084 - Avelumab (MSB0010718C), an Anti-PD-L1 Antibody, Evaluated in a Phase Ib Trial as a First-Line Treatment for Patients with Metastatic NSCLC (ID 1707)
09:30 - 09:30 | Author(s): K. Kelly
- Abstract
Background:
The programmed death-1 receptor (PD-1) and its ligand (PD-L1) are key therapeutic targets in the reactivation of the immune response against multiple cancers. Avelumab* (MSB0010718C) is a fully human anti-PD-L1 IgG1 antibody currently being investigated in clinical trials. The phase Ib study (NCT01772004) is an open-label, parallel group expansion trial in patients with metastatic or locally advanced solid tumors that includes a cohort of patients with non-small-cell lung cancer (NSCLC) who have not been previously treated for metastatic or recurrent disease. Prior to adding this first-line cohort, this study had enrolled a separate cohort of patients with NSCLC who had received a prior platinum-containing doublet regimen.
Methods:
This trial cohort is enrolling patients with histologically confirmed stage IV (according to IASLC) or recurrent NSCLC who have not previously received treatment for metastatic or recurrent disease. In addition, this cohort is restricted to patients without an activating EGFR mutation or ALK rearrangement. Patients with unknown EGFR or ALK status will be tested during screening and are required to have negative status for inclusion. Eligible patients also must have tumor archival material or fresh biopsy, an ECOG performance status of 0 or 1 at the time of trial entry, and disease with at least 1 measurable lesion according to RECIST 1.1. Exclusion criteria include prior therapy with immune checkpoint drugs or a known history of autoimmune disease. Up to 150 eligible patients will receive avelumab at 10 mg/kg as an infusion Q2W. Treatment will continue until disease progression, unacceptable toxicity, or any criterion for withdrawal occurs. Treatment may be continued despite progression according to RECIST 1.1 if the patient’s clinical status is stable and, according to investigator opinion, there is no need to start salvage therapy. The primary objective of the trial is to assess the safety and tolerability of avelumab as a first-line therapy. Select secondary objectives include: assessment of best overall response (BOR) and progression-free survival (PFS) according to RECIST 1.1; assessment of immune-related BOR and immune-related PFS (using modified Immune-Related Response Criteria); and assessment of overall survival. Association between tumor PD-L1 expression and efficacy will be evaluated. Immunomonitoring of cellular and soluble markers and intratumoral cellular surveillance will also be carried out. At each visit during the treatment phase, adverse events will be assessed and graded according to NCI-CTCAE v4.0. Tumor evaluation will be performed every 6 weeks until progression. Enrollment in this cohort began in March 2015. *Proposed INN.
Results:
not applicable
Conclusion:
not applicable
