Post Progression Research Articles

Clinical outcomes of sorafenib treatment failure for advanced hepatocellular carcinoma and candidates for regorafenib treatment in real-world practice.

As second-line therapy, regorafenib has been shown to provide a survival benefit for patients with hepatocellular carcinoma (HCC) who progress on sorafenib. In this retrospective study, we assessed the clinical outcomes of sorafenib treatment failure with regard to second-line chemotherapy. Patients (n = 160) with advanced HCC, Child-Pugh A liver function and Eastern Cooperative Oncology Group performance status (ECOG PS) 0-1 treated with sorafenib between June 2009 and September 2016 were enrolled. Among 147 patients with progressive disease (PD), we defined those with Child-Pugh A liver function and ECOG PS 0-1 at progression as candidates for second-line chemotherapy and those who had tolerated sorafenib (≥400mg/day for ≥20 of the last 28days of treatment) as candidates eligible for regorafenib treatment. Among all 160 patients, median overall survival was 10months, and median progression-free survival was 3.5months. Among the 147 patients with PD, 74 (50.3%) were candidates for second-line chemotherapy, and 45 (30.6%) were eligible for regorafenib treatment. The median post progression survival of the candidates for second-line chemotherapy (8.8months) was statistically longer (P = 0.0002) than that of the non-candidates (3.6months). Predictive factors for candidates were absence of macroscopic vascular invasion (MVI) (odds ratio [OR], 0.39; P = 0.009) and serum albumin >3.5g/dL (OR, 3.3; P = 0.005) at sorafenib initiation. Among patients with PD on sorafenib, approximately 30% were eligible for regorafenib treatment, whereas few patients with MVI or hypoalbuminemia at sorafenib initiation were eligible for regorafenib treatment.

Overexpression of S100A14 contributes to malignant progression and predicts poor prognosis of lung adenocarcinoma.

BackgroundS100A14 is a member of the S100 calcium‐binding protein family that exerts important phenotypic effects on cell proliferation, apoptosis, differentiation, and motility. However, the functional role and potential clinical significance of S100A14 in lung adenocarcinoma has not yet been clarified.MethodsWe analyzed genomic alterations of S100A14 using The Cancer Genome Atlas lung adenocarcinoma genomic dataset. S100A14 displayed significant copy number amplification in lung adenocarcinoma. We detected S100A14 expression in lung adenocarcinoma and analyzed the correlation between S100A14 expression and clinicopathological characteristics.ResultsImmunohistochemical analysis showed that S100A14 expression was obviously upregulated in lung adenocarcinoma tissues compared to matched normal counterparts. Statistical analysis revealed that S100A14 expression strongly correlated with poor differentiation, metastasis, stage, smoking, and EGFR mutation. Furthermore, our data indicated that S100A14 serum levels were higher in lung adenocarcinoma patients than healthy controls. Intriguingly, S100A14 serum levels were related to distant metastasis (P = 0.028). High S100A14 expression was significantly associated with overall (P = 0.0016) and post progression (P = 0.039) survival. In addition, we investigated the biological functions of S100A14 in lung adenocarcinoma cell lines. The results demonstrated that S100A14 promoted cell migration and invasion of SPCA1 and Glc‐82 cells.ConclusionsS100A14 increases the motility of lung adenocarcinoma cells, and might be a diagnostic and prognostic serum biomarker and potential therapeutic target for lung adenocarcinoma.

PCN140 - Cost-Effective Study of Alectinib in Treating Crizotinib-Failed Anaplastic Lymphoma Kinase Positive (ALK+) Non-Small Cell Lung Cancer (NSCLC) Patients in Taiwan

The primary aim was to evaluate the cost-effectiveness of alectinib in treating patients with ALK+ NSCLC who failed on prior crizotinib treatment in Taiwan. We assessed the incremental cost-effective ratio (ICER) of alectinib using a partitioned semi-Markov model provided by the manufacturer of alectinib with three post-treatment health states: progression-free (PF), post-progression (PP), and death. Overall survival and progression-free survival estimates derived from clinical trials were used for an indirect comparison between alectinib and ceritinib and for calculation of the life-years (LYs) and quality adjusted life-years (QALYs) gained after treatment initiation. The analysis was carried out from payer’s perspective (Taiwan National Health Insurance, NHI) and only included direct medical costs covered by the NHI program. The costs and outcomes were both discounted 3% annually over a 5-year time horizon. One-way sensitivity analyses and probabilistic sensitivity analyses were performed to evaluate the robustness of the ICER estimates. In the base case scenario, the incremental LYs and QALYs were 0.69 and 0.25, respectively while the incremental costs were New Taiwan Dollar (NTD) 1,226,449 (equals to USD 40,882 according an exchange rate of 1 USD to 30 NTD), yielding an ICER of NTD 4,834,193 (USD 161,140) per QALY gained. One-way sensitivity analyses revealed utility in PF state, reimbursement price of alectinib, cost of supportive care in PP state, and utility in PP state significantly influenced the ICER estimates, sequentially. The projected ICER ranged from NTD 5,818,353-2,829,273 (USD 193,945- 94,309) per QALY in the scenario analyses when time to treatment discontinuation was set to trial-observed treatment time and when utility in PP state=0.46 was used. While treatment with alectinib increased LYs, the ICERs exceeded the threshold of NTD 2,000,000 (USD 66,667) per QALY. The model estimates were highly sensitive to utility estimates associated with different health states and drug price.

Metabolic characterization of human aqueous humor in the cataract progression after pars plana vitrectomy

BackgroundWhile pars plana vitrectomy (PPV) has become the third most commonly performed surgery in the world, it can also induce multiple post complications easily. Among them, cataract progression is the most frequent one that can lead to blindness eventually.MethodsTo understand the underlying mechanisms of post PPV cataract progression, we performed comprehensive metabolic characterization of aqueous humor (AH) samples from 20 cataract patients (10 post PPV complication and 10 none PPV cataract) by a non-targeted metabolomic analysis using gas chromatography combined with time-of-flight mass spectrometer (GC/TOF MS).ResultsA total of 263 metabolites were identified and eight of them are determined to be significantly different (VIP ≥ 1 and p ≤ 0.05) between post PPV group and none PPV control group. The significantly changed metabolites included glutaric acid and pelargonic acid that play key roles in the regulation of oxidative stress and inflammatory responses. Furthermore, we constructed a metabolic regulatory network in each group based on metabolite-metabolite correlations, which reveals key metabolic pathways and regulatory elements including amino acids and lipids metabolisms that are related to cataract progression.ConclusionsAltogether, this work discovered some potential metabolite biomarkers for post PPV cataract diagnostics, as well as casted some novel insights into the underlying mechanisms of cataract progression after PPV.

Abstract P5-21-30: Retrospective review of palbociclib (Pal) efficacy and benefit from subsequent treatments following Pal progression in patients (pts) with hormone receptor positive (HR+) and HER2 negative (HER2-) metastatic breast cancer (MBC)

Abstract Background The cyclin-dependent kinase (CDK) 4/6 inhibitor Pal is approved for HR+ HER2- MBC. However, the optimal therapy following Pal progression is unknown. Therefore we conducted this retrospective study to review Pal efficacy and summarize the practice pattern and responses to subsequent treatments post Pal progression. Methods We performed a chart review of pts with HR+ HER2- MBC who began Pal treatment at Washington University Siteman Cancer Center between Feb 16, 2015 and July 13, 2016 and collected information on pts demographics, diagnosis, and treatment history. Duration of therapy was used to calculate the progression free survival (PFS) for each regimen. Treatment was considered first-line if administered without any prior systemic therapy or at least 1 year from completion of adjuvant hormonal therapy (HT). Treatments received after progression on 1st line therapy or upon relapse during or within 1 year from the completion of adjuvant HT were considered second-line regimens. Statistical analyses were performed on SAS software, version 9.4. The Kaplan-Meier method was used to generate time-to-event curves, from which median PFS was calculated. A stratified log-rank test was used for all comparisons, and the P value derived from the comparison was reported. Results We completed a chart review for 81 pts (78 female and 3 male; 63 Caucasian, 14 African American, and 4 other races) with HR+ HER2- MBC (68 were ER+PR+, 13 were ER+PR-) who received Pal plus letrozole (n=65) or fulvestrant (n=15) or anastrozole (n=1), with a median age of 62.0 years (range 28.1 - 85.6) at the start of Pal. The median follow up was 20.0 months (mos) (range 10.8 – 27.9). 25 pts were still on Pal treatment. The median PFS on Pal was 19.9 mos in the first-line setting (n=20), compared to 12.1 mos and 4.4 mos in the second-line (n=14) and subsequent lines (n=47), respectively (p=0.0287). Among the 54 pts who progressed on Pal, 38 moved on to the next treatment. 20 pts received chemotherapy and 16 pts received HT or a HT combination. 2 pts received fulvestrant plus Pal upon progression on letrozole plus Pal, and treatment was still ongoing at 4 mos and 7 mos of follow up, respectively. The most common treatments post Pal were single-agent capecitabine (Cape) (n=9) and the combination of exemestane (Exe) and everolimus (Eve) (n=8). The median PFS was 4.7 mos with Cape compared to 8.4 mos with Exe and Eve (p=0.60). The median PFS was 4.7 mos for the 20 pts who received chemo, whereas the median PFS was 4.9 mos with subsequent HT (n=16) (p=0.75). Conclusion Pal plus letrozole or fulvestrant is effective for the treatment of HR+ HER2- MBC, with activity observed beyond the 1st and 2nd line treatment settings. The PFS of Pal observed in this single center retrospective study is consistent with that of published data. Single-agent cape or the Exe and Eve combination were common treatment choices following progression on Pal. Although the study is limited by its small sample size, the median PFS of 8.4 mos with Exe and Eve indicates its potential efficacy in the setting of Pal progression. Additional pts and followup data will be presented. Citation Format: Xi J, Oza A, Thomas S, Naughton M, Ademuyiwa F, Weilbaecher KN, Suresh R, Bose R, Cherian MA, Hernandez-Aya L, Frith A, Peterson LL, Krishnamurthy J, Ma CX. Retrospective review of palbociclib (Pal) efficacy and benefit from subsequent treatments following Pal progression in patients (pts) with hormone receptor positive (HR+) and HER2 negative (HER2-) metastatic breast cancer (MBC) [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P5-21-30.

A randomized phase II trial of interleukin-2 and interferon-α plus bevacizumab versus interleukin-2 and interferon-α in metastatic renal-cell carcinoma (mRCC): results from the Danish Renal Cancer Group (DaRenCa) study-1

Background: Interleukin-2 (IL2)-based immunotherapy is curative for a small subset of patients with metastatic renal-cell carcinoma (mRCC). Preclinical data suggests that bevacizumab (BEV), a humanized anti-VEGF monoclonal antibody, has potential immunomodulatory effects by permitting efficient natural killer (NK) cell-mediated killing and by reverting immune suppression.Patient and methods: We performed a randomized phase II study comparing IL2/IFN (interferon)/BEV with IL2/IFN in favourable/intermediate-risk mRCC patients. One hundred and eighteen patients received IFN 3 MIU subcutaneously (sc) daily and IL2 2.4 MIU/m2 sc twice daily, 5 days per week for two consecutive weeks every 28-day-cycle, for 9 months; or supplemented with BEV 10 mg/kg, every 2 weeks intravenously (iv) until progression, unacceptable toxicity, or 1 year following no evidence of disease (NED). Primary end point was progression-free survival (PFS).Results: Baseline characteristics were well-balanced between the two arms; metastasis-free interval <1 year (75 versus 76%); prior nephrectomy (85 versus 86%); MSKCC favourable/intermediate-risk group (51/49 versus 52%/48%); three or more disease sites (41 versus 44%), respectively. The median PFS was 8.0 mo (95% CI, 4.2–11.9) with IL2/IFN/BEV and 8.1 mo (95% CI, 5.1–11.0) with IL2/IFN, p = .73. There was no difference in secondary endpoints, IL2/IFN/BEV versus IL2/IFN; median time-to-treatment failure (7.4 versus 5.6 mo, p = .54), response rate (44.1 versus 28.8%, p = .13), surgery of residual disease (17.0 versus 17.0%, p = 1.0), patients achieving NED (3.4 versus 8.5%, p = .44), and median overall survival (30.3 versus 34.1 mo, p = .39), respectively. TKI post progression was well-balanced (85 versus 78%). No new/unexpected toxicity was observed. Most common Grade 3/4 adverse events for IL2/IFN/BEV and IL2/IFN were fatigue (64 versus 61%), flu-like symptoms (37 versus 41%) and thrombosis (6.8 versus 18.6%, p = .01), respectively.Conclusions: The addition of BEV to IL-2/IFN did not add efficacy in mRCC. (ClinicalTrials.gov, NCT01274273.).

Immunomodulation in hepatocellular cancer.

Hepatocellular carcinoma (HCC) is the fastest growing malignancy in the United States in relation to mortality. HCC relies on a complex immunosuppressive network to modify the host immune system and evade destruction. Intrinsic to the liver's function and anatomy, native hepatic and immune cells produce many inhibitory cytokines that promote tolerogenicity and limit immune response. Since the introduction of sorafenib in 2008, no treatment has been able to demonstrate improved survival in patients with advanced HCC post disease progression treated with sorafenib. More recent studies have shown that sorafenib has an immunomodulatory function in addition to inhibition of multiple tyrosine kinases. Clinical trials have aimed to further enhance this immunomodulatory function with other treatments, most promisingly immune checkpoint inhibitors. Additionally, ongoing studies are using combinatorial approaches with immunomodulatory treatment and liver directed therapies such as transarterial chemoembolization (TACE), radiofrequency ablation (RFA), microwave ablation (MWA), and cryoablation. This article will review recent data describing the immunosuppressive network in HCC, recent results of immunotherapies, and combinatorial approaches to treat advanced HCC.

Visceral leishmaniasis: An immunological viewpoint on asymptomatic infections and post kala azar dermal leishmaniasis

Elimination of visceral leishmaniasis is a priority programme in Indian subcontinent. The World Health Organization has set a new target to eliminate kala-azar by the year 2020 as previous target elimination year (2015) has passed. The elimination programme has successfully curbed the rate of infection in endemic regions; however, there are still few challenges in its route. The current drug control regime is extremely limited and comprises only two (amphotericin B and miltefosine) drugs, which are also susceptible for parasites resistance. Moreover, these drugs do not produce sterile cure, and cured patients may develop post kala-azar dermal leishmaniasis even after a decade of cure leaving behind a potent source of parasitic reservoirs for further disease transmission. A significant proportion of endemic population remain seropositive but aymptomatic for many years without any clinical symptom that serve as latent parasitic reservoirs. The lack of tools to identify live parasites in asymptomatic infections and there association in disease transmission, parameters of sterile cure along with post kala-azar dermal leishmaniasis progression remain a major threat in its elimination. In this review, we discuss the potential of host immune inhibitory mechanisms to identify immune correlates of protective immunity to understand the mystery of asymptomatic infections, sterile cure and post kala azar dermal leishmaniasis.

Outcome of EGFR-mutated NSCLC patients with MET-driven resistance to EGFR tyrosine kinase inhibitors.

BackgroundSeveral mechanisms of acquired resistance to EGFR tyrosine kinase inhibitors (TKIs) in EGFR-mutated NSCLC have been described including the T790M mutation and MET amplification. Whereas T790M mutation confers prolonged survival and sensitivity to 3rd generation TKIs, data are lacking on clinical features and outcome of MET-driven resistant EGFR-mutated NSCLC patients.MethodsPatients with metastatic EGFR-mutated NSCLC displaying high MET overexpression or MET amplification, detected on a biopsy performed after progression on EGFR TKI, were identified in 15 centers. Clinical and molecular data were retrospectively collected.ResultsForty two patients were included. The median overall survival (OS), and the median post EGFR TKI progression overall survival (PPOS) were 36.2 months [95%CI 27.3-66.5] and 18.5 months [95%CI 10.6-27.4] respectively. Nineteen out of 36 tumors tested for MET FISH had MET amplification. A T790M mutation was found in 11/41 (26.8%) patients. T790M-positive patients had a better OS than T790M-negative patients (p=0.0224). Nineteen patients received a MET TKI. Objective response was reported in 1 out of 12 evaluable patients treated with a MET inhibitor as a single agent and in 1 of 2 patients treated with a combination of MET and EGFR TKIs.ConclusionMET-driven resistance to EGFR TKI defines a specific pattern of resistance characterized by low objective response rate to MET inhibitors given alone and overlapping with T790M mutations. Further studies are warranted to define adequate therapeutic strategies for MET-driven resistance to EGFR TKI.

Emergence of EGFR G724S mutation in EGFR-mutant lung adenocarcinoma post progression on osimertinib

Mutations in the epidermal growth factor receptor (EGFR) are drivers for a subset of lung cancers. Osimertinib is a third-generation tyrosine kinase inhibitor (TKI) recently approved for the treatment of T790M-positive non-small cell lung cancer (NSCLC); however, acquired resistance to osimertinib is evident and resistance mechanisms remain incompletely defined. The EGFR G724S mutation was detected using hybrid-capture based comprehensive genomic profiling (CGP) and a hybrid-capture based circulating tumor DNA (ctDNA) assays in two cases of EGFR-driven lung adenocarcinoma in patients who had progressed on osimertinib treatment. This study demonstrates the importance of both tissue and blood based hybrid-capture based genomic profiling at disease progression to identifying novel resistance mechanisms in the clinic.

The management of BRAF mutant melanoma brain metastases upon tyrosine kinase failure.

e21020 Background: Brain metastases (BM) failure on tyrosine kinase inhibitor (TKI) is a frequent complication in patients with BRAF mutant metastatic melanoma (MM) and is associated with a poor prognosis. We aimed to explore the outcome of these patients with modern therapeutic options. Methods: We retrospectively analysed 55 patients with treated BRAF mutant mm diagnosed with BM on TKI at a single site in Brisbane, QLD, Australia during 2009-2016. Basic clinico-pathological parameters, treatments used and mortality data were collected. Results: Patient characteristics included a median age of 53 (17-82) years, presence of seizures (N = 7), LDH &gt; 250 (N = 23) and presence of systemic disease (N = 54). BM were categorised as solitary (N = 8), 2-6 (N = 23), more than 6 (N = 13) and leptomeningeal disease (N = 11). Management of BM included surgical resection (N = 6), stereotactic radiosurgery (SRS) (N = 14), whole brain radiotherapy (N = 13) and best supportive care (N = 16). BRAF use post progression with BM was used (N = 10). Immunotherapy with Ipilimumab (N = 17) and PD1 inhibitor (N = 24) was used. With a median follow up of 5 months, 47 (85%) patients had died from MM. Death occurred due to progressive disease in the brain (N = 24), systemically (N = 5) or both (N = 18). The number of patients surviving over 6 months (N = 27) were associated with &lt; 6 BM, use of radiotherapy, use of anti PD1 antibodies and the use of ablative therapies with immunotherapy. Statistically improved overall survival (OS) were found with &lt; 6 BM, SRS use and PD1 inhibitor use. Ablative treatments (resection or SRS) with subsequent immunotherapy confers a median OS of 13 months in select patients. Conclusions: Despite improvements in systemic treatment for mm the outcomes of those with BRAF mutant mm on TKI who develop BM remains poor. Death is frequently due to PD within the brain. The use of ablative techniques and immunotherapy are optimal treatment options in this poor prognostic group.

A phase IV, randomized, double-blind, placebo (PBO)-controlled study of continued enzalutamide (ENZA) post prostate-specific antigen (PSA) progression in men with chemotherapy-naive metastatic castration-resistant prostate cancer (mCRPC).

5004 Background: We hypothesized resistance to the androgen receptor inhibitor ENZA is due to increases in androgens and can be overcome by combination with the androgen synthesis inhibitor abiraterone (abi). The phase 4 PLATO trial (NCT01995513) is evaluating the safety and efficacy of continued ENZA + abi/prednisone (abi/P) vs PBO + abi/P after PSA progression on ENZA. Methods: In Period (P) 1, men with chemotherapy-naïve mCRPC received ENZA (160 mg); men with no PSA increase from baseline at wk 13 and 21 continued treatment until PSA progression (≥ 25% increase and ≥ 2 ng/mL above nadir). Eligible men were then randomized 1:1 in P2 to ENZA + abi/P (1000 mg/10 mg) or PBO + abi/P. The primary endpoint (EP) was progression-free survival (PFS; radiographic or unequivocal clinical progression, or death on study) in P2, with a prespecified sensitivity analysis of radiographic PFS (rPFS); protected secondary EPs were time to PSA progression (TTPP) and PSA response ≥ 50% in P2. Results: 509 men enrolled in P1. At data cutoff (Oct 7, 2016), 84 were active, 174 discontinued, and 251 were randomized in P2 (ENZA + abi/P, n = 126; PBO + abi/P, n = 125). Median treatment duration in P2 was 5.6 mo for both arms. PFS event by radiographic/clinical/death was 38%/25%/2% for ENZA + abi/P and 55%/18%/1% for PBO + abi/P. Median PFS was 5.7 mo for ENZA + abi/P and 5.6 mo for PBO + abi/P (hazard ratio [HR], 0.83; 95% confidence interval [CI], 0.61, 1.12; P = 0.22). Median TTPP was 2.8 mo for both arms (HR, 0.87; 95% CI, 0.62, 1.24; P = 0.45). PSA response rate was 0.8% for ENZA + abi/P and 2.5% for PBO + abi/P ( P = 0.31). Median rPFS was 10.0 mo for ENZA + abi/P and 7.0 mo for PBO + abi/P (HR, 0.67; 95% CI, 0.47, 0.94; P = 0.02). The most common (≥ 15%) adverse events for ENZA + abi/P vs PBO + abi/P were back pain (21% vs 23%), hypertension (20% vs 7%), nausea (17% vs 9%), and fatigue (14% vs 15%). Conclusions: ENZA + abi/P post PSA progression on ENZA was associated with increased hypertension and nausea and did not result in a statistically significant improvement in composite PFS. The signal seen in rPFS needs further evaluation. Clinical trial information: NCT01995513.

A trial-based EuroQol EQ-5D health utility analysis in patients with classical Hodgkin lymphoma.

e19011 Background: Pembrolizumab has shown a high response in patients classic Hodgkin lymphoma (cHL) patients who have experienced disease progression after brentuximab vedotin in KEYNOTE (KN)-087 and the results have been presented. This study aimed to evaluate the health-related quality of life (HRQoL) of the trial patients in KN087. Methods: KN-087 is an ongoing single-arm multi-center, non-randomized Phase II trial evaluating pembrolizumab 200mg Q3W IV in patients with relapsed or refractory cHL. In KN-087, HRQoL data were collected at baseline and every drug administration over the 18 months of follow-up. HRQoL was assessed using both the EQ-5D and EORTC QLQ-C30 instruments. The generic health statuses assessed from both instrument were converted to population-based utility values using published algorithms. More specifically, US-based scoring was applied to US patients, UK-based scoring for UK patients and EU-based scoring for all other patients. HRQoL was reported by status of respond and disease progression. Response was defined based upon IWG criteria. Furthermore, stratified analyses were conducted to examine the health disabilities of the patients who experienced grade 3+ adverse events (AEs), and by ECOG performance and the number of prior therapies. Results: Among 210 trial patients, HRQoL data were collected for 205 patients at baseline and the mean health utility score was 0.759 (95% CI 0.730-0.788). Mean health utility score among responders and non-responders was 0.826 (95% CI 0.811-0.842) and 0.760 (95% CI 0.718-0.801), respectively. The difference is considered clinically significant. Mean utility decreased from 0.820 (95% CI 0.807-0.833) for time spent prior to progression to 0.806 (95% CI 0.780-0.832) post disease progression. Progression-free patients who experienced grade 3+ AEs (N=17) had a mean health utility of 0.736 (95% CI 0.662-0.811), compared with 0.825 (95% CI 0.811-0.838) among those did not. Conclusions: The results showed a substantial HRQoL impact of R/R cHL. Treatment response was associated with significant clinically meaningful improvement in HRQoL. The utility estimates from the study are important for economic evaluations of treatments in R/R cHL patients. Clinical trial information: NCT02453594.

Impact of atezolizumab (atezo) treatment beyond disease progression (TBP) in advanced NSCLC: Results from the randomized phase III OAK study.

9001 Background: Cancer immunotherapy (CIT) can have a positive impact on OS that exceeds response rate or PFS effects, termed post progression prolongation of survival (PPPS). This effect can also result from unconventional CIT response due to tumor immune infiltration or delayed response, reducing reliability of RECIST v1.1 (RECIST) PD as an indicator of treatment failure. In the primary analysis (N = 850) of OAK, a study of atezo vs docetaxel (doc) in 2L/3L NSCLC, OS favored atezo (HR 0.73; 95% CI: 0.62, 0.87), despite similar PFS between arms (HR 0.95; 95% CI: 0.82, 1.10). Here we evaluate clinical benefit from TBP, defined by post PD tumor regression, OS and safety. Methods: Patients (pts) received atezo 1200 mg IV q3w until PD or loss of clinical benefit per investigator or doc 75 mg/m2 IV q3w until PD per RECIST. No crossover was allowed. Primary outcome measure: OS. Atezo TBP pts were evaluated for post PD tumor change and for safety pre and post PD. OS from time of PD per RECIST was evaluated in both arms (data cutoff, July 7, 2016; minimum follow-up, 19 mo). Results: Among 332 atezo pts with PD, 51% (n = 168) continued atezo TBP; 7% (12/168) achieved subsequent response in target lesions (≥ 30% reduction from new baseline at PD); 49% (83/168) had stable target lesions (best change between +20% and −30%). mOS was 12.7 mo (95% CI: 9.3, 14.9) post PD for pts on atezo TBP (Table). Atezo TBP was not associated with increased safety risk. Conclusions: This is the first report from a Phase III study of CIT in NSCLC to evaluate post PD OS in pts continuing treatment beyond RECIST PD. Atezo TBP was associated with high frequency of stable or decreased target lesions, mOS &gt; 1 year and a tolerable safety profile, all supporting prolonged treatment benefit consistent with PPPS. NCT02008227 Clinical trial information: NCT02008227. [Table: see text]

NCI Breast Cancer Steering Committee Working Group (WG) report on meaningful and appropriate endpoints for clinical trials (CT) in metastatic breast cancer (MBC).

1073 Background: There is significant heterogeneity in the natural history of MBC. Several recent randomized CT have yielded statistically significant advantages for the experimental arm, but neither led to regulatory approval nor practice change. Formal guidance for industry on CT endpoints provided by the US FDA in 2007 was not disease-specific. Patient-focused drug development is mandated by Prescription Drug User Fee Act V. Our WG sought to create specific consensus on endpoints for MBC CT focusing on subtype and line of therapy, with sensitivity to various stakeholders. Methods: A WG composed of medical oncologists, statisticians, advocates, FDA and NCI liaisons performed a systematic literature review of MBC natural history, CT endpoints by subtype (HR+/HER2-, HR+/HER+, HR-/HER2-, HR-/HER2+), and line of therapy (n = 146 papers). External expertise was obtained on industry perspectives, big data and real world evidence (RWE), and patient reported outcomes (PROs). WG members voted anonymously on statements and positions generated from deliberation. Results: The WG reached consensus on definitions relevant to contemporary CT endpoints. WG recommendations on the appropriate choice of OS or PFS are sensitive to expected post progression survival (PPS), and proportional and absolute gains. Currently, for HR-/HER2- MBC, OS is preferred as the optimal primary endpoint regardless of line of therapy; PFS is preferred in settings where expected PPS is longer. Toxicity can outweigh modest gains in PFS; scant data exist to gauge how patients value PFS gain vs toxicity. Where new agents may prolong PFS without impacting OS, exploring/validating graphic approaches that capture grade and timing of toxicity and PROs is warranted. An overview of WG Consensus Statements will be presented in detail. Conclusions: CT design for MBC should be sensitive to natural history (PPS), availability of other effective agents, PROs and toxicity burden. As unique subtypes (e.g. AR+) and novel therapies (e.g. immunotherapy) emerge, reassessment of relevant benchmarks is indicated. Rigorous big data approaches providing insights from RWE may inform CT endpoints in the future.

Prospective evaluation of the factors predicting the prognosis of advanced hepatocellular carcinoma (HCC) patients treated with sorafenib.

e15674 Background: Several factors including pro-angiogenic cytokines have been reported as predictive markers for the treatment effect of sorafenib in patients with HCC; however, many of them were determined based on the results of retrospective studies. Methods: In this prospective cohort study (UMIN000009771), we recruited advanced HCC patients who were treated with sorafenib, and periodically measured serum levels of eight pro-angiogenic cytokines, which were risk factors for the prognosis reported by us and others. The effect of the cytokine expressions before and at 2 (4) weeks after starting sorafenib and at PD, on progression free survival (PFS), overall survival (OS), and post progression survival (PPS) were evaluated. The effect of early appearance of adverse events within 30 days, which were reported as other risk factors, was also evaluated. Results: Eighty patients were enrolled. Median PFS and OS were 3.1 and 11.7 months, respectively. There was no statistically significant variable that could predict PFS, which included patients’ characteristics, cytokines before the therapy, and early onset of adverse events. However, PFS of the patients who showed the decrease of platelet-derived growth factor after 2 weeks (HR2.78, 95%CI 1.35-6.21, P=0.005) or vascular endothelial growth factor after 4 weeks (HR3.31, 95%CI 1.59-6.83, P=0.001) compared to the values before sorafenib treatment was short. OS was short in patients with poor performance status, large tumor size (&gt;30mm), large tumor number (&gt;5), high des-gamma-carboxyprothrombin (DCP, &gt;100mAU/mL), high hepatocyte growth factor, and high angiopoietin-2 (Ang-2) before therapy, in addition to no hand foot syndrome within 30 days. Multivariate analysis with these factors revealed that high Ang-2 (HR2.25, 95%CI 1.08-4.86, p=0.029) and high DCP (HR3.55, 95%CI 1.25-12.7, p=0.014) were the independent risk factors for OS. High Ang-2 at PD could also be a marker of short PPS. Conclusions: The prediction of PFS, OS and PPS is possible by measuring serum pro-angiogenic cytokines at appropriate timing. Ang-2 is a key cytokine for predicting the prognosis of HCC patients treated with sorafenib.

The cost-effectiveness of alectinib in anaplastic lymphoma kinase-positive (ALK+) advanced NSCLC previously treated with crizotinib

Introduction Anaplastic lymphoma kinase (ALK) targeting drugs provide an important option for advanced non-small cell lung cancer patients with this distinct tumor type; however, there is considerable uncertainty as to which drug provides the optimal value after crizotinib treatment. This study estimated the cost-utility of alectinib vs ceritinib from a US payer perspective.Methods A cost-utility model was developed using partition survival methods and three health states: progression-free (PF), post-progression (PP), and death. Survival data were derived from the key clinical trials (alectinib: NP28761 & NP28673, ceritinib: ASCEND I and II). Costs included drugs, adverse events, and supportive care. Utilities were based on trial data and the literature. One-way and probabilistic sensitivity analyses (PSA) were performed to assess parameter uncertainty.Results Treatment with alectinib vs ceritinib resulted in increases of 2.55 months in the PF state, 0.44 quality adjusted life-years (QALYs), and $13,868, yielding a mean cost/QALY of $31,180. In the PSA, alectinib had a 96% probability of being cost-effective at a willingness-to-pay of $100,000/QALY. Drivers of model results were drug costs and utilities in the PF health state. The ICER ranged from $10,600–$65,000 per QALY in scenario analyses, including a sub-group analysis limited to patients with prior chemotherapy and crizotinib treatment.Conclusions Treatment with alectinib in ALK + crizotinib-treated patients increased time progression-free and QALYs vs ceritinib. The marginal cost increase was driven by longer treatment durations with alectinib. This model demonstrates that alectinib may be considered a cost-effective treatment after progression on crizotinib.

Abstract P2-16-01: Relationship between overall survival and surrogate measures in patients with metastatic breast cancer treated with chemotherapy

Abstract Background: While metastatic breast cancer (MBC) is considered an incurable disease, nearly one-fifth of patients live longer than five years following diagnosis. In an effort to identify novel agents earlier, surrogate end points of overall survival (OS) such as response or progression are often employed in randomized controlled trials (RCTs). The goal of this analysis is to evaluate patterns of outcome reporting and the relationship of OS with surrogate measures in RCTs of patients with MBC. Methods: The analysis was based on data from a systematic review of patients with MBC evaluating the clinical impact of chemotherapy intensity on survival. Reports of phase 2-3 RCTs published between 1990-2013 comparing more intense chemotherapy regimens (higher dose intensity or use of additional agents) with less intense were identified. For each RCT, clinical, treatment, demographic and outcome data were extracted. Outcomes evaluated included OS, progression free survival (PFS), and time to progression (TTP) with a focus on median survival and hazard ratios (HRs) as measures of treatment effect. Survival post progression (SPP) was calculated as the difference between median survival and median progression free time. The relations between various outcome measures were estimated utilizing weighted Pearson correlation coefficient (CORR) adjusted by Fisher's transformation. Weights were assigned proportionally to the sample size of individual RCTs. Results: The review identified 70 eligible RCTs including 15,043 patients with MBC. Average median OS, PFS, and TTP were 19.2, 6.9, and 8.1 months reported in 96%, 60%, and 43% of studies, respectively. Progression could be determined in 66 studies, while 6 RCTs provided both outcomes. TTP was more often utilized in earlier studies (65% in 1990-2000, 35% in 2001-2008, and 33% in 2009-2013) and it was superseded by PFS in later years (20%, 70% and 81%, respectively). Only 37%, 33%, and 11% of RCTs reported HRs for OS, PFS, and TTP, respectively. HRs were more often available in recent publications (20% in 1990-2000, 22% in 2001-2008, 63% in 2009-2013 provided HR for OS). The correlation between reported HR and HR estimated by the ratio of arm-specific median survival times was high for OS (CORR=0.87, 95%CI: 0.73-0.94) and TTP (CORR=0.92, 95%CI: 0.61-0.99) and slightly lower for PFS (CORR=0.72, 95%CI: 0.44-0.87). The relationship between OS and surrogate measures (PFS, TTP) was weaker. The correlation between HR for OS and PFS was 0.49 (95%CI: 0.21-0.69) and for OS and TTP it was 0.26 (95%CI: -0.13-0.58). Survival time following progression was dependent on treatment type and was longer in less intense arms than more intense (mean SPP: 12.4 months vs. 11.4 months, P=0.0155). Conclusions: In RCTs of patients with MBC treated with chemotherapy, when HR is not reported and if necessary statistical conditions are met, the HR approximated by ratio of median survival times may be a suitable proxy estimate. In agreement with other reports, neither PFS nor TTP are acceptable surrogate outcomes for OS in MBC, as survival following progression may be substantial. In these patients, crossover and post-trial treatments may influence the relationship between OS and surrogate measures. Citation Format: Culakova E, Poniewierski MS, Crawford J, Dale DC, Lyman GH. Relationship between overall survival and surrogate measures in patients with metastatic breast cancer treated with chemotherapy [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P2-16-01.

P3.02b-051 Outcome of Advanced EGFR-Mutated NSCLC Patients with MET-Driven Acquired Resistance to EGFR TKI. Results of the METEORE Study: Topic: EGFR Clinical

Several mechanisms of acquired resistance to EGFR TKIs have been described including the T790M mutation and MET amplification. Whereas the T790M mutation confers prolonged survival and sensitivity to 3rd generation TKIs, there is no data on outcome and treatment of MET-driven resistant EGFR-mutated NSCLC patients. Molecular and clinico-pathological data from patients with advanced EGFR-mutated NSCLC and MET overexpression or amplification on a post-progression (PP) sample obtained after treatment with EGFR TKI were retrospectively reviewed in 15 nationwide centers. MET overexpression was defined by MET immunochemistry (IHC) score 3+ and MET amplification was assessed by FISH and defined by MET/CEP7 ratio >2 or MET copy number >6 or MET clusters. 43 patients were included (24 del19, 16 L858R and 3 rare EGFR mutations). The median time between EGFR TKI initiation and PP biopsy was 13.8 months [2.1-61.3]. On PP biopsy, 20 tumors tested for FISH (53%) had MET amplification and all out of 37 samples tested for IHC were scored 3+. No epithelial to mesenchymal transformation was observed. A T790M mutation was found in 12/42 (29%) PP biopsies. 5 patients had both MET amplification and T790M mutation. The median overall survival (OS), and the median PP OS were 36.2 months [IC95% 27.3-45.6] and 18.5 months [IC95% 10.6-26.5], respectively. 16 patients received a MET TKI. Objective response was reported in 1 out of 12 evaluable patients treated with a MET TKI as single agent and in 1 of 2 patients treated with a combination of MET and EGFR TKIs. No significant difference was found according to the MET FISH status for OS and PP OS. 3 out of 9 evaluable T790M-positive patients had an objective response upon 3rd generation EGFR TKI. T790M-positive patients had a better OS (median 84.7 vs. 32.2 months, p=0.016) and PP OS (median 36.9 vs. 11 months, p=0.0141) than T790M-negative patients. Even when associated with MET-driven resistance to EGFR TKIs, the T790M mutation may be associated with relative sensitivity to 3rd generation EGFR TKIs and prolonged survival. MET TKIs alone yield low ORR, which emphasizes the need for further evaluation of combinations of EGFR and MET TKIs.

P3.02b-058 Second-Line Therapy in EGFR Activating Mutation Positive Advanced NSCLC: Analysis from a Randomized Phase III First-Line Trial: Topic: EGFR Clinical

To evaluate the efficacy of second line therapy in patients progressing on either a Pemetrexed-Platinum doublet or Gefitinib in an epidermal growth factor receptor (EGFR) activating mutation positive Stage IIIB/IV non-small cohort in the setting of a phase III clinical trial evaluating Pemetrexed-Platinum doublet versus Gefitinib as first line therapy. Patients were part of a randomized Phase III open label parallel group study comparing Gefitinib with Pemetrexed- Platinum doublet in the upfront setting in an EGFR mutation positive Stage IIIB/IV lung cancer population. On progression on first-line therapy, patients were started on second line therapy, if Eastern Cooperative Oncology Group (ECOG) performance status (PS) was 0-2 and baseline clinical and biochemical parameters were within acceptable limits. Patients who received Pemetrexed-Platinum in the first line were offered Gefitinib in the second-line while patients progressing on first-line Gefitinib were considered for Pemetrexed-Platinum doublet as second-line therapy. 187 patients were included for analysis. Out of these 157 patients were evaluable for response. 113 patients had received gefitinib as second line, while 74 patients had received other I.V second line chemotherapy. The response rate was 60.6% in Gefitinib cohort (60, n=99) and 31% in non-Gefitinib cohort (18, n=58), {p=0.30}. The median PFS was 7.4 months (95% CI:5.4-9.4) in gefitinib cohort, whereas it was 4.4 months in non-gefitinib cohort (95% CI:3.7 -5.2). Median OS in gefitinib cohort was 14 months (95% CI:10.8-17.2), while it was 9.8 months in non-gefitinib cohort (95% CI:7.8-11.7)(p-0.007). Patients started on gefitinib post progression on pemetrexed therapy had significant benefit, whereas it was limited in patients who received I.V chemotherapy post Gefitinib.