Increase In Median Progression-free Survival Research Articles

Deep Learning Artificial Intelligence Predicts Homologous Recombination Deficiency and Platinum Response From Histologic Slides.

Cancers with homologous recombination deficiency (HRD) can benefit from platinum salts and poly(ADP-ribose) polymerase inhibitors. Standard diagnostic tests for detecting HRD require molecular profiling, which is not universally available. We trained DeepHRD, a deep learning platform for predicting HRD from hematoxylin and eosin (H&E)-stained histopathological slides, using primary breast (n = 1,008) and ovarian (n = 459) cancers from The Cancer Genome Atlas (TCGA). DeepHRD was compared with four standard HRD molecular tests using breast (n = 349) and ovarian (n = 141) cancers from multiple independent data sets, including platinum-treated clinical cohorts with RECIST progression-free survival (PFS), complete response (CR), and overall survival (OS) endpoints. DeepHRD predicted HRD from held-out H&E-stained breast cancer slides in TCGA with an AUC of 0.81 (95% CI, 0.77 to 0.85). This performance was confirmed in two independent primary breast cancer cohorts (AUC, 0.76 [95% CI, 0.71 to 0.82]). In an external platinum-treated metastatic breast cancer cohort, samples predicted as HRD had higher complete CR (AUC, 0.76 [95% CI, 0.54 to 0.93]) with 3.7-fold increase in median PFS (14.4 v 3.9 months; P = .0019) and hazard ratio (HR) of 0.45 (P = .0047). There were no significant differences in nonplatinum treatment outcome by predicted HRD status in three breast cancer cohorts, including CR (AUC, 0.39) and PFS (HR, 0.98, P = .95) in taxane-treated metastatic breast cancer. Through transfer learning to high-grade serous ovarian cancer, DeepHRD-predicted HRD samples had better OS after first-line (HR, 0.46; P = .030) and neoadjuvant (HR, 0.49; P = .015) platinum therapy in two cohorts. DeepHRD can predict HRD in breast and ovarian cancers directly from routine H&E slides across multiple external cohorts, slide scanners, and tissue fixation variables. When compared with molecular testing, DeepHRD classified 1.8- to 3.1-fold more patients with HRD, which exhibited better OS in high-grade serous ovarian cancer and platinum-specific PFS in metastatic breast cancer.

BEAT-meso: A randomized phase III study of bevacizumab (B) and standard chemotherapy (C) with or without atezolizumab (A), as first-line treatment (TX) for advanced pleural mesothelioma (PM)—Results from the ETOP 13-18 trial.

LBA8002 Background: The currently approved frontline TXs for PM are the combination of ipilimumab/nivolumab or platinum plus pemetrexed. The addition of B to C has been shown to improve overall survival in a randomized clinical trial. While combined immunotherapy or single agent immunotherapy with C is superior to C alone, there is potential for a synergistic triple combination of C, B, and immunotherapy. Methods: BEAT-meso (NCT03762018) is an international open-label, 1:1 randomized phase III trial, stratified by histology and stage. The objective is to determine the efficacy and safety of adding A (1200 mg, Q3W until progression) to B (15mg/kg, Q3W until progression) and standard C (4-6 cycles of carboplatin AUC5 with pemetrexed 500 mg/m2, Q3W), as first-line TX for advanced PM. The trial is designed to detect an increase in the median overall survival (OS, primary endpoint) with the addition of A, aiming for a hazard ratio (HR) of 0.708, at 2.5% 1-sided alpha and 82% power (284 deaths, sample size 400 patients (pts)). In the pre-specified interim efficacy analysis (80% of the events, 01/2023), boundary was not crossed, and the trial continued to completion. Secondary endpoints include progression-free survival (PFS), objective response rate (ORR), disease control rate, duration of response (DoR), adverse events (AEs) assessed by CTCAE v5.0 and symptom-specific and global quality of life (QoL). Results: Between 04/2019 and 03/2022, a total of 400 pts was randomized, 200 per arm. The median age was 70 years, 79% were male, 50% were former smokers, 65% had ECOG performance status 1 and 78% had epithelioid histology. At a median follow-up of 35 months (m) (as of 1/09/2023), median OS was 20.5m [95% CI: 17.5-23.3] in the ABC and 18.1m [15.7-20.9] in the BC arm (deaths: 145 & 150; HRABC vs BC=0.84; [0.66 - 1.06], 2-sided stratified p=0.14, ITT final analysis). PFS was significantly longer in ABC with median 9.2m [8.1-10.9] vs 7.6m [6.9-8.3] in BC (HR=0.72; [0.59 - 0.89], 2-sided stratified p=0.0021). Histology shows a significant TX interaction for both PFS and OS. The OS HR is 0.51 [0.32-0.80] for non-epithelioid and 1.01 [0.77-1.32] for epithelioid (interaction p=0.012). In an exploratory analysis, post-progression OS was significantly different between the two arms, adjusted for post-progression TX (HR=0.76; [0.58 - 0.99]). The ORR was 55% in ABC and 49% in BC (p=0.27), while median DoR was 8.2m [6.8-9.7] in ABC and 5.6m [4.8-7.0] in BC (p=0.0041). Global QoL change was not significantly different between the two arms. Grade≥3 TX-related AEs occurred in 55% of pts in ABC and 47% of pts in BC (grade 5: 7 and 1 pt, respectively). Conclusions: The significant increase in median PFS with the addition of A did not translate into a significant increase in median OS. ABC demonstrated superiority over BC in non-epithelioid cases. Clinical trial information: NCT03762018 .

Progression-free survival as a surrogate endpoint for overall survival in patients with relapsed or refractory multiple myeloma.

The goal of the research was to assess the quantitative relationship between median progression-free survival (PFS) and median overall survival (OS) specifically among patients with relapsed/refractory multiple myeloma (RRMM) based on published randomized controlled trials (RCTs). Two bibliographic databases (PubMed and Embase, 1970-2017) were systematically searched for RCTs in RRMM that reported OS and PFS, followed by an updated search of studies published between 2010 and 2022 in 3 databases (Embase, MEDLINE, and EBM Reviews, 2010-2022). The association between median PFS and median OS was assessed using the nonparametric Spearman rank and parametric Pearson correlation coefficients. Subsequently, the quantitative relationship between PFS and OS was assessed using weighted least-squares regression adjusted for covariates including age, sex, and publication year. Study arms were weighted by the number of patients in each arm. A total of 31 RCTs (56 treatment arms, 10,450 patients with RRMM) were included in the analysis. The average median PFS and median OS were 7.1 months (SD 5.5) and 28.1 months (SD 11.8), respectively. The Spearman and Pearson correlation coefficients between median PFS and median OS were 0.80 (P < 0.0001) and 0.79 (P < 0.0001), respectively. In individual treatment arms of RRMM trials, each 1-month increase in median PFS was associated with a 1.72-month (95% CI 1.26-2.17) increase in median OS. Analysis of the relationship between PFS and OS incorporating more recent studies in RRMM further substantiates the use of PFS to predict OS in RRMM.

Abstract LB391: Deep learning AI predicts HRD and platinum response from histologic slides

Abstract Background: Cancers with homologous recombination deficiency (HRD) can benefit from platinum salts and PARP inhibitors. Standard diagnostic tests, including FDA-approved companion diagnostics, for detecting HRD require molecular profiling, which is not universally available with global testing rates lowest among minority, rural, and other underserved populations. Methods: We trained DeepHRD, a deep-learning platform for predicting HRD from hematoxylin and eosin (H&amp;E)-stained histopathological slides, using primary breast (n=1,008) and ovarian (n=459) cancers from The Cancer Genome Atlas (TCGA). DeepHRD was compared to four standard HRD molecular tests using breast (n=349) and ovarian (n=141) cancers from multiple external and independent datasets, including clinical cohorts with platinum complete response, progression-free survival (PFS) and overall survival (OS) endpoints. Results: DeepHRD detected HRD from held-out H&amp;E-stained breast cancer slides in TCGA with an AUC of 0.81 ([0.77-0.85]; 95% confidence interval). This performance was confirmed in two independent primary breast cancer cohorts (AUC=0.76; [0.71-0.82]). In an external platinum-treated metastatic breast cancer cohort, samples detected as HRD had a higher complete response (AUC=0.76; [0.54-0.93]) with 3.7-fold increase in median PFS (14.4 versus 3.9 months; p-value=0.0019) and hazard ratio (HR) of 0.45 (p=0.0047) after correcting for PAM50 molecular subtype and age at diagnosis. This deep-learning classifier outperformed four genomic HRD tests used in the clinic, including standard HRD score, BRCA1/2, 26-HR gene panel and single-base substitution signature 3 (SBS3). Multiresolution spatial mapping identified morphological features utilized by DeepHRD for detecting HRD, notably enriched for neoplastic and necrotic tissues, and a higher macrophage density. Through transfer learning to high-grade serous-ovarian cancer, DeepHRD-positive samples exhibited better overall survival after TCGA first-line (HR=0.46; p=0.030) and an external neoadjuvant (HR=0.49; p=0.015) platinum-treated cohorts. Conclusion: In summary, DeepHRD exhibits consistent hazard ratios ranging from 0.45 to 0.49 across the three clinical cohorts and captures 1.8- to 3.1-fold more HRD-positive breast and ovarian cancer patients. DeepHRD-positive breast cancer patients that received platinum exhibited better complete response and PFS. Similarly, DeepHRD-positive platinum-treated ovarian cancer patients had a better OS. DeepHRD’s ability to detect HRD from digital H&amp;E slides provides an important precision oncology tool that can be utilized in resource-constrained and underserved areas where genomic testing is generally not existent. Citation Format: Erik N. Bergstrom, Ammal Abbasi, Marcos Diaz-Gay, Loïck Galland, Sylvain Ladoire, Scott M. Lippman, Ludmil B. Alexandrov. Deep learning AI predicts HRD and platinum response from histologic slides [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB391.

Modified FOLFOXIRI plus cetuximab and avelumab as initial therapy in RAS wild-type unresectable metastatic colorectal cancer: Results of the phase II AVETRIC trial by GONO.

3575 Background: The modified schedule of FOLFOXIRI (mFOLFOXIRI) in combination with an anti-EGFR agent showed a manageable safety profile and remarkable activity in RAS wild-type (wt) metastatic colorectal cancer (mCRC). The association of an active cytotoxic regimen with cetuximab (cet) may increase the exposure of tumour-associated neoantigens and induce immunogenic cell death and antibody-dependent cell-mediated cytotoxicity thus enabling the effect of immune checkpoint inhibitors. The AVETRIC study aimed at exploring the efficacy and safety of first-line mFOLFOXIRI plus cet and avelumab (ave) in RAS wt mCRC patients (pts). Methods: AVETRIC is a prospective, open label, multicenter, phase II, single arm trial in which initially unresectable and previously untreated RAS wt mCRC pts received mFOLFOXIRI (irinotecan 150 mg/sqm, oxaliplatin 85 mg/sqm, folinate 200 mg/sqm leucovorin [LV], and 5-fluorouracil [5FU] 2400 mg/sqm) plus cet (500 mg/sqm) and ave (800 mg) every 2 weeks up to 12 cycles followed by maintenance with 5FU/LV plus cet and ave until disease progression. A safety run-in phase including the first 6 enrolled pts was planned. Due to the occurrence of grade 3-4 diarrhoea in 2 (33%) pts, the protocol study was amended to reduce the irinotecan dose to 130 mg/sqm. Primary endpoint was Progression Free Survival (PFS). Fifty-eight pts were needed to detect an increase in median PFS (mPFS) from 10.0 to 19.4 months (mos), setting one-sided α and β errors at 0.05 and 0.10, respectively. The trial is registered at Clinicaltrial.gov, NCT04513951. Results: Between Jun 2020 and Dec 2021, 62 pts were enrolled in 16 Italian centres. Main pts' characteristics were: median age 56 yrs, ECOG PS 0 87%, synchronous metastases 94%, liver-only disease 42%, left-sided primary tumour 89%; all pts had BRAF wt and proficient MMR (pMMR) tumours. The primary endpoint was met. At a median follow-up of 16.0 months, 39 (63%) events were recorded and mPFS was 14.1 months (90% CI 12.0-16.7, Brookmeyer-Crowley test p &lt; 0.001). Response rate and disease control rate were 82% and 98%, respectively, and R0 resection rate was 21% (27% in liver-only subgroup). Early tumour shrinkage was achieved in 74% pts and median deepness of response was 56%. In pts treated after study amendment (n = 56), main grade 3-4 adverse events were neutropenia (27%), diarrhoea (27%), skin rash (14%), asthenia (14%), nausea (11%), stomatitis (7%), febrile neutropenia (2%). Grade 3-4 immune-related adverse events occurred in 6% of pts. Overall survival results are still immature. Conclusions: AVETRIC study met its primary endpoint, showing that combining mFOLFOXIRI plus cet and ave achieves promising results in terms of PFS as well as response rate, in pts with pMMR RAS and BRAF wt mCRC. Translational analyses to evaluate the impact of immune-related biomarkers are ongoing. Clinical trial information: NCT04513951 .

A multi-center effectiveness comparison study of fruquintinib with constructed external control cohort of other targeted kinase inhibitors using real-world data in third-line treatment of metastatic colorectal cancer.

The objective of this study was to assess the comparative efficacy in third-line setting for metastatic CRC (mCRC) patients using matched population of FRESCO trial with fruquintinib and real-world data with other TKIs. The arm of fruquintinib from the FRESCO phase III trial (NCT02314819) included the data of patients with metastatic CRC that progressed after at least two lines of chemotherapy and received fruquintinib treatment. An external control arm was constructed using real-world data (RWD) of patients who received other TKIs based on key eligibility criteria of FRESCO. The baseline characteristics of two arms was balanced by propensity score matching (PSM). The Kaplan-Meier method and Cox proportional hazard model was used to evaluate progression free survival (PFS) and to estimate hazard ratios (HRs) and 95% confidence intervals (CIs), respectively. Overall, 128 patients were successfully matched by PSM in each, fruquintinib and other TKIs group. The patients in fruquintinib group showed significant increase in median PFS than other TKIs (3.71 vs. 2.49 months, HR = 0.67, 95%CI, 0.48-0.94, p = 0.019). In the subgroup analysis, fruquintinib showed a significant benefit in PFS compared with other TKIs among patients undergoing two or three previous chemotherapy regimens (HR 0.58, 95%CI 0.40-0.84; p=0.004), with rectum as primary disease site (HR 0.52, 95%CI 0.31-0.87; p=0.013), with left sided primary tumor location (HR 0.62, 95%CI 0.42-0.90; p=0.011), with multiple metastasis sites (HR 0.68, 95%CI 0.48-0.97; p=0.034) and with lung metastasis (HR 0.65, 95%CI 0.43-0.98; p=0.042). With the approach of establishing the external control arm from RWD, this study has demonstrated that treatment with fruquintinib significantly prolonged PFS as compared to other TKIs in patients as third-line mCRC treatment.

Second-line liposomal irinotecan plus fluorouracil and leucovorin in metastatic biliary tract cancer

In The Lancet Oncology, Changhoon Yoo and colleagues1 reported the results of the NIFTY trial, a multicentre, open-label, randomised, phase 2b study done in five academic institutions in South Korea to assess the efficacy of second-line liposomal irinotecan plus fluorouracil and leucovorin in patients with metastatic biliary tract cancer who had progressed on gemcitabine plus cisplatin. Patients treated with liposomal irinotecan plus fluorouracil and leucovorin showed a significant increase in median progression-free survival (7·1 months, 95% CI 3·6–8·8) compared with patients treated with fluorouracil and leucovorin alone (1·4 months, 95% CI 1·2–1·5; hazard ratio 0·56, 95% CI 0·39–0·81; p=0·0019).

Efficacy of EDP ± mitotane chemotherapy in the treatment of metastatic adrenocortical carcinoma. Predictive and prognostic factors of efficacy

Introduction. Adrenocortical carcinoma (ACC) is an orphan disease with an unfavorable prognosis. The most effective therapeutic option in the treatment of ACC is EDP plus mitotane combination chemotherapy. However, no studies comparing the efficacy of the EDP regimen with or without mitotane have been published.Materials and methods. A retrospective analysis of health records of patients with histologically confirmed metastatic ACC, who received at least one chemotherapy cycle with EDP ± mitotane. The study included 73 patients, 49 of which received a combination of EDP and mitotane and 24 were treated with EDP chemotherapy.Results. The objective response rate was 18,4 % in the EDP + mitotane group versus 4,1 % in the EDP group. Disease control was reported in 25 (51 %) and 13 (54,2 %) patients, respectively. No significant differences were found in progression-free survival (PFS) rates between the EDP and EDP + mitotane groups; the median PFS rate was 6,5 and 6,0 months, respectively. The median overall survival (OS) in the total population was 20,9 months; no significant differences were found between the groups. However, an increase in median PFS was observed in patients who achieved a therapeutic concentration of mitotane. Moreover, the achievement of therapeutic mitotane concentrations was the only factor significantly associated with improved PFS (HR 0.44, p = 0.006). Significant unfavorable prognostic factors associated with lower OS were Ki-67 level in the primary tumor &gt; 20 % (HR 10.5, p = 0.006) and more than 1 site of metastases (HR 3.82, p = 0.02).Conclusions. This study showed that the addition of mitotane to EDP chemotherapy does not improve the median PFS and OS in the total patient population, however, the achievement of therapeutic mitotane concentrations is significantly associated with improved progression-free survival.

A Randomized Phase III Trial of Busulfan + Melphalan Vs Melphalan Alone for Multiple Myeloma

Background: High-dose melphalan (Mel) 200 mg/m2 is considered the standard of care preparative regimen for autologous hematopoietic stem cell transplantation (auto-HCT) for multiple myeloma. Two recent retrospective analyses suggested that a combination of busulfan (Bu) and Mel (Bu-Mel) may be associated with a longer progression-free survival (PFS) compared to Mel alone. In this randomized phase III trial we compared the safety and efficacy of Bu-Mel vs. Mel.Methods: Patients were randomized to either Bu-Mel or Mel using the Pocock-Simon method within 12 months of the start of induction therapy. In the Bu-Mel arm, Bu 130 mg/m2 was infused daily for 4 days, either as a fixed dose or to target an average daily area under the curve of 5000 μmol-min, followed by 2 daily doses of Mel at 70 mg/m2. Mel 200 mg/m2 was given as a single dose in the Mel only arm. The trial was designed to detect a 14-month increase in median PFS in the Bu-Mel arm with two-sided tests having nominal overall type I error .029 and power .80, with up to 3 tests using O'Brien-Fleming decision boundaries. The primary objective was to compare PFS between the two arms. Secondary objectives were to compare the response rates, toxicity and overall survival (OS).Results: Two-hundred and four patients (Bu-Mel: 104, Mel: 100) were enrolled from October 2011 to March 2017. Patient characteristics are summarized in Table 1. There was no significant difference between the two arms in age, gender, race, cytogenetic risk status, ISS stage, serum LDH, induction regimens, response to induction, or maintenance therapy. One-hundred-day non-relapse mortality (NRM) was 0% in both arms and 1-year NRM was 2% vs. 0% in Bu-Mel vs. Mel (p=0.11). NCICTCv3.0 grade 1-3 diarrhea was seen in 59 (57%) and 78 (78%) patients in Bu-Mel vs. Mel, respectively (p=0.002). Grade 1-3 mucositis (96% vs. 49%, p <0.001), rise in ALT (33% vs 1%, p <0.001) and neutropenic fever (71% vs. 30%, p <0.001) were seen at a higher rate in the Bu-Mel arm. No second primary malignancies have been seen in either arm to date. At day 90 after auto-HCT, 27 (26%) and 33 (33%) patients had achieved complete remission (CR; p=0.29), and 49 (47%) and 55 (55%) patients had achieved at least near CR (nCR; p=0.27) in Bu-Mel and Mel, respectively. Minimal residual disease (MRD) analysis by multiparametric flow cytometry (MFC) was performed at day 100 in 86 and 77 patients in Bu-Mel and Mel, respectively. Fifty (58%) and 47 (61%) achieved MRD negative status in Bu-Mel and Mel arms, respectively (p=0.75). At last evaluation, 52 (51%) and 49 (49%) patients had achieved a CR (p=0.89), and 70 (67%) and 67 (67%) patients had achieved at least nCR (p=1.00) in Bu-Mel and Mel, respectively. Median follow up was 22.1 months (range 0.7 - 64.8). Kaplan-Meier estimates of median PFS was 64.7 months in the Bu-Mel arm, and 34.4 months in the Mel only arm (p=0.013) (Figure 1). This significant difference in PFS was maintained after adjusting for the type of maintenance therapy received (p=0.019). With a median follow up of 28.1 months, there was no difference in OS between the Bu-Mel or Mel only arms (p=0.94). In a fitted Bayesian regression model, the posterior probability that patients receiving Bu-Mel had a smaller risk of progression and/or death compared with patients receiving Mel alone is 0.982, which is highly significant.Conclusions: In this phase III trial, Bu-Mel regimen was safe, and associated with a significantly longer PFS than Mel alone. This significant difference in PFS continued even after adjusting for maintenance therapy. Potential explanations for a longer PFS without a significant difference in response rates include a deeper MRD negativity or selective targeting of clonogenic myeloma progenitor cells by Bu-Mel. [Display omitted] DisclosuresShah:Indapta Therapeutics: Other: Stock Ownership; Celgene: Research Funding; Celgene, Indapta Therapeutics, Takeda: Consultancy; TeneoBio, Inc.: Honoraria. Patel:Juno: Consultancy; Celgene: Consultancy; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding. Thomas:Celgene: Research Funding; Bristol Myers Squibb: Research Funding. Manasanch:celgene: Consultancy; quest diagnostics: Research Funding; adaptive biotechnologies: Consultancy; sanofi: Research Funding; takeda: Consultancy; merck: Research Funding. Lee:Adaptive: Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy; Eutropics Pharmaceuticals: Research Funding; Daiichi Sankyo: Research Funding; Pimera Inc: Consultancy; Takeda: Consultancy. Orlowski:BioTheryX: Consultancy, Membership on an entity's Board of Directors or advisory committees.

Stereotactic Radiotherapy for the Treatment of Patients With Oligo-progressive Metastatic Renal Cell Carcinoma Receiving Vascular Endothelial Growth Factor Receptor Tyrosine Kinase Inhibitor: Data From the Real World

This retrospective observational study evaluated the role of hypo-fractionated stereotactic radiotherapy (SRT) in patients with oligo-progressive metastatic renal cell carcinoma (mRCC) treated with first-line oral tyrosine kinase inhibitors (TKI). Data on local control, delay of further progression, and safety are reported. Between January 2010 and December 2016, 28 patients with mRCC who showed oligo-progressive disease while receiving first-line pazopanib were treated with hypofractionated SRT to progressive metastatic sites to delay the change of systemic therapy. First and second progression-free survival (PFS-1 and PFS-2) were recorded, as well as objective response and toxicity. After pazopanib therapy, nine partial remissions (32%), 12 stable disease (43%) and seven progressions (25%) were recorded. The median time to progression from first-line pazopanib until oligo-progression was 9.45 months (PFS-1 range=2-30 months). Seventeen patients (61%) showed progression at pre-existing tumor sites, and 11 patients (39%) showed the appearance of new metastases. Progression-free survival after radiation therapy was 4.55 months (PFS-2 range=1-11 months). PFS-1 plus PFS-2 was 14.0 months (range=3-41 months). Severe grade 3-4 toxicities were seen only occasionally. Patients with oligo-progressive mRCC treated with first-line pazopanib may benefit from hypo-fractionated high-dose SRT at progressing sites achieving a further increase in median progression-free survival. Further studies and prospective validation are required to establish if this minimally invasive approach may have a positive impact on overall survival and reported outcomes.

Peripheral Neuropathy Symptoms, Pain and Functioning in Relapsed or Refractory Multiple Myeloma Patients Treated with Selinexor, Bortezomib, and Dexamethasone

Peripheral Neuropathy Symptoms, Pain and Functioning in Relapsed or Refractory Multiple Myeloma Patients Treated with Selinexor, Bortezomib, and Dexamethasone

NRG GY012: A randomized phase II study comparing single-agent olaparib, single agent cediranib, and the combination of cediranib/olaparib in women with recurrent, persistent or metastatic endometrial cancer.

TPS5609 Background: The Cancer Genome Atlas and others identified genomic events suggesting that endometrial cancer (EC) should be susceptible to DNA repair inhibition. Mutations in classical homologous recombination genes occur in 22% of EC, ARID1A 41% and PTEN loss occurs in 55% of EC. Data from pre-clinical models suggest poly ADP-ribose polymerase (PARP) inhibitors alone or in combination may be an effective therapeutic strategy in EC (Hansen 2016). Combinations of angiogenic inhibitors and PARP inhibitors have demonstrated synergistic effects and have been well tolerated in other tumor types. This study has been designed to compare 2 experimental arms exploring DNA repair inhibition versus cediranib alone which has previously shown promising activity in GOG 229J (Bender 2015). Methods: This is a multicenter randomized three arm study for patients with recurrent, metastatic or persistent EC. Patients are randomized 1:1:1 to cediranib PO 30 mg OD; olaparib 300 mg PO BID or the combination of cediranib 20 mg PO OD with olaparib 300 mg PO BID. All treatment cycles are 28 days. Primary endpoint is progression free survival (PFS). The study is powered to detect an increase in median PFS from 3.6 (based on cediranib alone) to 7.2 months with 90% power, using a one-sided test with α = 0.05 per comparison. Forty patients will be enrolled per arm, with an interim futility analysis planned. Eligibility includes endometroid, serous, and mixed histology EC; at least 1 prior line of chemotherapy (no more than 2 lines for metastatic disease), prior endocrine or immunotherapy is allowed; ECOG PS ≤ 2; adequate hepatic, bone marrow, coagulation and renal function. Archival tumor tissue and blood samples are being collected for translational studies. The study is open across the NRG network; 24 patients are enrolled to date . Amendments are planned to include additional arms investigating combination strategies targeting DNA repair and angiogenesis. Clinical trial information: 03660826.

TheraSphere Yttrium-90 Glass Microspheres Combined With Chemotherapy Versus Chemotherapy Alone in Second-Line Treatment of Patients With Metastatic Colorectal Carcinoma of the Liver: Protocol for the EPOCH Phase 3 Randomized Clinical Trial.

BackgroundColorectal cancer is one of the most common cancers and causes of cancer-related death. Up to approximately 70% of patients with metastatic colorectal cancer (mCRC) have metastases to the liver at initial diagnosis. Second-line systemic treatment in mCRC can prolong survival after development of disease progression during or after first-line treatment and in those who are intolerant to first-line treatment.ObjectiveThe objective of this study is to evaluate the efficacy and safety of transarterial radioembolization (TARE) with TheraSphere yttrium-90 (90Y) glass microspheres combined with second-line therapy in patients with mCRC of the liver who had disease progression during or after first-line chemotherapy.MethodsEPOCH is an open-label, prospective, multicenter, randomized, phase 3 trial being conducted at up to 100 sites in the United States, Canada, Europe, and Asia. Eligible patients have mCRC of the liver and disease progression after first-line chemotherapy with either an oxaliplatin-based or irinotecan-based regimen and are eligible for second-line chemotherapy with the alternate regimen. Patients were randomized 1:1 to the TARE group (chemotherapy with TARE in place of the second chemotherapy infusion and subsequent resumption of chemotherapy) or the control group (chemotherapy alone). The addition of targeted agents is permitted. The primary end points are progression-free survival and hepatic progression-free survival. The study objective will be considered achieved if at least one primary end point is statistically significant. Secondary end points are overall survival, time to symptomatic progression defined as Eastern Cooperative Oncology Group Performance Status score of 2 or higher, objective response rate, disease control rate, quality-of-life assessment by the Functional Assessment of Cancer Therapy-Colorectal Cancer questionnaire, and adverse events. The study is an adaptive trial, comprising a group sequential design with 2 interim analyses with a planned maximum of 420 patients. The study is designed to detect a 2.5-month increase in median progression-free survival, from 6 months in the control group to 8.5 months in the TARE group (hazard ratio [HR] 0.71), and a 3.5-month increase in median hepatic progression-free survival time, from 6.5 months in the control group to 10 months in the TARE group (HR 0.65). On the basis of simulations, the power to detect the target difference in either progression-free survival or hepatic progression-free survival is >90%, and the power to detect the target difference in each end point alone is >80%.ResultsPatient enrollment ended in October 2018. The first interim analysis in June 2018 resulted in continuation of the study without any changes.ConclusionsThe EPOCH study may contribute toward the establishment of the role of combination therapy with TARE and oxaliplatin- or irinotecan-based chemotherapy in the second-line treatment of mCRC of the liver.Trial RegistrationClinicalTrials.gov NCT01483027; https://clinicaltrials.gov/ct2/show/NCT01483027 (Archived by WebCite at http://www.webcitation.org/734A6PAYW)International Registered Report Identifier (IRRID)RR1-10.2196/11545

1068P - Cetuximab in combination with methotrexate (MTX) as first-line treatment in recurrent or metastatic (R/M) squamous cell carcinoma of the head and neck (SCCHN): A phase Ib randomized phase II study versus single agent MTX

Background: First-line palliative treatment in R/M SCCHN consists of the combination of cetuximab with cisplatin and 5-FU with a median progression free survival (PFS) and overall survival (OS) of 5.5 and 10.1 months, respectively, at the expense of substantial toxicity. Single agent MTX has minimal side effects, but response rate, gain in PFS and OS are limited. We hypothesized that adding cetuximab to MTX could improve PFS without adding major toxicities. Because this combination had not been tested before, we first performed a phase Ib study followed by a randomized phase II study. Methods: In the phase Ib study, patients (pts) with previously untreated R/M SCCHN were treated with weekly MTX 40 mg/m2 and cetuximab 250 mg/m2, after a loading dose of cetuximab 400 mg/m2. The primary objectives of the phase Ib study were feasibility and safety of the combination of cetuximab and MTX. In the phase II study pts were randomized to either MTX or the combination (1:2). The primary objective of the phase II study was to detect an increase in median PFS from 3 to 5 months with combination vs single agent MTX. Secondary endpoints were toxicity and OS. Results: Six pts were included in the phase Ib study. No dose limiting toxicities were observed, median PFS was 24.4 weeks (range 7.1-55.0). In the phase II study 45 pts were included; 15 pts received MTX (73% male, median age 64 years (range 50-77)) and 30 pts cetuximab and MTX (77% male, median age 69 years (range 46-80)). In the phase II study median PFS was significantly different: 8.0 weeks (range 3.0-39.0) in the MTX arm and 17.0 weeks (range 3.9-76.6+) in the combination arm (p=.009). Nine pts in the combination arm experienced a serious adverse event (SAE), 3 were possible treatment-related (pneumonia, pneumonitis and hypersensitivity reaction) compared with 5 pts with an SAE in the MTX group, all unrelated. OS and detailed toxicity results will be presented later. Conclusions: The combination of cetuximab and MTX in pts with R/M SCCHN is feasible. This randomised phase II study met its primary endpoint: a significantly longer PFS in the cetuximab and MTX combination arm, while toxicity was acceptable. Clinical trial identification: NCT02054442. Legal entity responsible for the study: Carla M.L. van Herpen. Funding: Merckgroup. Disclosure: E. Meerten: Advisory board: Merck. C.M.L. van Herpen: Corporate-sponsored research: AstraZeneca, BMS, MSD, Merck. All other authors have declared no conflicts of interest.

Abstract 2579: Loss of chromosome 18q11.2-18q12.1 is predictive for progression-free survival in metastatic colorectal cancer patients treated with bevacizumab

Abstract Introduction: Most patients with metastatic colorectal cancer (mCRC) have a limited benefit from the addition of bevacizumab to standard combination chemotherapy. However, a subset of patients benefits substantially, highlighting an unmet clinical need for a predictive biomarker of response to bevacizumab. Previously, we demonstrated that losses in chromosome 5q34, 17q12 and 18q12.1-21.1 have a significant correlation with progression free survival (PFS) in patients treated with, but not without bevacizumab. These data warrant extensive validation. Patients: For validation, two cohorts of patients that received bevacizumab were analysed, one of 121 mCRC patient samples of the European multicenter study Angiopredict and one of 81 mCRC patient samples from the Italian multicenter study MoMA. A third cohort was included of 90 mCRC samples from patients that did not receive bevacizumab. Genome wide copy number aberrations were correlated with PFS, Results: Loss of chromosome 18q11.2-18q21.1 most significantly associated with PFS in both cohorts that received bevacizumab (Angiopredict: HR=0.61, p=0.016; MoMa: HR=0.55, p=0.019). No significant association with PFS was observed in the cohort that did not receive bevacizumab (HR=0.85, p=0.67). Patients of all three cohorts without an 18q11.2-21.1 loss had similar PFS regardless of treatment (Angiopredict, median PFS 211 days; MoMa, median PFS 232 days; no bevacizumab, median PFS 189 days). No significant associations with PFS were found for chromosome 5q34 and 17q for any of the cohorts. Conclusion: We conclude that loss of chromosomal region 18q11.2-18q21.1 is consistently predictive for PFS in patients receiving bevacizumab. 18q11.2 loss provides an increase in median PFS of 83 days, compared to patients without this loss. No significant increase was found for patients that did not received bevacizumab. Citation Format: Erik van Dijk, Hedde Biesma, Martijn Cordes, Dominiek Smeets, Maarten Neerincx, Sudipto Das, Verena Murphy, Anna Barat, Orna Bacon, Jochen H.M. Prehn, Johannes Betge, Gaiser Timo, Bozena Fender, Gerrit A. Meijer, Deborah A. McNamara, Rut Klinger, Miriam Koopman, Matthias P.A. Ebert, Elaina W. Kay, Bryan T. Hennessey, Henk M.W. Verheul, William M. Gallagher, Darran P. O'Connor, Cornelis J.A. Punt, Fotios Loupakis, Diether Lambrechts, Annette Byrne, Nicole C.T. van Grieken, Bauke Ylstra. Loss of chromosome 18q11.2-18q12.1 is predictive for progression-free survival in metastatic colorectal cancer patients treated with bevacizumab [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2579.

A randomized phase II study of trastuzumab and pertuzumab (TP) compared to cetuximab and irinotecan (CETIRI) in advanced/metastatic colorectal cancer (mCRC) with HER2 amplification: S1613.

TPS3620 Background: Despite advances in systemic therapy, few patients are cured, creating a large unmet need for strategies targeting novel signaling and resistance pathways. The HER2 pathway, which has been successfully targeted in breast and gastric cancer, is one such unique potential target in mCRC. HER2 amplifications (HER2amp) have been identified in a small but distinct subset (6-8%) of KRAS wild-type mCRC. HER2amp is associated with resistance to anti-EGFR therapy (cetuximab/panitumumab) and short progression-free survival (PFS) ( < 3 mos.) (Raghav ASCO 2016). Preliminary clinical data (MyPathway Study) has shown promising activity of dual-anti-HER2 inhibition using TP in HER2amp and KRAS wild-type mCRC (Response rate 52%, 95% CI 31 - 72%; and median PFS 5.7 months, 95% CI 4 – 12 mos.) (Hurwitz GIASCO 2017). Methods: S1613 is a multicenter, randomized phase 2 study assessing efficacy of TP relative to CETIRI in HER2amp mCRC. This is a 2 step study. All anti-EGFR naïve mCRC patients (pts) without known activating mutations in KRAS/NRAS/BRAF will be screened in step 1 for HER2amp by a central lab using immunohistochemistry and dual-probe in-situ hybridization. Screening can be performed at any time, even during treatment on 1st/2nd line of therapy. If HER2amp positive, pts will be randomized in step 2 after progression on 1st/2nd lines of therapy to either TP [pertuzumab (840mg loading dose + 420mg every 3 weeks) and trastuzumab (8mg/kg loading dose + 6mg/kg every 3 weeks)] or CETIRI [irinotecan (180 mg/m2 IV every 14 days) and cetuximab (500 mg/m2 IV every 14 days)]. Prior irinotecan is allowed. Crossover to TP will be allowed after progression on CETIRI arm. A total of 122 eligible patients will provide 80% power to detect an increase in median PFS to 5.1 months from 3 months (HR 0.59) based on a two-sided type I error of 5%, 33 months of accrual and 7 months of follow-up. The primary endpoint of PFS will be analyzed in all eligible patients per intent-to-treat. Randomization will be stratified by prior use of irinotecan and HER2/CEP17 ratio. The study is now activated and open to enrollment to all NCI - NCTN institutions. Clinical trial information: NCT03365882.

Beyond Concurrent Chemoradiation: The Emerging Role of PD-1/PD-L1 Inhibitors in Stage III Lung Cancer.

Concurrent chemoradiation (cCRT) with platinum-based chemotherapy is standard-of-care therapy for patients with stage III unresectable non-small cell lung cancer (NSCLC). Although cCRT is potentially curative, 5-year overall survival has hovered around 20%, despite extensive efforts to improve outcomes with increasing doses of conformal radiation and intensification of systemic therapy with either induction or consolidation chemotherapy. PD-1/PD-L1 immune checkpoint inhibitors have demonstrated unprecedented efficacy in patients with stage IV NSCLC. In addition, preclinical and early clinical evidence suggests that chemotherapy and radiation may work synergistically with anti-PD-1/PD-L1 therapy to promote antitumor immunity, which has led to the initiation of clinical trials testing these drugs in patients with stage III NSCLC. A preliminary report of a randomized phase III trial, the PACIFIC trial, demonstrated an impressive increase in median progression-free survival with consolidative durvalumab, a PD-L1 inhibitor, compared with observation after cCRT. Here, we discuss the clinical and translational implications of integrating PD-1/PD-L1 inhibitors in the management of patients with unresectable stage III NSCLC. Clin Cancer Res; 24(6); 1271-6. ©2018 AACR.

Progression-Free Survival as a Surrogate Endpoint for Overall Survival in Patients with Relapsed or Refractory Multiple Myeloma

In a previous study, the quantitative relationship between progression-free survival (PFS) and overall survival (OS) in multiple myeloma (MM) was assessed. However, that analysis combined studies of newly-diagnosed MM and relapsed/refractory MM (rrMM) and, since that analysis, there have been several randomized controlled trials (RCTs) of novel treatments for rrMM. The aim of this study is to provide an update of that analysis using randomized controlled trials (RCTs) only conducted in rrMM. Two bibliographic databases (PubMed and Embase) were systematically searched for RCTs published between 1970 to 2017. Firstly, the association between median PFS and median OS was assessed using the non-parametric Spearman’s rank correlation coefficient. Secondly, the quantitative relationship between PFS and OS was assessed using the Two Stage Least Square (2SLS) estimator. This approach was justified by relevant statistical tests in favor of the instrumental variable approach. 22 RCTs (42 treatment arms, 7,884 rrMM patients) were included. The average median PFS and median OS were 8.26 months (SD= 4.85), and 24.34 months (SD= 9.80), respectively. The correlation coefficient of median PFS and median OS was 0.712 (P < 0.00001). After adjustment for median age, sex and publication year, a 3.10 month (95%CI: 2.20 to 4.00) increase in median OS is estimated for each additional month increase in median PFS. Based on newer evidence from RCTs, PFS can be used to predict OS in rrMM and this analysis suggests that novel treatments may be providing additional months of OS gained for each month of PFS.

A single arm, prospective multicenter phase II study FOLFIRINOX in patients with advanced and recurrent biliary tract cancer.

TPS514 Background: The current standard of care for patients with advanced biliary tract cancer (BTC) is gemcitabine and cisplatin (GC) combination chemotherapy. Despite intensive researches, no trials have proved better overall survival (OS) over GC. Recently, FOLFIRINOX provided a remarkable survival benefit over gemcitabine in patients with metastatic pancreatic cancer. Given the promising results of FOLFIRI and FOLFOX in patients with advanced BTC, FOLFIRINOX can be an attractive option in patients with advanced BTC as well. Methods: This is a single-arm, open-label, multi-center phase II study to evaluate the safety and efficacy of FOLFIRINOX in patients with advanced BTC. The major inclusion criteria are as follows; unresectable or recurrent BTC, histologically or cytologically confirmed adenocarcinoma, no prior chemotherapy or radiation therapy, age of 20-75 years, an ECOG PS of 0 or 1, at least one measurable lesion, adequate hematological, liver and renal function. The major exclusion criteria are as follows; UGT genetic polymorphisms of homozygous UGT1A1*6 or *28 or heterozygous UGT1A1*6 and *28, massive pleural effusion or ascites. FOLFIRINOX consists of oxaliplatin of 85 mg/m2, irinotecan of 180 mg/m2, leucovorin of 400 mg/m2 administered by intravenous infusion and fluorouracil of 400 mg/m2 by intravenous bolus and of 2,400 mg/m2 by continuous intravenous infusion every 2 weeks. The primary outcome is progression-free survival (PFS), and the secondary outcomes are OS, tumor response and safety. PFS and OS will be calculated from the date of enrollment until the date of documentation of disease progression or death in patients without disease progression and the date of death. Tumor response will be evaluated according to the RECIST version 1.1 every 2 months. Safety will be evaluated with the CTCAE version 4.0. A total of 35 patients will be required to provide 75% power to detect an increase in median PFS from 6 months provided by standard care of GC to 10 months in patients receiving FOLFIRINOX, with a 24 months of recruitment and 18 months of follow-up. A phase III trial will be considered when this study shows the lower limit of the 80% confidence interval for PFS is longer than 6 months. Clinical trial information: UMIN000020801.

Efficacy of Abiraterone and Enzalutamide in Pre- and Postdocetaxel Castration-Resistant Prostate Cancer: A Trial-Level Meta-Analysis.

We examined the comparative efficacies of first-line abiraterone and enzalutamide in pre- and postdocetaxel settings in castration-resistant prostate cancer (CRPC) through a trial level meta-analysis. A mixed method approach was applied to 19 unique studies containing 17 median overall survival (OS) estimates and 13 median radiographic progression-free survival (PFS) estimates. We employed a random-effects meta-analysis to compare efficacies of abiraterone and enzalutamide with respect to OS and PFS. In the predocetaxel setting, enzalutamide use was associated with an increase in median OS of 5.9 months (p < 0.001), hazard ratio (HR) = 0.81, and an increase in median PFS of 8.3 months (p < 0.001), HR = 0.47 compared to abiraterone. The advantage of enzalutamide improved after adjusting for baseline Gleason score to 19.5 months (p < 0.001) and 14.6 months (p < 0.001) in median OS and PFS, respectively. In the postdocetaxel setting, the advantage of enzalutamide use was nominally significant for median PFS (1.2 months p = 0.02 without adjustment and 2.2 months and p = 0.0007 after adjustment); there was no significant difference in median OS between the two agents. The results from this comprehensive meta-analysis suggest a survival advantage with the use of first-line enzalutamide over abiraterone in CRPC and highlight the need for prospective clinical trials.