bluuebunny/crossref_metadata_2025 huggingface dataset:
Randomized phase II trial of cisplatin/gemcitabine with or without LY293111, a multiple eicosonaid pathway modulator, in patients with chemotherapy naïve advanced non-small cell lung carcinoma
Authors: Janne P. A. , Paz-Ares Rodriguez L. , Gottfried M. , Reaume M. N. , Kaukel T. , Oh Y. W. , Sykes A. , Enas N. , Brail L. H. , Von Pawel J.
Published: March 2020

7024

Background: The eicosanoid pathway is altered in NSCLC. Pharmacological activators of peroxisome proliferator-activated receptor-gamma (PPARγ) have been shown to inhibit lung tumors in vitro. LY293111 inhibits the eicosanoid pathway, is a PPARγ agonist and modulates adipophilin and adiponectin expression levels in vitro. LY293111 is well tolerated and can be administered with cisplatin/gemcitabine. A randomized phase II study in NSCLC was undertaken. Methods: Pts with stage IIIB/IV NSCLC were randomized to two doses of LY293111 (200 mg BID (Arm A) or 600 mg BID (Arm B) or placebo (Arm C) alone for 7 days followed by concurrent cisplatin (75 mg/m2;d1) and gemcitabine (1250 mg/m2;d1,8) q21 days. Treatment was continued until disease progression or toxicity. Primary endpoint was PFS with 75% power to detect 33% improvement compared to placebo (5 months). Calculated sample size was 65 pts/arm (195 total) with a one sided type I error of 0.2. Changes in adipophilin mRNA expression and adiponectin serum levels were assessed at baseline and day 7. Results: Between 09/03 and 07/04, 201 pts were randomized and 195 treated. Demographics (all pts): M:F (65%:35%); median age 61 (range 27–87); stage IIIB/IV (15%:85%); ECOG PS (0:36%;1:64%). Demographics were well balanced between the 3 arms. Most common CTC grade 3/4 toxicities were nausea (8%), vomiting (7%), fatigue (6%) and diarrhea (6%) with only diarrhea related to dose of LY293111 (p=0.03). Response rates (CR+PR) were similar in all 3 arms (A:20%; B:27%; C:21%). There was no significant difference in median PFS (95% CI) between the arms (A: 4.6 months (3.2–5.0); B:6.0 months (4.6–7.2); C:6.0 months (5.2–7.0)). Median survival (95% CI) was similar in all 3 arms (A: 7.3 months (6.2–9.4); B:7.9 months (7.2–9.7); C: 9.0 months (7.7–12.5). Median change in serum adiponectin levels at d7 were significantly higher in arm B vs. placebo (p < 0.05). Adipophilin expression at d7 was increased in a dose dependent manner (p=NS) in arms A and B vs. placebo. Conclusions: LY293111 in combination with cisplatin/gemcitabine did not increase median PFS compared to placebo in pts with NSCLC. Pharmacodynamic modulation was observed but did not impact efficacy.

[Table: see text]
Sequencing of single-agent (SA) docetaxel (T) and gemcitabine (G) therapy for patients (pts) with advanced non-small cell lung cancer (NSCLC): Results of three consecutive randomized trials
Authors: Manegold C. , Thatcher N. , Kortsik C. , Koschel G. , Mezger J. , Schott Von Römer K. , Pilz L. R.
Published: March 2020

7035

Background: Standard doublet chemotherapy (DCT) is often clinically inappropriate. Since T and G show efficacy and favourable toxicity as SAs in 1st- and 2nd-line setting, sequencing of T and G may be an equally effective alternative to DCT for palliation. Three studies (S1-S3) were conducted: two to identify an optimal SA-sequence (S1/S2), and one to compare sequential SA to a platin-free doublet (S3). Methods: Common eligibility criteria included histologically confirmed stage IIIB or IV, performance status (PS) 0–2, and no prior chemotherapy. S1/S2 examined treatment feasibility (TF) of G or T with introduction of the opposite agent in case of progression. TF was defined as pt ability to receive ≥2 cycles (cyc) of 1st-line and if progressive ≥2 cyc of 2nd-line therapy and to survive ≥7 months (mos). In S1, G 1000 mg/m2 and T 35 mg/m2 was given on days (d) 1, 8, 15 (q4w) and in S2, G 1250 mg/m2 (d 1, 8) and T 100 mg/m2 (d 1; q3w). In S3, pts received G 1000 mg/m2 (d 1, 8) and T 75 mg/m2 (d 1; q3w) either concomitantly (G+T; 6 cyc) or sequentially (G→T; 3 cyc each). Primary endpoint of S3 was clinically relevant haematotoxicity (CRHT) defined as thrombocytopenia with platelet transfusions, anaemia with RBC-transfusions or febrile neutropenia with i.v. antibiotics (IVAB). Results: 819 pts were included (1998–2004): 85% of pts had stage IV disease and PS≤1. In S1 and S2 for (G→T)/(T→G) respectively: TF was 28/20% and 38/49% (p=.04); median survival (MS) was 9.0/5.0 mos (p=.03) and 6.3/8.6 mos; and median time to progression (TTP) was 4.3/2.2 mos and 2.4/3.3 mos. In S3, CRHT occurred less frequently with SA therapy (p<.001), transfusions and IVAB treatment days were less common. QoL also favoured SA therapy. For (G+T)/(G→T), MS was 7.3/7.4 mos, response rate was 33/22% (p=.05) and TTP was 6.3/4.9 mos (p=.04). Conclusions: Sequencing modern SA was effective and well tolerated. Weekly T and G regimens seem less feasible than 3-weekly but compared to the nonplatinum doublet CRHT and IVAB are reduced with better QoL and cost-effectiveness.

[Table: see text]
Two consecutive phase 1–2 studies of cisplatin (P)-based 1st-line chemotherapy (CT) in elderly patients (pts) with advanced non-small cell lung cancer (NSCLC). The MILES-2P studies
Authors: Perrone F. , Illiano A. , Piantedosi F. V. , Bearz A. , Favaretto A. , Lorusso V. , Manzione L. , Iaffaioli R. V. , Valerio M. R. , Gridelli C.
Published: March 2020

7037

Background: P-based CT needs prospective testing in elderly pts with advanced NSCLC. In two consecutive studies, with equal design, feasible dose of P combined with gemcitabine (PG) or vinorelbine (PV) were identified and toxicity and activity were described. Methods: Advanced (stage IV or IIIb with supraclavear nodes or pleural effusion) NSCLC pts, aged >70 years, PS 0–1, were eligible. P was given on day (d) 1, starting dose-finding at 50 mg/m2 (level 0), with G (fixed dose: 1000 mg/m2 dd 1&8) or V (fixed dose: 25 mg/m2 dd 1&8); at each level <2 unacceptable toxicities in cycle 1–3 (UT) out of 6 evaluable pts were needed to escalate; CT was given every 3 weeks, up to 6 cycles. A two-stage flexible optimal design was applied at the feasible dose. With rate of pts without UT as endpoint, type I and II error =0.10, p0=0.70, p1=0.85, ≥47 pts without UT out of 60 enrolled were required at the final stage. NCI-CTC for toxicity and RECIST for response coding were used. Results: From June 2002 to November 2004, 159 pts were enrolled (38 in dose-finding and 121 in phase 2); 45% of them were aged ≥75. P was feasible at 60 mg/m2 (level +1) with G, and 40 mg/m2 (level -1) with V. With PG (n=60): 50 (83%) pts without UT; response rate (RR): 43%, 95% exact CI: 31–57; median progression-free (PFS) and overall survival (OAS): 25 and 44 wks, respectively. Toxicity (≥5% of pts): g3 anemia (5%), RBC transfusion (8%), g3–4 platelets (10%), g2–3 cardiac (10%), g2 renal (7%). With PV (n=61): 50 (82%) pts without UT, 2 toxic deaths (1 with febrile neutropenia [FN] and 1 with cardiac toxicity); RR 36%, 95% exact CI: 24–49; median PFS and OAS: 21 and 33 wks, respectively. Toxicity (≥5% of pts): g3 anemia (5%), RBC transfusion (8%), FN (5%), g≥2 neurologic (5%). Conclusions: The combination of cisplatin and gemcitabine (with P 60 mg/m2) is safe, active, and deserves comparison vs single-agent chemotherapy in elderly pts with advanced NSCLC.

No significant financial relationships to disclose.
Stereotactic hypofractionated high-dose irradiation (STI) for stage I non-small cell lung cancer (NSCLC): Mature results in 300 cases of a Japanese multi-institutional study
Authors: Onishi H. , Nagata Y. , Shirato H. , Karasawa K. , Gomi K. , Hiraoka M. , Kimura T. , Hayakawa K. , Kokubo M. , Takai Y.
Published: March 2020

7045

Background: With the increasing accuracy of localization for tumor-bearing areas using various new techniques, hypofractionated or single high-dose stereotactic irradiation (STI) has been actively investigated for stage I NSCLC in Japan. The current study retrospectively evaluated Japanese multi-institutional results for high-dose STI for stage I NSCLC. Methods: From 1993 to 2003, stereotactic three-dimensional treatment was performed using 3–10 non-coplanar dynamic arcs or 6–20 static ports for a total of 300 stage I (median age, 75 years; T1N0M0, n = 193; T2N0M0, n = 107) patients with primary NSCLC (adenocarcinoma, n = 138; squamous cell carcinoma, n = 129; and others, n = 33) in 14 institutions. Totally 190 patients were medically inoperable, and other 110 were medically operable but selected STI. A total dose of 18–75 Gy at the isocenter was administered in 1–22 fractions. Median calculated biological effective dose (BED) was 108 Gy (range, 57–180 Gy). Results: Median follow-up period of survivors was 38 months (range; 2–128 months). Pulmonary complications of NCI-CTC criteria (version 2.0) grade ≥ 3 were noted in 9 patients (3.0%). Local progression occurred in 44 patients (14.7%), and 5-year local control rate was high (86%) for BED ≥100 Gy (n = 227) compared to 67% for <100 Gy (n = 73) (P < 0.001). Overall 5-year survival rates of operable and inoperable patients were 65% and 37%, respectively. Overall 5-year survival rates in operable cases was high (74%) for BED ≥100 Gy (n = 85) compared to 37% for <100 Gy (n = 24) (P < 0.01). In a subset of operable patients irradiated with BED ≥100, 3-year locally progression-free survival rates was high (81%) for stage IA (n = 60) compared to 67% for stage IB (n = 23) (P < 0.05) Conclusions: Local control and survival rates of STI for stage I NSCLC are better with BED ≥100 Gy compared to <100 Gy. Survival rates in selected patients (medically operable, BED ≥100 Gy) were excellent, and potentially comparable to those of surgery. Stage IB patients displayed higher rate of local progression than stage IA. We have started multi-institutional prospective study for stage IA NSCLC with a schedule of total dose of 48 Gy in 4 fractions during 4–8 days.

No significant financial relationships to disclose.
Induction (ICT) or consolidation chemotherapy (CT) with cisplatin (C) and paclitaxel (P) plus concurrent chemo-radiation (CT/TRT) with cisplatin and vinorelbine (V) for unresectable non-small cell lung cancer (NSCLC) patients (pts): Randomized phase II trial GFPC-GLOT-IFCT 02–01
Authors: Fournel P. , Vergnenégre A. , Robinet G. , Léna H. , Gervais R. , Le Caer H. , Souquet P. J. , Chavaillon J. M. , Chouaid C. , Martel-Lafay I.
Published: March 2020

7048

Background: Concurrent CT/TRT is the standard treatment for unresectable stage III NSCLC, but the optimal sequencing of TRT and CT is not well defined.Consolidation CT with taxane seems to be a good approach (SWOG 95–04). Methods: Unresectable stage III NSCLC pts (weight loss < 10%, ECOG PS 0–1, no supraclavicular lymph node or superior vena cava syndrome) were eligible. in Arm A, pts received 2 cycles of C 80 mg/m2 and P 200 mg/m2 followed by a concurrent CT/TRT including TRT as 66 Gy in 33 fractions and C 80 mg/m2 d1,29 and 57 and V d1,8,29,36,57 and 64. In Arm B, the same CT/TRT began on d1 followed by 2 cycles of C and P. The primary objective was response rate at the end of treatment, assessed by RECIST criteria. 132 pts were needed. Results: From 05/2002 to 03/2005, 133 pts were included by 35 centers. 5 pts were ineligible. Both groups were well-matched for baseline characteristics. 30 pts were stage IIIAN2 and 98 stage IIIB. Toxicities (106 pts analyzable) grade 3–4 by CTC and RTOG criteria (Arm A/Arm B) were: neutropenia 36%/41%, infection 11%/15%, esophagitis 6%/13%, pneumonitis 0%/1%. 5 toxic deaths were observed (2 sepsis, 1 massive hemoptysis, 1 post-irradiation pneumonitis, 1 esophageal fistula). In Arm A, objective response rate was 36% after ICT. At the end of treatment, response rate (Arm A/Arm B) was in intent to treat: progression 19%/19%, stable-disease 6%/11%, objective response 55%/48%. 13 pts were not evaluable for response in Arm A and 14 in Arm B [ table ]. Conclusions: Toxicities and response rates are similar in both arms, but ICT followed by CT/TRT appears to provide a better therapeutic outcome.

[Table: see text]

No significant financial relationships to disclose.
Prospective evaluation of RRM1 as a predictor of response to gemcitabine/carboplatin (GC) in non-small cell lung cancer (NSCLC)
Authors: Bepler G. , Sharma A. , Greenberg H. , Cantor A. , Li X. , Hazelton T. , Walsh F. , Simon G.
Published: March 2020

7054

Background: RRM1 is the regulatory subunit of ribonucleotide reductase. It is a molecular target of G. RRM1 increases upon continuous exposure of cell lines to G. Preliminary data suggest improved survival for patients with low as opposed to high tumoral expression of RRM1 when treated with G-based chemotherapy. Methods: We determined the efficacy of G and C as induction therapy in patients with locally advanced NSCLC. Trial eligibility included measurable disease, no prior chemotherapy or RT, PS 0–1, and no weight loss. Patients were staged with CT, PET, and brain MRI. GC consisted of two 28-day cycles of G, 1,000 mg/m2 d1&8 and C, AUC 5 d 1. Unidimensional tumor measurements were obtained before and after GC. The study required tumor collection prior to therapy by core needle biopsy. Specimens were frozen in LN. Tumor cells were collected by LCM. Real-time quantitative RT-PCR gene analysis was performed in triplicate per sample for RRM1 and 18SrRNA. Results: Between 11/03 and 7/05, 30 eligible patients were enrolled, and the required tumor biopsies were obtained in all. In one patient, a pneumothorax developed that required chest tube placement. Disease response ranged from a 9% increase to a 100% decrease. 14/26 had SD, 11/26 PR, and 1/26 CR. The patients’ age was 47- 87 years; 12 were women; 13 had IIIA and 13 IIIB; 10 had sq, 7 ad, and 9 LC or NOS NSCLC. RRM1 expression ranged from 0.18 to 129.3. There was a significant (p = 0.014) inverse correlation (r = −0.474) between RRM1 expression and disease response. When grouping patients into those with response (CR/PR) and without response (SD), RRM1 expression was significantly (p = 0.027) associated with response. No significant association was found between RRM1 expression and other parameters. Conclusions: In a prospective clinical trial intratumoral RRM1 expression was significantly and inversely correlated with disease response to gemcitabine and carboplatin. These results strongly suggest that tumoral RRM1 expression is a major predictor of disease response to gemcitabine-based chemotherapy.

No significant financial relationships to disclose.
Prospective FDG-PET and CT assessment of discontinuation of erlotinib (E) or gefitinib (G) in patients with EGFR TKI sensitive non-small cell lung cancer (NSCLC) who subsequently progress radiographically on E or G (“acquired resistance”) followed by re-initiation of E or G and the subsequent addition of everolimus (RAD001)
Authors: Riely G. J. , Kris M. G. , Schwartz L. H. , Akhurst T. , Zhao B. , Milton D. T. , Moore E. , Tyson L. , Pao W. , Miller V. A.
Published: March 2020

7065

Background: About 10% of patients (pts) with NSCLC have a radiographic response to E or G. A dependence on signaling through the epidermal growth factor receptor (EGFR) is thought to underlie this response. Despite initial regression, these pts invariably develop acquired resistance to E or G. Optimal management of these patients is unknown. In patients with acquired resistance, we sought to evaluate changes in tumor metabolism by PET and size by CT after discontinuation of E or G, resumption of E or G, and then the addition of the mTOR inhibitor everolimus to E or G. Methods: Pts with stage IV NSCLC with exon 19 or 21 EGFR mutation or previous radiographic response after treatment with E or G and then radiographic progression after > 6 months of treatment were eligible. All pts had 4 FDG-PET/CT and helical CT scans: baseline, 3 weeks after discontinuation of E or G, 3 weeks after restarting E or G, and 3 weeks after combined treatment with everolimus (5 mg daily) and E or G. CT measurements were uni-dimensional. Results: To date, 9 pts (5 on G, 4 on E) have enrolled with 6 pts completing all 4 PET/CT and CT assessments. Within 3 weeks of discontinuation of E or G, 7 of 9 (77%, 95% CI 40–97%) developed symptomatic disease progression. Three of 6 pts had an increase in SUV of >50% and increase in CT measurements >15% 3 weeks after discontinuation of E or G. Three of 6 pts had decrease in SUV of >10% 3 weeks after resumption of E or G. Two of 6 pts had further reduction of SUV > 50% and >10% decrease in CT measurements 3 weeks after everolimus was added to E or G. Conclusions: In EGFR TKI-sensitive patients who develop acquired resistance: 1) Discontinuation of E or G results in rapid symptomatic progression and increases in SUV on PET of indicator lesions. 2) Both symptoms and SUV values improve on re-initiation of E or G, suggesting that some tumor cells remain sensitive to EGFR blockade. 3) We saw further improvement when everolimus was combined with E or G. Based on these data we now recommend continuing E or G in similar patients. Support: Novartis, CA05826, MSKCC “Steps for Breath.”

[Table: see text]
A factorial phase III randomized trial of rofecoxib and prolonged constant infusion of gemcitabine at 10mg/m2/min (PCI-G) in first-line treatment of adult patients (pts) with advanced non-small cell lung cancer (NSCLC): The GECO study
Authors: Gridelli C. , Ceribelli A. , Gebbia V. , Gamucci T. , Ciardiello F. , Carrozza F. , Favaretto A. , Daniele B. , Galetta D. , Morabito A.
Published: March 2020

7069

Background: Preclinical and clinical evidence suggest that rofecoxib and PCI-G might improve efficacy of treatment of advanced NSCLC. Methods: Advanced (stage IV or IIIb with supraclavear nodes or pleural effusion) NSCLC pts, aged <70, PS 0–1, were eligible. A 2x2 factorial design was applied to test if addition of rofecoxib (50 mg daily) or PCI-G could improve overall survival (OAS) compared with standard first-line treatment [cisplatin (80 mg/m2 d 1) and gemcitabine (1200 mg/m2 dd 1&8) every 21 days]. To have 80% power of detecting a 0.67 HR of death, with bilateral alpha = 0.05, 400 pts were planned and 200 deaths were required for each comparison. Response was assessed with RECIST, quality of life (QoL) by EORTC questionnaires. Results: From Jan ’03 to May ’05, 400 pts were enrolled. Rofecoxib arms were closed (Oct 1st,’04) due to manufacturer decision of drug withdrawing for safety issues. As of Dec ’05, analyses include 400 pts (246 deaths) for PCI-G and 240 pts (enrolled as of Jul 1st,’04 to have a 3-month chance of treatment) for rofecoxib comparison (168 deaths). Median age was 60. PCI-G did not improve OAS (median 47.3 vs 42.9 weeks with standard infusion, HR 0.97, 95% CI 0.75–1.25), nor any other secondary end-point. Rofecoxib did not prolong OAS (median 43.6 vs 44.1 weeks without rofecoxib, HR 1.01, 95% CI 0.74–1.38), but improved response rate (41.2% vs 26.4%, p = 0.02), global QoL, physical and role functioning, fatigue, pain and analgesic consumption. In both comparisons, there was no clinically relevant difference in toxicity. Conclusions: Neither PCI-G nor rofecoxib prolonged OAS. Rofecoxib improved response rate and several QoL items, including pain-related and global QoL. Partially supported by AIRC; rofecoxib freely supplied by MS&D Italy.

No significant financial relationships to disclose.
Independent review of fatal interstitial lung disease (ILD) in TRIBUTE: paclitaxel + carboplatin ± erlotinib in advanced non-small cell lung cancer (NSCLC)
Authors: Gandara D. R. , Yoneda K. , Shelton D. , Beckett L. A. , Ramies D. A. , Bloss J. , Herbst R. S.
Published: March 2020

7071

Background: ILD is a rare but serious complication of EGFR tyrosine kinase inhibitor (TKI) therapy, fatal in about 1/3 of cases. The incidence, severity & risk factors for ILD remain poorly understood, but it is reported to be more common in Asian patients receiving gefitinib. Whether the risk of ILD with gefitinib exceeds that of erlotinib is unclear. Whether concurrent chemotherapy increases the risk of ILD is also unclear. Methods: This study was designed to determine the incidence of ILD leading to death in 1,059 TRIBUTE patients randomized to chemotherapy plus erlotinib or placebo (Herbst: JCO, 2005). A blinded review of fatal SAEs was performed by an independent 3 person panel comprised of a medical oncologist (DRG), radiologist (DS), and pulmonologist (KY) unassociated with the study. Fatal respiratory SAEs (41 met criteria) were assigned to 1 of 4 potential attributions: progressive NSCLC; concurrent illness; toxicities not related to study drug; or ILD. Each panel member first made an independent assignation based on case report forms/source documents; then each case was discussed jointly. If needed, consensus was reached by vote. Results: Fatal SAEs were reported in 80/1059 patients (7.6%): 53/526 patients on erlotinib (10.1%) & 27/533 on placebo (5.1%) (p = 0.002). Consensus assignation for 41 respiratory SAEs was as follows: NSCLC: 18 (44%), concurrent illness: 15 (37%), toxicities not related to study drug: 5 (12%), ILD: 3 (7%). There were no statistical differences in assignation by study arm. However, all 3 ILD cases occurred in the erlotinib arm (3/523; overall incidence 0.6%). Case details will be provided. Conclusions: 1) To our knowledge, this analysis of TRIBUTE is the only independent blinded assessment of respiratory SAEs & ILD related to an EGFR TKI (erlotinib) + chemotherapy. 2) Overall, there were 41 fatal respiratory SAEs (3.9%). Fatal ILD occurred in 0.6% of cases treated with the combination. Using estimates that 1/3 of EGFR TKI-induced ILD cases are fatal, the overall incidence in this study arm was likely around 1.5–2%, not inconsistent with prior reports of TKIs alone. 3) Further studies designed to better define the underlying pathophysiology and risk factors for ILD are needed.

[Table: see text]
Vatalanib (V) for patients with previously untreated advanced malignant mesothelioma (MM): A phase II study by the Cancer and Leukemia Group B (CALGB 30107)
Authors: Jahan T. M. , Gu L. , Wang X. , Kratzke R. A. , Dudek A. Z. , Green M. R. , Vokes E. E. , Kindler H. L.
Published: March 2020

7081

Background: Targeting both vascular endothelial growth factor (VEGF) and platelet derived growth factor (PDGF) may be an appropriate therapeutic strategy in MM. MM express VEGF, PDGF, and their receptors, suggesting autocrine growth-stimulating loops. VEGF inhibitors and PDGF inhibitors have in vitro activity in MM. In MM patients (pts), high VEGF levels correlate with poor outcome. Vatalanib inhibits VEGF and PDGF receptor tyrosine kinases. Methods: We conducted a phase II trial of V in pts with unresectable, histologically-confirmed MM, measurable disease, no prior therapy, ECOG performance status (PS) 0–1. Primary endpoint: 3-month (mo) progression-free survival (PFS). V 1250 mg, was given orally daily. CT scans were obtained Q6 weeks. Baseline serum VEGF, PDGF were determined. Results: 47 eligible pts (46 evaluable) enrolled at 19 sites from 7/03–11/04. Pt characteristics: male 92%, median age 75 (range 51–92; 64% were >70). Histology: epithelial 80%, sarcomatoid 11%, biphasic 9%. Site of origin: pleura 87%, peritoneum 6%, other 6%. PS 0/1: 21%/ 79%. 261 cycles were administered, median 3, range 1–32; 2 pts continue treatment. Grade 3/4 toxicities: neutropenia 2%, lymphopenia 2%, nausea/vomiting 15%/9%, increased ALT/AST 9%/6%, hypertension 2%, gastrointestinal bleed 2%. Partial response: 11% (5 pts), stable disease 66%. 3-mo PFS: 55% (95% CI: 40%, 68%), median PFS: 4.1 mo; median survival 10.0 mo. Median baseline serum levels in 40 pts: VEGF 425 pg/mL, PDGF 22754 pg/mL. There was no correlation between baseline VEGF or PDGF levels and response, PFS, or survival. Conclusions: The study did not achieve the protocol-specified 3-mo PFS of 75%. However, the objective response rate of 11% and median survival of 10 months are similar to other active single-agents for MM, which suggests that V may warrant further study in this disease.

[Table: see text]
Pneumonectomy following induction chemoradiotherapy (CRT) in NSCLC at Fox Chase Cancer Center (FCCC): Peri-operative mortality rate is lower than expected
Authors: Brown K. M. , Scott W. J. , Langer C. , Feigenberg S. , King E. , Goldberg M.
Published: March 2020

7107

Background: Induction CRT is used commonly prior to resection for NSCLC. Selected data cite increased operative mortality in patients (pts) requiring pneumonectomy following induction CRT (> 25% in RTOG 9309). We reviewed the FCCC experience with pneumonectomy for NSCLC and compared operative outcomes in pts who had induction CRT to those who had surgery (S) as initial treatment. Methods: Retrospective review of pts undergoing pneumonectomy for NSCLC from 1993–2005. Perioperative variables were analyzed for impact on operative mortality and complications. Results: 169 pts were analyzed: 110 (65%) were male; median age was 64 (range 39–84). 39 had induction CRT; 16 had preoperative chemo only and 3 had preoperative radiation only. Overall operative mortality was 13/169 (7.7%); for CRT pts, mortality was 5/39 (12.8%) compared to 7/111 (6.3%) for S pts (p = NS). In the CRT group, one pt died from respiratory failure due to radiation pneumonitis of the remaining lung; one pt died from complications of pneumonia, and the remainder died of respiratory failure. In the S group, 3 pts died of respiratory failure, 2 died after discharge of unknown causes, and one each died of pulmonary hypertension and empyema. Complications occurred in 19/39 (48.7%) of CRT pts compared to 39/111 (35%) in S patients (p = NS). Cardiac arrhythmias and pneumonia were the most common complications in both groups. A pre-op DLCO <60% predicted was associated with increased operative death (p = 0.045) and complications (p = 0.066) in the CRT group; this association was not present in the S group. There was no difference in DLCO between the groups. Age, diabetes, tobacco, laterality of surgery, and pre-op FEV1 did not predict operative complications or death in any group. Conclusions: Induction chemoradiotherapy pre-pneumonectomy is not associated with a statistically significant increase in perioperative morbidity or mortality vs those undergoing surgery alone. Mortality rate for CRT appears lower than that seen in RTOG 9309. DLCO <60% is a risk factor in pts with induction CRT, but not in our pts undergoing surgery alone.

No significant financial relationships to disclose.
Analysis of prognostic factors in chemo-naïve patients with advanced NSCLC and poor performance status (PS): Cox regression analysis of two phase III trials
Authors: O’Brien M. , Bonomi P. , Langer C. , O’Byrne K. , Bandstra B. , Ross H. , Sandler A. , Socinski M. , Paz-Ares L.
Published: March 2020

7113

Background: Two phase III trials in chemo-naïve PS2 patients with advanced NSCLC compared paclitaxel poliglumex (PPX) to either gemcitabine or vinorelbine (STELLAR 4), or PPX/carboplatin to paclitaxel/carboplatin (STELLAR 3). While overall survival (OS) was similar between treatment arms in both studies, individual patient characteristics may be predictive of benefit. Methods: STELLAR 3 and STELLAR 4 enrolled 400 and 381 chemo-naïve PS2 patients, respectively. The impact of pre-defined baseline characteristics on OS was evaluated by univariate and step-wise multivariate Cox regression analysis. Treatment differences between subgroups were also estimated by Cox analysis. Results: Univariate Cox analysis of potential risk factors showed pre-baseline weight loss, extra-thoracic metastasis, and a low lung cancer symptom (LCS) score to be highly significant (p < 0.001). In STELLAR 4, tobacco use was also a highly significant risk factor. Important primary baseline factors predicting survival as determined by multivariate analysis are summarized in the table . Other baseline factors evaluated but not predictive of survival included gender, number of comorbidities, age, and history of tobacco use. Treatment differences between subgroups were not statistically significant; however, a strong trend towards improved survival was observed for women receiving PPX in STELLAR 4 compared to those in the control-arm (HR = 0.65; p = 0.069). In contrast, men had similar survival between treatment arms (HR = 1.08; p = 0.579). Conclusion: In this large PS2 patient population, weight loss, presence of extra-thoracic metastasis, low LCS scores, and high LDH were found to be important clinical determinants of survival. In addition, significant differences in survival based on geographic region in STELLAR 3 highlight the importance of stratification by region.

[Table: see text]

[Table: see text]
Are age and comorbidity independent prognostic factors in the treatment of metastatic NSCLC? A review of prospectively randomized national cancer institute of Canada Clinical Trials Group (NCIC CTG) trials
Authors: Asmis T. R. , Ding K. , Whitehead M. , Seymour L. , Shepherd F. A. , Winton T. , Leighl N. , Goss G.
Published: March 2020

7117

Background: This study analyzed all patients enrolled in two large prospectively randomized trials of systemic chemotherapy to determine whether age and/or co-morbidity are independent predictors of outcome. Methods: Baseline information was recorded, including ongoing medical problems and current medications. This information was extracted and scored using the validated Charlson co-morbidity scale. Scores were then correlated with other clinical data, which included age, gender, race, performance status, histology, stage, weight, LDH, chemotherapy (type, total dose, dose intensity), response and survival. Results: A total of 1,255 patients (481 in BR10 and 774 in BR18) were included in this analysis, the median age was 61.2 years (range 34.2 to 88.7), 827 were less than 65yrs, and 428 65yrs or older. 391 had other medical conditions besides the primary disease of lung cancer, 310 with a Charlson co-morbidity score of 1, and 81 with a cumulative score of 2 or higher. There were more male patients with co-morbidity (35% vs. 21%, p < 0.0001); fewer patients with histologic subtype of adeno with co-morbidity (26% vs. 35%, p = 0.001); and more older patients with co-morbidity (42% vs. 26%, p < 0.001). There was no difference in overall survival in the elderly (≥65) as compared to the younger patients (<65). In contrast, patients with co-morbidity were associated with a shorter survival (p = 0.01). A cumulative Charlson score of 1 was associated with a hazard ratio of 1.28 (95% CI 1.09–1.5; p =0.003), and a cumulative score of 2+ was associated with a hazard ratio of 1.09 (95% C.I. 0.83 -1.44, p = 0.52). Conclusions: From these two large randomized NCIC CTG trials, one observes that age over 65 is not associated with a worse outcome. However, the presence of co-morbidity does appear to be a negative prognostic factor and co-morbity is more common in older patients.

No significant financial relationships to disclose.
Vinorelbine (NVB) oral (NVBo) in combination with carboplatin (CBDCA) followed by maintenance therapy with single agent vinorelbine oral in stage III/IV non-small cell lung cancer (NSCLC): Final results of a multicenter international phase II trial
Authors: Abratt R. P. , Macha H. , Del Barco S. , Aubert D. , Mitrovic M. , Parlier Y. , Gatzemeier U.
Published: March 2020

7126

Background: NVB i.v. day 1 (25 mg/ m2) & NVBo day 8 (60 mg/ m2) and CBDCA AUC 5 have been previously studied in chemonaive NSCLC patients (pts) (O’Brien et al, Ann Oncol 2004; 15: 921). We investigated the efficacy and safety of NVBo weekly with CBDCA AUC 5 q3w for 4 cycles(Cy) followed by maintenance therapy with single agent NVBo in non progressive pts. Methods: Inoperable NSCLC stage IIIB, stage IV or delayed relapse of any stage becoming unresectable, KPS ≥ 80%, treated with combination therapy every 3 weeks for 4 Cy: NVBo 60 mg/m2 on days 1, 8 and 15 (Cy1), 80 mg/m2 (Cy2–4) in absence of neutropenia NCI CTC V2 G3/4; CBDCA AUC 5 day 1, administered over 1 hour. Maintenance therapy if pts did not have a PD: NVBo 60 mg/m2 for the first three weekly administrations, followed by NVBo at 80 mg/m2/week until PD. Results: from December 2003 to January 2005 57/56 pts have been registered/treated: median age 61 yrs (37–71); median KPS 90%; male 71.4%; Squamous cell 30%, Adenocarcinoma 50%; Stage III/IV 32.1/62.5% ; median dose intensity NVBo (% RDI) : combination, 50.1 mg/m2/w (67.3%), maintenance 56.2 mg/m2/w (70.2%); pts with NVBo dose escalation from 60 to 80 mg/m2 during combination : 36/52 (69.2%). Tolerance (% of pts with G3/4 NCI CTC V2) : Neutropenia 23.2/44.6; Platelets 16.1/1.8; Hb 19.6/3.6; Nausea 7.1/0; Vomiting 7.1/0; Diarrhea 5.4/0. No G3/4 toxicity was reported for Infection, Bilirubin, Creatinine, Stomatitis, and motor/sensory Neuropathy. Febrile Neutropenia was reported in 5 patients (8.9%). Efficacy: (RECIST) Percent Overall Response rates (n =56 pts) PR 17.9, SD 53.6, PD 23.2, NE 5.4; Progression-Free Survival 4.3 (95% CI [3.1–5.1]) months; Overall Survival 9.7 (95% CI [7.7–11.9]) months. Conclusions: NVBo on a weekly schedule and CBDCA AUC5 in combination therapy for 4 Cy followed by NVBo in maintenance therapy is an effective and safe treatment regimen for advanced NSCLC. The avoidance of further CBDCA administrations after 4 Cy and the use of NVBo as a maintenance therapy until PD has promise as an alternative to the 6 Cy option and calls for further comparative studies.

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A phase II evaluation of the combination of paclitaxel protein-bound and carboplatin in the first-line treatment of advanced non-small cell lung cancer (NSCLC)
Authors: Allerton J. P. , Hagenstad C. T. , Webb R. T. , Smith G. B. , Birch R. , Goggins T. F. , Katakkar S. B. , Khan W. , Mehta N. D. , Greco F. A.
Published: March 2020

7127

Background: Abraxane (A) is a cremophor free, albumin-bound nanoparticle of paclitaxel (P) approved for the treatment of metastatic breast cancer. Belani et al. (JCO 21: 2933–2939, 2003) reported that P 100 mg/m2 days 1, 8 and 15 q 28 days with C AUC 6 on day 1 led to a 32% response rate in 132 patients (pts) with NSCLC. The median time to progression (TTP) was 35 weeks (wks) for stage IIIB and 29 wks for stage IV. Methods: This study was designed to determine if substituting A for P at an identical dose would lead to an improved response rate, TTP or decreased toxicity. Results: Fifty-six pts with stage IIIB/IV NSCLC previously untreated with chemotherapy were enrolled. The median age was 66 (range 37 - 83); 37 were male and median ECOG performance status was 1 (range 0–2). Thirteen pts were stage IIIB. Metastases included bone (17), liver (7), brain (2) and lymph nodes (16). Currently a total of 239 cycles of therapy have been administered with a median of 4 (range 1–8) cycles per pt. In 194 (81%) full dose A was administered on days 1, 8 and 15. The table below shows toxicities compared to P: Seven pts (13%) experienced grade (G) 1 neuropathy and 3 pts (5%) experienced G 2 neuropathy. Five pts were inevaluable for response due to removal from study after <2 cycles of treatment (2 died from progressive disease, 2 because of toxicity - thrombocytopenia and neutropenia - and 1 refused). Of 51 evaluable pts 1 (2%) had a complete response and 23 patients (45%) achieved a partial response. Four of 10 evaluable stage IIIB pts obtained a PR. Twenty-one pts were stable for at least 12 weeks of whom twenty remain stable at 12–29 weeks and one progressed at 23 weeks. A total of 13 pts have progressed and 3 pts have died. The Kaplan-Meier estimate of median TTP is 23 wks and maximum follow up is 34 wks. Conclusions: We conclude that combining A and C is tolerable and active in the treatment of newly-diagnosed NSCLC and antitumor activity compares favorably to that of P/C. Further studies are warranted in this population.

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Components of metabolic syndrome correlate with longer survival in NSCLC in bexarotene-treated patients with high hypertriglyceridemia in SPIRIT I and II trials: A retrospective analysis
Authors: Dziewanowska Z. , Zhang J. , Sun S. , Groves E. , Negro-Vilar A.
Published: March 2020

7137

Background: Bexarotene activates RXR receptors regulating cell proliferation, differentiation, apoptosis and many aspects of lipid metabolism. Both SPIRIT I and II trials (ASCO 2005) showed that a large (36%) subgroup of bexarotene-treated patients showing high sensitivity to hypertriglyceridemia had a significantly longer survival in both studies. This subgroup included males, smokers, stage IV and weight loss, factors associated with poorer survival. A recent study in retinoid-treated patients revealed those developing high hypertriglyceridemia, as well as their parents, have a familial predisposition to hyperlipidemia and the metabolic syndrome (Ann Intern Med, 2002, 136:582). We evaluated baseline and in-treatment patient characteristics in relation to triglyceride responses and overall survival after bexarotene treatment to further extend that observation to NSCLC patients. Methods: A pooled analysis of 595 patients treated with bexarotene in SPIRIT I and II trials assessed factors related to metabolic syndrome (BMI, HDL, LDL and Total cholesterol [T-chol], T-chol/HDL ratio, triglycerides, glucose, blood pressure) at baseline and during treatment at the time of high-triglyceridemia. Individual and composite risk factor scores were evaluated by logistic and Cox-regression analysis in two subgroups, e.g., Responders (high trigs, long survival) and Non-responders (low trigs, shorter survival). Results: Among in-treatment risk factors, Responders (N = 215) had significantly higher (p < 0.0001) BMI, trigs, T-chol, T-chol/HDL ratio and lower HDL (p < 0.0001) than Non-responders (N = 380). A composite risk score (the sum of the individual in-treatment dichotomous risk scores) analysis also showed a significantly (p < 0.0001) higher score for metabolic risk factors in the Responder/longer survival subgroup. Hazard ratio analysis by Cox-regression showed a 13% survival benefit for each composite score increase. Conclusions: Baseline and in-treatment triglycerides and other key metabolic syndrome factors are important predictors and contributors to the beneficial survival impact of bexarotene in this important subgroup of NSCLC patients.

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Secondary primary cancer in the long-term survivors with concurrent chemoradiotherapy for locally advanced non-small cell lung cancer
Authors: Takigawa N. , Segawa Y. , Kiura K. , Tabata M. , Ueoka H. , Yonei T. , Shibayama T. , Takata I. , Matsuo K. , Tanimoto M.
Published: March 2020

7147

Background: Although concurrent chemoradiotherapy (CT/RT) is associated with increased survival for patients (pts) with locally advanced non-small cell lung cancer (NSCLC), long-outcomes beyond 5 years have not been fully analyzed. Methods: Between 1994 and 1999, we conducted two phase II studies examining concurrent CT/RT for treatment of surgically unresectable stage IIIA or IIIB NSCLC. One regimen consisted of three cycles of 5-fluorouracil 500mg/m2 and cisplatin 20mg/m2, days 1–5, every 4 weeks and concurrent hyperfractionated thoracic RT (1.25Gy twice daily, total 62.5–70Gy) [FP-TRT] (Segawa et al. BJC 82, 2000). The other consisted of docetaxel 40mg/m2 and cisplatin 40mg/m2, days 1, 8, 29 and 36 and concurrent thoracic RT (2Gy daily, total 60Gy) [DP-TRT] (Kiura et al. BJC 89, 2003). Long-term data is presented. Results: In 50 pts treated with FP-TRT, the median survival time (MST) was 1.6 years (yr; 95% confidential interval [CI]: 0.91 - 2.25 yr) by a median follow-up time of 10.4 yr and the actual 5 yr-survival rate was 30%. In 15 long-term survivors, 3 and 2 pts died due to primary NSCLC and secondary primary cancer (SPC), respectively, 1 was lost to follow-up, and 9 are still alive. In 42 pts treated with DP-TRT, the MST was 2.1 yr (95% CI: 0.82 - 2.48 yr) by a median follow-up time of 6.3 yr and the actual 5 yr-survival rate was 31%. In 13 long-term survivors, 1 pt died due to primary NSCLC, 1 died due to SPC, 1 was lost to follow-up, and 10 are still alive. Overall, 7 of 92 pts enrolled in these studies developed SPCs (2 NSCLC, 1 small cell lung cancer, 2 esophageal cancers, 2 gall bladder cancers) although no pts developed leukemia or myelodysplastic syndrome. An observed incidence rate of SPCs was 2356.1/100,000 (95% CI: 947.6 - 4856.0). Cumulative incidence was 5.8% (standard error [SE] 4.0%) at 5 yr, 10.0% (SE 5.6%) at 8 yr and 60.8% (SE 18.9%) at 10 yr. The median time from the beginning of CT/RT to the diagnosis of SPC was 9.6 yr (95% CI: 8.1 - 11.1 yr). Conclusions: Approximately 30% of pts survived more than 5 years after concurrent CT/RT, however, they were still at risk of dying from primary NSCLC. Occurrence of SPC in long-term survivors should be concerned in follow-up.

No significant financial relationships to disclose.
Patient attitude and survival in advanced non-small cell lung cancer (NSCLC): Results of a prospective observational study
Authors: Altug S. , Wang L. , Chu D. , Park K. , Hsu H. , Cok G. , Roubec J. , Patil S. , Damyanov D. , Reece W.
Published: March 2020

7148

Background: A physician’s ability to accurately identify a patient’s attitude toward treatment is critical. The primary objective of this study (B9E-AA-JHSH) was to evaluate patient attitudes as predictors of survival independently of currently known predictive variables, and secondarily, whether physician-assessed patient attitudes differed from patient-assessed attitudes. Methods: This was a non-interventional, prospective, observational study of patients from 19 countries of Asia, Central Eastern Europe, and Latin America. Eligible patients had stage IIIB/IV NSCLC not amenable to curative surgery/radiotherapy, gemcitabine and cis/carboplatin as part of treatment, and were chemonaive. Physicians and patients used a 7-item questionnaire to assign patient attitudes to 1 of 4 categories using a pre-defined algorithm: A = Cure; B = Maximum extension of survival with acceptance of high toxicity; C = Maximum extension of survival only if coupled with normal lifestyle; and D = Symptom relief. Enrolled patients were followed until 18 months from enrolment, death, or loss to follow up. Results: From Sept 2002 to Dec 2003, 1,985 patients were enrolled; the majority were male (73.4%), <70 yrs (83.9%), and had stage IV disease (79.2%), PS 0–1 (79.2%), and tumor-related symptoms (89.2%). Distribution of patient-assessed attitudes were A = 0%, B = 55%, C = 25%, and D = 20%. From category B-D, median survival (B = 14.6 months, C = 13.5, D = 12.5) and 1-year survival (B = 57.6%, C = 56.2%, D = 51.2%) both decreased but the differences were not statistically significant. Adjustment for known predictive variables eliminated this decreasing trend. Physician-assessed patient attitudes were lower than patient-assessed attitudes (p < .0001); however, the difference was less for patients with disease-related symptoms (p = .03). Conclusions: This is the largest analysis to date of patient attitudes when treated with gemcitabine and cis/carboplatin. Patient attitudes were not significant predictors of survival; however, physicians do underestimate patients’ desire for extended survival compared to symptom relief. Also, it was interesting to see a comparatively longer median and 1-year survival in routine practice compared to reports in clinical trial settings.

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ECOG 3503: A pilot study to determine if downstream markers of EGFR linked signaling pathways predict response to erlotinib (OSI-774) in the first-line treatment of patients with advanced non-small cell lung cancer (NSCLC)
Authors: Kolesar J. , Brahmer J. , Li S. , Guaglianone P. , Patel J. , Keppen M. , Hidalgo M. , Carbone D. , Siegfried J. , Schiller J.
Published: March 2020

7162

Background: Markers of response and survival in patients (pts) who benefit from erlotinib (Elb) remain controversial. In another study, pts who developed a rash on Elb survived longer. The primary objective of this study is to prospectively identify downstream markers of EGFR linked signaling pathways that are predictive of response. The secondary objectives are to estimate response rate (RR), disease control rate, time to progression, survival, and if a grade (gr) 2 rash is a predictor of response and survival. Methods: Pts with advanced NSCLC (Stage IIIB with pleural effusion and IV, no prior systemic treatment, performance status 0–2, no symptomatic CNS metastasis, and adequate renal, hepatic and hematologic function) were accrued to this single arm study. Elb was taken orally once a day until disease progression or unacceptable toxicity. Starting at 150 mg per day, the dose was escalated by 25 mg once every 2 weeks until a gr 2 rash developed, other toxicities precluded escalation, or a maximum dose of 250 mg reached. Response was evaluated by RECIST criteria. Paraffin-fixed tumor tissue was collected on all patients for correlative studies. Results: Over 8 months, 137 pts (58 M, 79 F) were recruited with a median age of 70 (41–92). Most pts were Caucasian (92%) and had adenocarcinoma (54%). Dose escalation occurred in 53/117 of pts, with 11 getting a dose of 250mg. Only 58 pts have been evaluated for response so far. The preliminary RR is 1% (1/58) with stable disease rate of 18% (32/58). Pts have received a median of 4 cycles of treatment (range 0–10). Most pts went off trial because of progression of disease (38%, 52/137) with only 8% (11/137) stopping because of toxicities (42% unknown). Of the 123 pts evaluated for toxicity, 44 (36%) and 10 (8%) had a grade 1 / 2 and 3 rash respectively. Grade 1 / 2 diarrhea occurred in 16% (20/123) and Grade 3 diarrhea in 10% (13/123). One pt died of pneumonitis of unclear cause. Conclusions: Mature toxicity, response, and survival data as well as laboratory studies which include IHC, EGFR mutation and FISH analysis, and genotype and allele frequency will be available at the meeting.

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EGFR genomic gain in Japanese non-small cell lung cancer patients treated with gefitinib
Authors: Varella-Garcia M. , Mitsudomi T. , Yatabe Y. , Kosaka T. , Nakajima E. , Franklin W. , Bunn P. A. , Hirsch F. R.
Published: March 2020

7164

Background: Increased EGFR gene copy numbers evaluated by fluorescence in situ hybridization (FISH) is excellent predictor of clinical benefit from EGFR tyrosine kinase inhibitors (TKIs) in Caucasian non small-cell lung cancer (NSCLC) patients. This study was performed to verify how this marker performs in Oriental patients. Methods: A cohort of 59 Japanese patients with recurrent NSCLC after surgery was treated with gefitinib 250 mg daily. The cohort included 46% of females, 47% of never-smokers, 68% of patients had prior chemotherapy and 59% had stage III-IV at the time of surgery. Adenocarcinoma was the most common histology (85%). FISH was performed using EGFR /CEP 7 and PathVysion probes (Vysis/Abbott). Specimens were classified as FISH+ when showing gene amplification or high polysomy (≥4 copies of the gene in ≥40% of tumor cells). Effectiveness of gefitinib was concluded when there was 30% tumor shrinkage in imaging studies and/or elevated CEA level decreased to <50% of baseline. Results: FISH results were available in 51 tumors: 35 (69%) were EGFR+ and 29 (57%) were HER2+. There was a significant association between EGFR+ and HER2+ (p = 0.012) and between EGFR FISH+ and of EGFR mutations (p = 0.003). All 9 tumors exhibiting clustered EGFR gene amplification harbored mutations. Response rate assessed in 43 patients was 59% in EGFR+ and 33% in EGFR- (p = 0.11). Gefitinib treatment produced response in 5 (83%) cases with gene amplification and 12 (52%) cases with high polysomy. Response rate was 77% in 22 cases positive for FISH and mutation and 100% in 5 cases with EGFR mutation/FISH- cases. No responses were observed in EGFR WT patients, neither in 9 FISH+ nor in 10 FISH- cases. Survival was not significantly impacted by EGFR (p = 0.42) or HER2 (p = 0.40) FISH status, while EGFR mutation was significantly associated with longer survival (p = 0.005). Conclusion: Patients in this Japanese cohort had more frequently FISH+ status than in the Caucasian populations, which may contribute to higher sensitivity to EGFR TKIs. However, the predictive power of EGFR FISH status for TKI sensitivity seems to be lower supporting significant differences in the mechanisms of EGFR pathway activation in Oriental and Caucasian populations.

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