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The aim of this work was to examine uniaxial, torsion, and multi-axial fatigue characteristics of ER100S-1 low carbon steel specimens fabricated with wire arc additive manufacturing (WAAM) technique, a subcategory of directed energy deposition (DED). Two distinct specimen orientations were tested—vertical and horizontal, extracted perpendicular and parallel to the WAAM deposited layers, respectively. Fracture surfaces of the tested specimens were analysed under scanning electron microscope (SEM) to observe fracture mechanisms corresponding to different specimen orientations, different fatigue loading conditions, and to interpret the fatigue results obtained from the tests. Finally, the obtained stress–life results were compared with the fatigue data available in the literature for a series of wrought and WAAM-built structural steel specimens. Moreover, the S–N curves obtained in this study were evaluated against the fatigue design curve recommended for offshore marine welded structures in DNV standard. Test results have shown advantageous characteristics of WAAM-built ER100S-1 specimens compared with behaviours of other structural steels and conservative prediction of its fatigue life by the design curve available in the DNV standard.

We hypothesised that zanubrutinib, a highly selective next-generation Bruton tyrosine kinase (BTK) inhibitor, would be a safe and active treatment for patients intolerant of ibrutinib, acalabrutinib, or both. We aimed to assess whether zanubrutinib would prolong treatment duration by minimising treatment-related toxicities and discontinuations in patients with previously treated B-cell malignancies.This ongoing, phase 2, multicentre, open-label, single-arm study was done in 20 centres in the USA. Patients aged 18 or older with previously treated B-cell malignancies (chronic lymphocytic leukaemia, small lymphocytic lymphoma, mantle cell lymphoma, Waldenström macroglobulinaemia, or marginal zone lymphoma) who became intolerant of ibrutinib, acalabrutinib, or both, were orally administered zanubrutinib 160 mg twice daily or 320 mg once daily per investigator. The primary endpoint was recurrence and change in severity of ibrutinib or acalabrutinib intolerance events based on investigator-assessed adverse events. Secondary endpoints were investigator-assessed overall response rate; duration of response; disease control rate; and progression-free survival. Analyses included all patients who received any dose of the study drug. This study is registered with ClinicalTrials.gov, NCT04116437.Between Oct 14, 2019, and Sept 8, 2021, 67 patients (36 [54%] men and 31 [46%] women) who were intolerant of ibrutinib (n=57; cohort 1) or of acalabrutinib or acalabrutinib and ibrutinib (n=10; cohort 2) were enrolled. 63 (94%) patients were White, one (2%) had multiple ethnicities, and three (5%) had unreported or unknown ethnicity. Most intolerance events (81 [70%] of 115 for ibrutinib; 15 [83%] of 18 for acalabrutinib) did not recur with zanubrutinib. Of the recurring events, seven (21%) of 34 ibrutinib intolerance events and two (67%) of three acalabrutinib intolerance events recurred at the same severity with zanubrutinib; 27 (79%) ibrutinib intolerance events and one (33%) acalabrutinib intolerance event recurred at a lower severity with zanubrutinib. No events recurred at higher severity. No grade 4 intolerance events recurred. 64 (96%) of 67 patients had one or more adverse events with zanubrutinib; the most common adverse events were contusion (in 15 [22%] of 67 patients), fatigue (14 [21%]), myalgia (ten [15%]), arthralgia (nine [13%]), and diarrhoea (nine [13%]). Atrial fibrillation occurred in three (4%) patients (all grade 2). Eight (12%) of 67 patients had serious adverse events (anaemia, atrial fibrillation, bronchitis, COVID-19, COVID-19 pneumonia, febrile neutropenia, salmonella gastroenteritis, transfusion reaction, trigeminal nerve disorder, and urinary tract infection). No treatment-related deaths occurred. The median follow-up time was 12·0 months (IQR 8·2-15·6). Among the 64 efficacy-evaluable patients, disease control rate was 93·8% (60; 95% CI 84·8-98·3) and overall response rate was 64·1% (41; 95% CI 51·1-75·7). The median duration of response was not reached; the 12-month event-free duration of response rate was 95·0% (95% CI 69·5-99·3). Similarly, median progression-free survival was not reached; 18-month progression-free survival was 83·8% (95% CI 62·6-93·6).Patients intolerant of previous BTK inhibitors have limited treatment options. These results suggest that zanubrutinib, a safe and viable treatment for patients with B-cell malignancies, might fill that unmet need for those who exhibit intolerance to ibrutinib or acalabrutinib.BeiGene.

ObjectiveThe recent phase 3 trial AGO-OVAR16 demonstrated that pazopanib maintenance improved median progression-free survival in patients with ovarian cancer whose disease did not progress during first-line treatment. However, this improvement was not seen in the subset of East Asian patients. The current analysis evaluated the efficacy and safety of pazopanib maintenance in East Asian patients from AGO-OVAR16 and a separate East Asian study.Materials and MethodsEast Asian patients from AGO-OVAR16 (n = 209) and the East Asian study (N = 145) were randomized 1:1 to receive pazopanib 800 mg/d or placebo for up to 24 months. The primary end point for each study was progression-free survival by RECIST (Response Evaluation Criteria in Solid Tumors) based on investigator assessment. Clinical and genetics data were analyzed separately by study or pooled according to separate predetermined statistical plans.ResultsPazopanib maintenance had a detrimental effect on median progression-free survival versus placebo in East Asian patients from the combined studies (n = 354; 17.9 vs 21.5 months; hazard ratio, 1.114; 95% confidence interval, 0.818–1.518; P = 0.4928). Pazopanib maintenance showed a disadvantage in overall survival in East Asian patients from AGO-OVAR16 versus placebo (hazard ratio, 1.706; 95% confidence interval, 1.010–2.883; P = 0.0465); overall survival analysis was not performed in the East Asian study because of insufficient event numbers. Pazopanib-treated patients had a significantly higher incidence of grade 3 or higher hypertension (27%) and neutropenia (13%) versus placebo.ConclusionsThe treatment effect of maintenance pazopanib in East Asian patients seemed to differ from that in non-Asian patients. In study-specific and pooled analyses, none of the potential factors analyzed could satisfactorily explain the different efficacy results of pazopanib in East Asian patients.

Background. The CHER-LOB randomized phase II study showed that the combination of lapatinib and trastuzumab plus chemotherapy increases the pathologic complete remission (pCR) rate compared with chemotherapy plus either trastuzumab or lapatinib. A biomarker program was prospectively planned to identify potential predictors of sensitivity to different treatments and to evaluate treatment effect on tumor biomarkers. Materials and Methods. Overall, 121 breast cancer patients positive for human epidermal growth factor 2 (HER2) were randomly assigned to neoadjuvant chemotherapy plus trastuzumab, lapatinib, or both trastuzumab and lapatinib. Pre- and post-treatment samples were centrally evaluated for HER2, p95-HER2, phosphorylated AKT (pAKT), phosphatase and tensin homolog, Ki67, apoptosis, and PIK3CA mutations. Fresh-frozen tissue samples were collected for genomic analyses. Results. A mutation in PIK3CA exon 20 or 9 was documented in 20% of cases. Overall, the pCR rates were similar in PIK3CA wild-type and PIK3CA-mutated patients (33.3% vs. 22.7%; p = .323). For patients receiving trastuzumab plus lapatinib, the probability of pCR was higher in PIK3CA wild-type tumors (48.4% vs. 12.5%; p = .06). Ki67, pAKT, and apoptosis measured on the residual disease were significantly reduced from baseline. The degree of Ki67 inhibition was significantly higher in patients receiving the dual anti-HER2 blockade. The integrated analysis of gene expression and copy number data demonstrated that a 50-gene signature specifically predicted the lapatinib-induced pCR. Conclusion. PIK3CA mutations seem to identify patients who are less likely to benefit from dual anti-HER2 inhibition. p95-HER2 and markers of phosphoinositide 3-kinase pathway deregulation are not confirmed as markers of different sensitivity to trastuzumab or lapatinib. Implications for Practice: HER2 is currently the only validated marker to select breast cancer patients for anti-HER2 treatment; however, it is becoming evident that HER2-positive breast cancer is a heterogeneous disease. In addition, more and more new anti-HER2 treatments are becoming available. There is a need to identify markers of sensitivity to different treatments to move in the direction of treatment personalization. This study identified PIK3CA mutations as a potential predictive marker of resistance to dual anti-HER2 treatment that should be further studied in breast cancer.

Purpose Pazopanib is an oral, multikinase inhibitor of vascular endothelial growth factor receptor (VEGFR) -1/-2/-3, platelet-derived growth factor receptor (PDGFR) -α/-β, and c-Kit. Preclinical and clinical studies support VEGFR and PDGFR as targets for advanced ovarian cancer treatment. This study evaluated the role of pazopanib maintenance therapy in patients with ovarian cancer whose disease did not progress during first-line chemotherapy. Patients and Methods Nine hundred forty patients with histologically confirmed cancer of the ovary, fallopian tube, or peritoneum, International Federation Gynecology Obstetrics (FIGO) stages II-IV, no evidence of progression after primary therapy consisting of surgery and at least five cycles of platinum-taxane chemotherapy were randomized 1:1 to receive pazopanib 800 mg once per day or placebo for up to 24 months. The primary end point was progression-free survival by RECIST 1.0 assessed by the investigators. Results Maintenance pazopanib prolonged progression-free survival compared with placebo (hazard ratio [HR], 0.77; 95% CI, 0.64 to 0.91; P = .0021; median, 17.9 v 12.3 months, respectively). Interim survival analysis based on events in 35.6% of the population did not show any significant difference. Grade 3 or 4 adverse events of hypertension (30.8%), neutropenia (9.9%), liver-related toxicity (9.4%), diarrhea (8.2%), fatigue (2.7%), thrombocytopenia (2.5%), and palmar-plantar erythrodysesthesia (1.9%) were significantly higher in the pazopanib arm. Treatment discontinuation related to adverse events was higher among patients treated with pazopanib (33.3%) compared with placebo (5.6%). Conclusion Pazopanib maintenance therapy provided a median improvement of 5.6 months (HR, 0.77) in progression-free survival in patients with advanced ovarian cancer who have not progressed after first-line chemotherapy. Overall survival data to this point did not suggest any benefit. Additional analysis should help to identify subgroups of patients in whom improved efficacy may balance toxicity (NCT00866697).

Pazopanib and sunitinib provided a progression-free survival benefit, as compared with placebo or interferon, in previous phase 3 studies involving patients with metastatic renal-cell carcinoma. This phase 3, randomized trial compared the efficacy and safety of pazopanib and sunitinib as first-line therapy.We randomly assigned 1110 patients with clear-cell, metastatic renal-cell carcinoma, in a 1:1 ratio, to receive a continuous dose of pazopanib (800 mg once daily; 557 patients) or sunitinib in 6-week cycles (50 mg once daily for 4 weeks, followed by 2 weeks without treatment; 553 patients). The primary end point was progression-free survival as assessed by independent review, and the study was powered to show the noninferiority of pazopanib versus sunitinib. Secondary end points included overall survival, safety, and quality of life.Pazopanib was noninferior to sunitinib with respect to progression-free survival (hazard ratio for progression of disease or death from any cause, 1.05; 95% confidence interval [CI], 0.90 to 1.22), meeting the predefined noninferiority margin (upper bound of the 95% confidence interval,1.25). Overall survival was similar (hazard ratio for death with pazopanib, 0.91; 95% CI, 0.76 to 1.08). Patients treated with sunitinib, as compared with those treated with pazopanib, had a higher incidence of fatigue (63% vs. 55%), the hand-foot syndrome (50% vs. 29%), and thrombocytopenia (78% vs. 41%); patients treated with pazopanib had a higher incidence of increased levels of alanine aminotransferase (60%, vs. 43% with sunitinib). The mean change from baseline in 11 of 14 health-related quality-of-life domains, particularly those related to fatigue or soreness in the mouth, throat, hands, or feet, during the first 6 months of treatment favored pazopanib (P0.05 for all 11 comparisons).Pazopanib and sunitinib have similar efficacy, but the safety and quality-of-life profiles favor pazopanib. (Funded by GlaxoSmithKline Pharmaceuticals; COMPARZ ClinicalTrials.gov number, NCT00720941.).

617 Background: ALTTO (NCT00490139) is a large adjuvant breast cancer (ABC) study evaluating lapatinib, alone and in combinations with trastuzumab and taxanes. Characterization of hepatic abnormali...

617 Background: The lapatinib-taxane combination led to shorter PFS than trastuzumab-taxane in HER2+ metastatic breast cancer. We investigated the prognostic and predictive effects of pretreatment ...

601 Background: Lapatinib (L) was associated with shorter progression-free survival (PFS) than trastuzumab (T) when combined with a taxane (Tax) as first line therapy for HER2+ MBC. We report the e...

366 Background: Pazopanib (P) and sunitinib (S) are multi-kinase angiogenesis inhibitors that positively impact progression-free survival (PFS) in patients (pts) with metastatic renal cell carcinoma (mRCC) (NEJM 2007 356:115; JCO 2009 29:475). The safety profile of multi-kinase angiogenesis inhibitors has been shown to vary depending upon ethnic background (Oncology 2011 80:395). Methods: Treatment naïve pts with clear cell mRCC and measurable disease were randomized 1:1 to P, 800mg QD continuous dosing or S, 50 mg QD for 4 weeks followed by 2 weeks off treatment. Primary endpoint was PFS. A subgroup analysis compared PFS (Cox analysis with treatment as only covariate) and AEs between the Asian, North American (NA), and European (EU) populations. Of the 1,110 pts 367 were from Asia (188 P, 179 S). Results: PFS in the Asian subgroup was consistent with NA and EU. HR (95% CI): Asia 1.07 (0.81, 1.42); NA 1.18 (0.90, 1.53); EU 1.03 (0.79, 1.36). Median PFS mos (95% CI) P: Asia 8.4 (8.3,11.1); EU 8.5 (8.0, 11.0); NA 8.3 (6.6, 11.0); S: Asia 11.1 (8.2, 14.3); EU 9.0 (8.1, 12.9); NA 10.5 (8.2, 13.4). AEs in >25% of pts in any arm in any region and a difference of 15% between any region within an arm are shown. Conclusions: In both arms, PFS in the Asian population was similar to NA and EU. In the Asian population increased incidences of hematotoxicity, hypertension, HFS, LFT increase, proteinuria, and decreased incidences of GI symptoms, headache were observed in both arms. Consistent with NA and EU, more frequent AEs in the Asian population (>10% difference between arms): ALT increase (P); HFS, thrombocytopenia, neutropenia (S). [Table: see text]

346 Background: Pazopanib and sunitinib are targeted therapies associated with particular treatment-related side effects that may affect patients’ QoL. COMPARZ was a randomized, open-label, parallel group, phase III study of pazopanib vs. sunitinib in 1,110 subjects with advanced RCC who had not received prior systemic therapy. The study demonstrated pazopanib is non-inferior to sunitinib with respect to progression-free survival. The study also confirmed the differentiated safety profiles of the two drugs. Methods: QoL endpoints were assessed using the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F), the Functional Assessment of Cancer Therapy-Kidney Symptom Index-19 (FKSI-19), the Cancer Therapy Satisfaction Questionnaire (CTSQ), and a Supplementary Quality of Life Questionnaire (SQLQ). Research to validate the SQLQ is currently ongoing. Each instrument was administered at baseline (except CTSQ) and then day 28 of every cycle. Changes in mean scores over time were analyzed and compared using a repeated measures analysis of covariance. Comparisons were pre-specified at the first 6 months of treatment as this time was expected to be a key interval during which tolerability issues may have occurred. Results: During the first 6 months, treatment differences in change from baseline for 11 of the 14 QoL domains studied were statistically significant (p < 0.05), all of which favored pazopanib. Further analysis up to 12 months of treatment, showed the treatment differences observed for fatigue scores increased over time with pazopanib improving and sunitinib remaining relatively flat. The difference in limitations due to foot soreness between the two treatments also progressively increased with time over 12 months favoring pazopanib. Conclusions: In this study, better patient-reported QoL scores for pazopanib indicate subjects experienced less worsening of fatigue, as well as mouth/throat, hands, and feet soreness, and fewer limitations due to soreness, while on pazopanib compared with sunitinib. The differences observed are likely to be clinically meaningful. The FACIT-F and SQLQ results are also highly consistent with the previously-reported PISCES study.