Amy Karon

Among patients with metastatic melanoma, detectable circulating levels of BRAF^V600 mutated circulating tumor DNA and elevated levels of circulating hepatocyte growth factor separately predicted significantly worse survival, regardless of treatment.

After adjusting for lactate dehydrogenase, ECOG (Eastern Cooperative Oncology Group) status, disease stage, and treatment, hazard ratios for overall survival were 1.75 (95% confidence interval, 1.35-2.28) for detectable versus undetectable circulating tumor DNA (ctDNA) and 1.24 (95% CI, 1.00-1.53) for high versus low circulating hepatocyte growth factor (cHGF), reported William Lu, PhD, of Genentech in South San Francisco, with his associates. Their retrospective, exploratory analysis of the phase 3 BRIM-3 trial was published in JCO Precision Oncology.

BRIM-3 was a multicenter, open-label trial of 675 patients with previously untreated unresectable stage IIIC or stage IV melanoma that tested positive for the BRAF^V600 mutation. Patients received either vemurafenib or dacarbazine therapy.

Baseline ctDNA, baseline cHGF, and ECOG performance status most strongly predicted overall survival, said the investigators. Patients whose mutant ctDNA fraction exceeded 0.039 had an 11.5-month shorter median overall survival on vemurafenib (P less than .001) and a 13.9-month shorter median overall survival on dacarbazine (P less than .001) than patients whose mutant ctDNA fraction was less than 0.039, they explained. Similarly, median overall survival times were 5.4 months shorter for vemurafenib (P = .002) and 12.3 months shorter for dacarbazine (P less than .001) when patients had high (more than 438 pg/mL) versus low circulating cHGF.

Median overall survival for vemurafenib was shortest (7.3 months) in the subgroup of 64 patients with detectable BRAF^V600 ctDNA and elevated cHGF, according to the researchers. In contrast, median overall survival for vemurafenib was longest (22.0 months) when patients had undetectable ctDNA and an ECOG status of 0.

“Although similar studies have been performed, to our knowledge, our study is unique in its size and in its design as a randomized trial,” Dr. Lu and associates concluded. “The biomarkers in this study can be readily acquired and measured, and require only small volumes of plasma.” They suggested validating the findings in a separate dataset.

F. Hoffman-La Roche provided funding. Roche Molecular Systems makes the Cobas 4800 BRAF^V600 Mutation Test used in the study. Dr. Lu disclosed employment and research funding from Genentech/Roche.

SOURCE: Lu W et al. JCO Precis Oncol. 2018 Apr 25. doi: 10.1200/PO.17.00168.

Among patients with metastatic melanoma, detectable circulating levels of BRAF^V600 mutated circulating tumor DNA and elevated levels of circulating hepatocyte growth factor separately predicted significantly worse survival, regardless of treatment.

After adjusting for lactate dehydrogenase, ECOG (Eastern Cooperative Oncology Group) status, disease stage, and treatment, hazard ratios for overall survival were 1.75 (95% confidence interval, 1.35-2.28) for detectable versus undetectable circulating tumor DNA (ctDNA) and 1.24 (95% CI, 1.00-1.53) for high versus low circulating hepatocyte growth factor (cHGF), reported William Lu, PhD, of Genentech in South San Francisco, with his associates. Their retrospective, exploratory analysis of the phase 3 BRIM-3 trial was published in JCO Precision Oncology.

BRIM-3 was a multicenter, open-label trial of 675 patients with previously untreated unresectable stage IIIC or stage IV melanoma that tested positive for the BRAF^V600 mutation. Patients received either vemurafenib or dacarbazine therapy.

Baseline ctDNA, baseline cHGF, and ECOG performance status most strongly predicted overall survival, said the investigators. Patients whose mutant ctDNA fraction exceeded 0.039 had an 11.5-month shorter median overall survival on vemurafenib (P less than .001) and a 13.9-month shorter median overall survival on dacarbazine (P less than .001) than patients whose mutant ctDNA fraction was less than 0.039, they explained. Similarly, median overall survival times were 5.4 months shorter for vemurafenib (P = .002) and 12.3 months shorter for dacarbazine (P less than .001) when patients had high (more than 438 pg/mL) versus low circulating cHGF.

Median overall survival for vemurafenib was shortest (7.3 months) in the subgroup of 64 patients with detectable BRAF^V600 ctDNA and elevated cHGF, according to the researchers. In contrast, median overall survival for vemurafenib was longest (22.0 months) when patients had undetectable ctDNA and an ECOG status of 0.

“Although similar studies have been performed, to our knowledge, our study is unique in its size and in its design as a randomized trial,” Dr. Lu and associates concluded. “The biomarkers in this study can be readily acquired and measured, and require only small volumes of plasma.” They suggested validating the findings in a separate dataset.

F. Hoffman-La Roche provided funding. Roche Molecular Systems makes the Cobas 4800 BRAF^V600 Mutation Test used in the study. Dr. Lu disclosed employment and research funding from Genentech/Roche.

SOURCE: Lu W et al. JCO Precis Oncol. 2018 Apr 25. doi: 10.1200/PO.17.00168.

Among patients with metastatic melanoma, detectable circulating levels of BRAF^V600 mutated circulating tumor DNA and elevated levels of circulating hepatocyte growth factor separately predicted significantly worse survival, regardless of treatment.

After adjusting for lactate dehydrogenase, ECOG (Eastern Cooperative Oncology Group) status, disease stage, and treatment, hazard ratios for overall survival were 1.75 (95% confidence interval, 1.35-2.28) for detectable versus undetectable circulating tumor DNA (ctDNA) and 1.24 (95% CI, 1.00-1.53) for high versus low circulating hepatocyte growth factor (cHGF), reported William Lu, PhD, of Genentech in South San Francisco, with his associates. Their retrospective, exploratory analysis of the phase 3 BRIM-3 trial was published in JCO Precision Oncology.

BRIM-3 was a multicenter, open-label trial of 675 patients with previously untreated unresectable stage IIIC or stage IV melanoma that tested positive for the BRAF^V600 mutation. Patients received either vemurafenib or dacarbazine therapy.

Baseline ctDNA, baseline cHGF, and ECOG performance status most strongly predicted overall survival, said the investigators. Patients whose mutant ctDNA fraction exceeded 0.039 had an 11.5-month shorter median overall survival on vemurafenib (P less than .001) and a 13.9-month shorter median overall survival on dacarbazine (P less than .001) than patients whose mutant ctDNA fraction was less than 0.039, they explained. Similarly, median overall survival times were 5.4 months shorter for vemurafenib (P = .002) and 12.3 months shorter for dacarbazine (P less than .001) when patients had high (more than 438 pg/mL) versus low circulating cHGF.

Median overall survival for vemurafenib was shortest (7.3 months) in the subgroup of 64 patients with detectable BRAF^V600 ctDNA and elevated cHGF, according to the researchers. In contrast, median overall survival for vemurafenib was longest (22.0 months) when patients had undetectable ctDNA and an ECOG status of 0.

“Although similar studies have been performed, to our knowledge, our study is unique in its size and in its design as a randomized trial,” Dr. Lu and associates concluded. “The biomarkers in this study can be readily acquired and measured, and require only small volumes of plasma.” They suggested validating the findings in a separate dataset.

F. Hoffman-La Roche provided funding. Roche Molecular Systems makes the Cobas 4800 BRAF^V600 Mutation Test used in the study. Dr. Lu disclosed employment and research funding from Genentech/Roche.

SOURCE: Lu W et al. JCO Precis Oncol. 2018 Apr 25. doi: 10.1200/PO.17.00168.

The second-generation anaplastic lymphoma kinase (ALK) inhibitor alectinib (Alcensa) topped chemotherapy in crizotinib-pretreated ALK+ non–small cell lung cancer (NSCLC), according to results from the phase 3 ALUR trial.

Median investigator-assessed progression-free survival was 9.6 months with alectinib and 1.4 months with chemotherapy (hazard ratio, 0.15; P less than .001), reported Silvia Novello, MD, PhD, of University of Turin (Italy) and her associates. Among patients with measurable central nervous system disease, the rate of CNS objective response was significantly higher for alectinib (54%) versus chemotherapy (0%; P less than .001), Dr. Novello and her associates reported in Annals of Oncology.

The multicenter, open-label ALUR trial was the first to directly compare alectinib with standard chemotherapy in patients with ALK-rearranged NSCLC that previously had been treated with both platinum-based chemotherapy and crizotinib. In all, 107 patients were randomly assigned on a 2:1 basis to receive either alectinib (600 mg twice daily) or chemotherapy (clinician’s choice of pemetrexed 500 mg/m² or docetaxel 75 mg/m² every 3 weeks).

A blinded independent review committee calculated median progression-free survival (PFS) times that were 2.5 months shorter for alectinib and 0.2 months longer for chemotherapy. Consequently, the hazard ratio for PFS was somewhat attenuated at 0.32 but remained highly significant (95% confidence interval, 0.17-0.59). “[Median] PFS with alectinib in ALUR has exceeded that observed with [second-line] ceritinib” during the ASCEND-5 study, the researchers wrote. In ASCEND-5, median independent review committee–assessed PFS time was 5.4 months, which is 1.7 months shorter than that for alectinib in ALUR. In each study, chemotherapy yielded a median PFS time of 1.6 months, which facilitated intertrial comparisons, they wrote.

Rates of all-grade and serious adverse events were similar between arms in ALUR. Alectinib therapy caused no fatal adverse events, while chemotherapy was associated with one fatality deemed unrelated to treatment. Alectinib was more likely to produce constipation, dyspnea, and hyperbilirubinemia, while chemotherapy was more likely to cause nausea, alopecia, neutropenia, diarrhea, pruritus, stomatitis, and bacterial pneumonia. Although patients stayed on alectinib a median of 14 weeks longer than on chemotherapy, they were less likely to stop alectinib (6%) than chemotherapy (9%) for adverse events.

Dr. Novello disclosed personal fees from Roche, which markets alectinib. Eleven coinvestigators also disclosed employment, stock ownership, or other financial ties to Roche.

SOURCE: Novello S et al. Ann Oncol. 2018 Apr 14. doi: 10.1093/annonc/mdy121.

The second-generation anaplastic lymphoma kinase (ALK) inhibitor alectinib (Alcensa) topped chemotherapy in crizotinib-pretreated ALK+ non–small cell lung cancer (NSCLC), according to results from the phase 3 ALUR trial.

Median investigator-assessed progression-free survival was 9.6 months with alectinib and 1.4 months with chemotherapy (hazard ratio, 0.15; P less than .001), reported Silvia Novello, MD, PhD, of University of Turin (Italy) and her associates. Among patients with measurable central nervous system disease, the rate of CNS objective response was significantly higher for alectinib (54%) versus chemotherapy (0%; P less than .001), Dr. Novello and her associates reported in Annals of Oncology.

The multicenter, open-label ALUR trial was the first to directly compare alectinib with standard chemotherapy in patients with ALK-rearranged NSCLC that previously had been treated with both platinum-based chemotherapy and crizotinib. In all, 107 patients were randomly assigned on a 2:1 basis to receive either alectinib (600 mg twice daily) or chemotherapy (clinician’s choice of pemetrexed 500 mg/m² or docetaxel 75 mg/m² every 3 weeks).

A blinded independent review committee calculated median progression-free survival (PFS) times that were 2.5 months shorter for alectinib and 0.2 months longer for chemotherapy. Consequently, the hazard ratio for PFS was somewhat attenuated at 0.32 but remained highly significant (95% confidence interval, 0.17-0.59). “[Median] PFS with alectinib in ALUR has exceeded that observed with [second-line] ceritinib” during the ASCEND-5 study, the researchers wrote. In ASCEND-5, median independent review committee–assessed PFS time was 5.4 months, which is 1.7 months shorter than that for alectinib in ALUR. In each study, chemotherapy yielded a median PFS time of 1.6 months, which facilitated intertrial comparisons, they wrote.

Rates of all-grade and serious adverse events were similar between arms in ALUR. Alectinib therapy caused no fatal adverse events, while chemotherapy was associated with one fatality deemed unrelated to treatment. Alectinib was more likely to produce constipation, dyspnea, and hyperbilirubinemia, while chemotherapy was more likely to cause nausea, alopecia, neutropenia, diarrhea, pruritus, stomatitis, and bacterial pneumonia. Although patients stayed on alectinib a median of 14 weeks longer than on chemotherapy, they were less likely to stop alectinib (6%) than chemotherapy (9%) for adverse events.

Dr. Novello disclosed personal fees from Roche, which markets alectinib. Eleven coinvestigators also disclosed employment, stock ownership, or other financial ties to Roche.

SOURCE: Novello S et al. Ann Oncol. 2018 Apr 14. doi: 10.1093/annonc/mdy121.

The second-generation anaplastic lymphoma kinase (ALK) inhibitor alectinib (Alcensa) topped chemotherapy in crizotinib-pretreated ALK+ non–small cell lung cancer (NSCLC), according to results from the phase 3 ALUR trial.

Median investigator-assessed progression-free survival was 9.6 months with alectinib and 1.4 months with chemotherapy (hazard ratio, 0.15; P less than .001), reported Silvia Novello, MD, PhD, of University of Turin (Italy) and her associates. Among patients with measurable central nervous system disease, the rate of CNS objective response was significantly higher for alectinib (54%) versus chemotherapy (0%; P less than .001), Dr. Novello and her associates reported in Annals of Oncology.

The multicenter, open-label ALUR trial was the first to directly compare alectinib with standard chemotherapy in patients with ALK-rearranged NSCLC that previously had been treated with both platinum-based chemotherapy and crizotinib. In all, 107 patients were randomly assigned on a 2:1 basis to receive either alectinib (600 mg twice daily) or chemotherapy (clinician’s choice of pemetrexed 500 mg/m² or docetaxel 75 mg/m² every 3 weeks).

A blinded independent review committee calculated median progression-free survival (PFS) times that were 2.5 months shorter for alectinib and 0.2 months longer for chemotherapy. Consequently, the hazard ratio for PFS was somewhat attenuated at 0.32 but remained highly significant (95% confidence interval, 0.17-0.59). “[Median] PFS with alectinib in ALUR has exceeded that observed with [second-line] ceritinib” during the ASCEND-5 study, the researchers wrote. In ASCEND-5, median independent review committee–assessed PFS time was 5.4 months, which is 1.7 months shorter than that for alectinib in ALUR. In each study, chemotherapy yielded a median PFS time of 1.6 months, which facilitated intertrial comparisons, they wrote.

Rates of all-grade and serious adverse events were similar between arms in ALUR. Alectinib therapy caused no fatal adverse events, while chemotherapy was associated with one fatality deemed unrelated to treatment. Alectinib was more likely to produce constipation, dyspnea, and hyperbilirubinemia, while chemotherapy was more likely to cause nausea, alopecia, neutropenia, diarrhea, pruritus, stomatitis, and bacterial pneumonia. Although patients stayed on alectinib a median of 14 weeks longer than on chemotherapy, they were less likely to stop alectinib (6%) than chemotherapy (9%) for adverse events.

Dr. Novello disclosed personal fees from Roche, which markets alectinib. Eleven coinvestigators also disclosed employment, stock ownership, or other financial ties to Roche.

SOURCE: Novello S et al. Ann Oncol. 2018 Apr 14. doi: 10.1093/annonc/mdy121.

For adults with metastatic, treatment-naive renal clear cell carcinoma, an alternate (2 weeks on, 1 week off) oral sunitinib schedule might be more tolerable than the approved 4:2 schedule, according to the results of a single-arm, multicenter, phase 2 trial.

After a median follow-up of 17 months, 25% of 59 patients had experienced grade 3 fatigue, hand-foot syndrome, or diarrhea, 37% had required dose reductions, and only 10% had stopped treatment because of toxicity. Rates of treatment discontinuation and dose reduction compared favorably with those seen with the 4:2 schedule in the pivotal COMPARZ (Pazopanib Versus Sunitinib in the Treatment of Locally Advanced and/or Metastatic Renal Cell Carcinoma) trial (37% and 51%, respectively), reported Eric Jonasch, MD, of the University of Texas MD Anderson Cancer Center, Houston, and his associates in the Journal of Clinical Oncology.

Sunitinib, a multitargeted receptor tyrosine kinase inhibitor, is standard first-line therapy for metastatic clear cell renal cell carcinoma. But side effects impede treatment, and moderate to severe diarrhea, fatigue, and hand-foot syndrome are especially hard to manage without dose-reducing or interrupting therapy. These and other toxicities tend to peak during the second half of the Food and Drug Administration–approved 4-week treatment cycle, the investigators noted. Building on retrospective studies that have reported less toxicity with an alternate 2:1 schedule, they powered their trial to test whether this schedule would produce grade 3 or worse diarrhea, fatigue, or hand-foot syndrome in no more than 15% of patients.

Despite missing this endpoint, “the initial 2:1 schedule and subsequent schedule and dose alterations ensured that 90% [of patients] could continue treatment and avoid protracted high-grade toxicities,” the investigators said. Sunitinib showed “robust” efficacy – a 57% overall response rate and 13.7-month median progression-free survival – even though most patients were intermediate risk (67%) or poor risk (10%), they added. The nonrandomized data support using the alternate 2:1 schedule to maintain quality of life and extend treatment duration, they concluded.

Pfizer makes sunitinib and funded the study. Dr. Jonasch disclosed research funding, travel reimbursement, and an advisory relationship with Pfizer.
 

SOURCE: Jonasch E et al. J Clin Oncol. 2018 Apr 11. doi: 10.1200/JCO.2017.77.1485.

For adults with metastatic, treatment-naive renal clear cell carcinoma, an alternate (2 weeks on, 1 week off) oral sunitinib schedule might be more tolerable than the approved 4:2 schedule, according to the results of a single-arm, multicenter, phase 2 trial.

After a median follow-up of 17 months, 25% of 59 patients had experienced grade 3 fatigue, hand-foot syndrome, or diarrhea, 37% had required dose reductions, and only 10% had stopped treatment because of toxicity. Rates of treatment discontinuation and dose reduction compared favorably with those seen with the 4:2 schedule in the pivotal COMPARZ (Pazopanib Versus Sunitinib in the Treatment of Locally Advanced and/or Metastatic Renal Cell Carcinoma) trial (37% and 51%, respectively), reported Eric Jonasch, MD, of the University of Texas MD Anderson Cancer Center, Houston, and his associates in the Journal of Clinical Oncology.

Sunitinib, a multitargeted receptor tyrosine kinase inhibitor, is standard first-line therapy for metastatic clear cell renal cell carcinoma. But side effects impede treatment, and moderate to severe diarrhea, fatigue, and hand-foot syndrome are especially hard to manage without dose-reducing or interrupting therapy. These and other toxicities tend to peak during the second half of the Food and Drug Administration–approved 4-week treatment cycle, the investigators noted. Building on retrospective studies that have reported less toxicity with an alternate 2:1 schedule, they powered their trial to test whether this schedule would produce grade 3 or worse diarrhea, fatigue, or hand-foot syndrome in no more than 15% of patients.

Despite missing this endpoint, “the initial 2:1 schedule and subsequent schedule and dose alterations ensured that 90% [of patients] could continue treatment and avoid protracted high-grade toxicities,” the investigators said. Sunitinib showed “robust” efficacy – a 57% overall response rate and 13.7-month median progression-free survival – even though most patients were intermediate risk (67%) or poor risk (10%), they added. The nonrandomized data support using the alternate 2:1 schedule to maintain quality of life and extend treatment duration, they concluded.

Pfizer makes sunitinib and funded the study. Dr. Jonasch disclosed research funding, travel reimbursement, and an advisory relationship with Pfizer.
 

SOURCE: Jonasch E et al. J Clin Oncol. 2018 Apr 11. doi: 10.1200/JCO.2017.77.1485.

For adults with metastatic, treatment-naive renal clear cell carcinoma, an alternate (2 weeks on, 1 week off) oral sunitinib schedule might be more tolerable than the approved 4:2 schedule, according to the results of a single-arm, multicenter, phase 2 trial.

After a median follow-up of 17 months, 25% of 59 patients had experienced grade 3 fatigue, hand-foot syndrome, or diarrhea, 37% had required dose reductions, and only 10% had stopped treatment because of toxicity. Rates of treatment discontinuation and dose reduction compared favorably with those seen with the 4:2 schedule in the pivotal COMPARZ (Pazopanib Versus Sunitinib in the Treatment of Locally Advanced and/or Metastatic Renal Cell Carcinoma) trial (37% and 51%, respectively), reported Eric Jonasch, MD, of the University of Texas MD Anderson Cancer Center, Houston, and his associates in the Journal of Clinical Oncology.

Sunitinib, a multitargeted receptor tyrosine kinase inhibitor, is standard first-line therapy for metastatic clear cell renal cell carcinoma. But side effects impede treatment, and moderate to severe diarrhea, fatigue, and hand-foot syndrome are especially hard to manage without dose-reducing or interrupting therapy. These and other toxicities tend to peak during the second half of the Food and Drug Administration–approved 4-week treatment cycle, the investigators noted. Building on retrospective studies that have reported less toxicity with an alternate 2:1 schedule, they powered their trial to test whether this schedule would produce grade 3 or worse diarrhea, fatigue, or hand-foot syndrome in no more than 15% of patients.

Despite missing this endpoint, “the initial 2:1 schedule and subsequent schedule and dose alterations ensured that 90% [of patients] could continue treatment and avoid protracted high-grade toxicities,” the investigators said. Sunitinib showed “robust” efficacy – a 57% overall response rate and 13.7-month median progression-free survival – even though most patients were intermediate risk (67%) or poor risk (10%), they added. The nonrandomized data support using the alternate 2:1 schedule to maintain quality of life and extend treatment duration, they concluded.

Pfizer makes sunitinib and funded the study. Dr. Jonasch disclosed research funding, travel reimbursement, and an advisory relationship with Pfizer.
 

SOURCE: Jonasch E et al. J Clin Oncol. 2018 Apr 11. doi: 10.1200/JCO.2017.77.1485.

Intra-amniotic therapy with a novel recombinant protein enabled three patients with X-linked hypohidrotic ectodermal dysplasia (XLHED) to sweat normally, researchers reported.

For up to 22 months of postnatal follow-up, patients had no hyperthermia and were not hospitalized for respiratory reasons, reported Holm Schneider, MD, of the University of Erlangen-Nürnberg, Erlangen, Germany, and his associates. Treatment may have induced premature delivery at 33 weeks of a pair of twins, although most twins are born preterm, they noted. “Combined with the ability to identify affected fetuses through noninvasive sonographic prenatal screening, the approach we describe here represents a new means of protein-replacement therapy to correct XLHED,” they wrote online April 25 in the New England Journal of Medicine.

XLHED is caused by loss-of-function variants of the gene encoding ectodysplasin A (EDA). The investigational recombinant fusion protein Fc-EDA (EDI200) developed by Edimer Pharmaceuticals, which contains the receptor-binding domain of EDA and the Fc domain of human immunoglobulin G1, has shown no signs of toxicity in nonhuman primates. In prior studies, its intra-amniotic infusion prevented XLHED in EDA-deficient murine fetuses, while human postnatal Fc-EDA therapy was ineffective (NCT01775462).

Based on these data, University Hospital Erlangan approved a parental request for compassionate use of Fc-EDA in male twin fetuses with genetic deficiency of EDA. Treatment (100 mg/kg estimated fetal body weight) occurred at gestational weeks 26 and 31. Despite premature delivery at 33 weeks, 5-minute Apgar scores were 9 for one twin and 10 for the other. Cord blood testing detected Fc-EDA, suggesting its continuous uptake into fetal blood. The twins both had normal sweat-duct density, sweated as much as healthy controls, salivated normally, and had 8-10 tooth germs; their 5-year-old brother with XLHED had only three teeth and one tooth germ.

Parents of another EDA-deficient fetus also requested compassionate use of Fc-EDA, which was administrated as a single dose (because of limited supply) at gestational week 26. Birth occurred at week 39 and Apgar scores all were 10s. Sweat pore density was slightly low, compared with healthy controls, and by age 4 months, the patient had developed moderate urticaria pigmentosa.

In all cases, maternal circulation showed no trace of Fc-EDA within 24 hours of treatment.

Funders included Edimer Pharmaceuticals, Deutsche Forschungsgemeinschaft, Swiss National Science Foundation, the German-Swiss-Austrian ectodermal dysplasia patient organization, and the National Foundation for Ectodermal Dysplasias. Three of the investigators have either patents issued or patents pending related to the treatment, one is an employee of Edimer Pharmaceuticals, and two have grants from some of the abovementioned companies or organizations.
 

SOURCE: Schneider H et al. N Engl J Med. 2018 Apr 25. doi: 10.1056/NEJMoa1714322.

Intra-amniotic therapy with a novel recombinant protein enabled three patients with X-linked hypohidrotic ectodermal dysplasia (XLHED) to sweat normally, researchers reported.

For up to 22 months of postnatal follow-up, patients had no hyperthermia and were not hospitalized for respiratory reasons, reported Holm Schneider, MD, of the University of Erlangen-Nürnberg, Erlangen, Germany, and his associates. Treatment may have induced premature delivery at 33 weeks of a pair of twins, although most twins are born preterm, they noted. “Combined with the ability to identify affected fetuses through noninvasive sonographic prenatal screening, the approach we describe here represents a new means of protein-replacement therapy to correct XLHED,” they wrote online April 25 in the New England Journal of Medicine.

XLHED is caused by loss-of-function variants of the gene encoding ectodysplasin A (EDA). The investigational recombinant fusion protein Fc-EDA (EDI200) developed by Edimer Pharmaceuticals, which contains the receptor-binding domain of EDA and the Fc domain of human immunoglobulin G1, has shown no signs of toxicity in nonhuman primates. In prior studies, its intra-amniotic infusion prevented XLHED in EDA-deficient murine fetuses, while human postnatal Fc-EDA therapy was ineffective (NCT01775462).

Based on these data, University Hospital Erlangan approved a parental request for compassionate use of Fc-EDA in male twin fetuses with genetic deficiency of EDA. Treatment (100 mg/kg estimated fetal body weight) occurred at gestational weeks 26 and 31. Despite premature delivery at 33 weeks, 5-minute Apgar scores were 9 for one twin and 10 for the other. Cord blood testing detected Fc-EDA, suggesting its continuous uptake into fetal blood. The twins both had normal sweat-duct density, sweated as much as healthy controls, salivated normally, and had 8-10 tooth germs; their 5-year-old brother with XLHED had only three teeth and one tooth germ.

Parents of another EDA-deficient fetus also requested compassionate use of Fc-EDA, which was administrated as a single dose (because of limited supply) at gestational week 26. Birth occurred at week 39 and Apgar scores all were 10s. Sweat pore density was slightly low, compared with healthy controls, and by age 4 months, the patient had developed moderate urticaria pigmentosa.

In all cases, maternal circulation showed no trace of Fc-EDA within 24 hours of treatment.

Funders included Edimer Pharmaceuticals, Deutsche Forschungsgemeinschaft, Swiss National Science Foundation, the German-Swiss-Austrian ectodermal dysplasia patient organization, and the National Foundation for Ectodermal Dysplasias. Three of the investigators have either patents issued or patents pending related to the treatment, one is an employee of Edimer Pharmaceuticals, and two have grants from some of the abovementioned companies or organizations.
 

SOURCE: Schneider H et al. N Engl J Med. 2018 Apr 25. doi: 10.1056/NEJMoa1714322.

Intra-amniotic therapy with a novel recombinant protein enabled three patients with X-linked hypohidrotic ectodermal dysplasia (XLHED) to sweat normally, researchers reported.

For up to 22 months of postnatal follow-up, patients had no hyperthermia and were not hospitalized for respiratory reasons, reported Holm Schneider, MD, of the University of Erlangen-Nürnberg, Erlangen, Germany, and his associates. Treatment may have induced premature delivery at 33 weeks of a pair of twins, although most twins are born preterm, they noted. “Combined with the ability to identify affected fetuses through noninvasive sonographic prenatal screening, the approach we describe here represents a new means of protein-replacement therapy to correct XLHED,” they wrote online April 25 in the New England Journal of Medicine.

XLHED is caused by loss-of-function variants of the gene encoding ectodysplasin A (EDA). The investigational recombinant fusion protein Fc-EDA (EDI200) developed by Edimer Pharmaceuticals, which contains the receptor-binding domain of EDA and the Fc domain of human immunoglobulin G1, has shown no signs of toxicity in nonhuman primates. In prior studies, its intra-amniotic infusion prevented XLHED in EDA-deficient murine fetuses, while human postnatal Fc-EDA therapy was ineffective (NCT01775462).

Based on these data, University Hospital Erlangan approved a parental request for compassionate use of Fc-EDA in male twin fetuses with genetic deficiency of EDA. Treatment (100 mg/kg estimated fetal body weight) occurred at gestational weeks 26 and 31. Despite premature delivery at 33 weeks, 5-minute Apgar scores were 9 for one twin and 10 for the other. Cord blood testing detected Fc-EDA, suggesting its continuous uptake into fetal blood. The twins both had normal sweat-duct density, sweated as much as healthy controls, salivated normally, and had 8-10 tooth germs; their 5-year-old brother with XLHED had only three teeth and one tooth germ.

Parents of another EDA-deficient fetus also requested compassionate use of Fc-EDA, which was administrated as a single dose (because of limited supply) at gestational week 26. Birth occurred at week 39 and Apgar scores all were 10s. Sweat pore density was slightly low, compared with healthy controls, and by age 4 months, the patient had developed moderate urticaria pigmentosa.

In all cases, maternal circulation showed no trace of Fc-EDA within 24 hours of treatment.

Funders included Edimer Pharmaceuticals, Deutsche Forschungsgemeinschaft, Swiss National Science Foundation, the German-Swiss-Austrian ectodermal dysplasia patient organization, and the National Foundation for Ectodermal Dysplasias. Three of the investigators have either patents issued or patents pending related to the treatment, one is an employee of Edimer Pharmaceuticals, and two have grants from some of the abovementioned companies or organizations.
 

SOURCE: Schneider H et al. N Engl J Med. 2018 Apr 25. doi: 10.1056/NEJMoa1714322.

Patients with inflammatory bowel disease had about a 28% higher risk of Parkinson’s disease (PD) than that of matched controls in a large retrospective analysis of administrative health care claims.

But tumor necrosis factor (TNF) inhibitor therapy appeared to attenuate this risk, wrote Inga Peter, PhD, of Icahn School of Medicine at Mount Sinai, New York, and her associates. Patients with inflammatory bowel disease (IBD) who received TNF inhibitors were 78% less likely to develop PD than were those who did not (P = .03). “Reducing systemic inflammation in at-risk individuals may decrease the incidence of PD [Parkinson disease],” the researchers wrote. The study was published online April 23 in JAMA Neurology.

The researchers queried the Truven Health MarketScan database and the Medicare Supplemental Database for patients with IBD from 2000 through 2016. The databases included more than 170 million patients, of whom 144,018 had at least two IBD-related claims, at least 6 months of follow-up, and no baseline PD diagnosis. These patients were matched by age, sex, and treatment year with 720,090 individuals without IBD from the same databases.

A total of 1,796 patients had at least two recorded PD diagnoses and had filled at least one associated prescription, said the researchers. Based on this PD definition, patients with IBD developed PD at a 28% higher rate than that of matched controls (adjusted IRR, 1.28; 95% CI, 1.14 to 1.44; P less than .001).

Among the IBD patients, those receiving anti-TNF therapy developed about 0.08 cases of PD for every 1,000 person-years, versus 0.76 PD cases per 1,000 person-years in the group not receiving anti-TNF therapy. After adjustment for age, sex, and time at risk, anti-TNF therapy was associated with a 78% reduction in the incidence of PD among IBD patients (adjusted incidence rate ratio, 0.22; 95% confidence interval, 0.05-0.88; P = .03).

“In summary, we showed a potential clinical link between IBD and PD, supporting shared mechanisms involved in the pathogenesis of these diseases,” the researchers wrote. “Moreover, our data suggest that early exposure to anti-TNF therapy may reduce the risk of PD among patients with IBD, potentially owing to a reduction in systemic inflammation. These findings should be further assessed and confirmed by other studies.”

Dr. Peter received support from the Leona M. and Harry B. Helmsley Charitable Trust. AbbVie employed three coinvestigators. Two coinvestigators had other ties to Abbvie and Amgen.

SOURCE: Peter I et al. JAMA Neurol. 2018 Apr 23. doi: 10.1001/jamaneurol.2018.0605.

Patients with inflammatory bowel disease had about a 28% higher risk of Parkinson’s disease (PD) than that of matched controls in a large retrospective analysis of administrative health care claims.

But tumor necrosis factor (TNF) inhibitor therapy appeared to attenuate this risk, wrote Inga Peter, PhD, of Icahn School of Medicine at Mount Sinai, New York, and her associates. Patients with inflammatory bowel disease (IBD) who received TNF inhibitors were 78% less likely to develop PD than were those who did not (P = .03). “Reducing systemic inflammation in at-risk individuals may decrease the incidence of PD [Parkinson disease],” the researchers wrote. The study was published online April 23 in JAMA Neurology.

The researchers queried the Truven Health MarketScan database and the Medicare Supplemental Database for patients with IBD from 2000 through 2016. The databases included more than 170 million patients, of whom 144,018 had at least two IBD-related claims, at least 6 months of follow-up, and no baseline PD diagnosis. These patients were matched by age, sex, and treatment year with 720,090 individuals without IBD from the same databases.

A total of 1,796 patients had at least two recorded PD diagnoses and had filled at least one associated prescription, said the researchers. Based on this PD definition, patients with IBD developed PD at a 28% higher rate than that of matched controls (adjusted IRR, 1.28; 95% CI, 1.14 to 1.44; P less than .001).

Among the IBD patients, those receiving anti-TNF therapy developed about 0.08 cases of PD for every 1,000 person-years, versus 0.76 PD cases per 1,000 person-years in the group not receiving anti-TNF therapy. After adjustment for age, sex, and time at risk, anti-TNF therapy was associated with a 78% reduction in the incidence of PD among IBD patients (adjusted incidence rate ratio, 0.22; 95% confidence interval, 0.05-0.88; P = .03).

“In summary, we showed a potential clinical link between IBD and PD, supporting shared mechanisms involved in the pathogenesis of these diseases,” the researchers wrote. “Moreover, our data suggest that early exposure to anti-TNF therapy may reduce the risk of PD among patients with IBD, potentially owing to a reduction in systemic inflammation. These findings should be further assessed and confirmed by other studies.”

Dr. Peter received support from the Leona M. and Harry B. Helmsley Charitable Trust. AbbVie employed three coinvestigators. Two coinvestigators had other ties to Abbvie and Amgen.

SOURCE: Peter I et al. JAMA Neurol. 2018 Apr 23. doi: 10.1001/jamaneurol.2018.0605.

Patients with inflammatory bowel disease had about a 28% higher risk of Parkinson’s disease (PD) than that of matched controls in a large retrospective analysis of administrative health care claims.

But tumor necrosis factor (TNF) inhibitor therapy appeared to attenuate this risk, wrote Inga Peter, PhD, of Icahn School of Medicine at Mount Sinai, New York, and her associates. Patients with inflammatory bowel disease (IBD) who received TNF inhibitors were 78% less likely to develop PD than were those who did not (P = .03). “Reducing systemic inflammation in at-risk individuals may decrease the incidence of PD [Parkinson disease],” the researchers wrote. The study was published online April 23 in JAMA Neurology.

The researchers queried the Truven Health MarketScan database and the Medicare Supplemental Database for patients with IBD from 2000 through 2016. The databases included more than 170 million patients, of whom 144,018 had at least two IBD-related claims, at least 6 months of follow-up, and no baseline PD diagnosis. These patients were matched by age, sex, and treatment year with 720,090 individuals without IBD from the same databases.

A total of 1,796 patients had at least two recorded PD diagnoses and had filled at least one associated prescription, said the researchers. Based on this PD definition, patients with IBD developed PD at a 28% higher rate than that of matched controls (adjusted IRR, 1.28; 95% CI, 1.14 to 1.44; P less than .001).

Among the IBD patients, those receiving anti-TNF therapy developed about 0.08 cases of PD for every 1,000 person-years, versus 0.76 PD cases per 1,000 person-years in the group not receiving anti-TNF therapy. After adjustment for age, sex, and time at risk, anti-TNF therapy was associated with a 78% reduction in the incidence of PD among IBD patients (adjusted incidence rate ratio, 0.22; 95% confidence interval, 0.05-0.88; P = .03).

“In summary, we showed a potential clinical link between IBD and PD, supporting shared mechanisms involved in the pathogenesis of these diseases,” the researchers wrote. “Moreover, our data suggest that early exposure to anti-TNF therapy may reduce the risk of PD among patients with IBD, potentially owing to a reduction in systemic inflammation. These findings should be further assessed and confirmed by other studies.”

Dr. Peter received support from the Leona M. and Harry B. Helmsley Charitable Trust. AbbVie employed three coinvestigators. Two coinvestigators had other ties to Abbvie and Amgen.

SOURCE: Peter I et al. JAMA Neurol. 2018 Apr 23. doi: 10.1001/jamaneurol.2018.0605.

For adults whose stage T3 or greater rectal cancer shows a pathological complete response to neoadjuvant chemoradiation and resection, perioperative adjuvant therapy was associated with significantly improved outcomes, according to the results of two observational cohort studies of the National Cancer Database.

In the first study, Fahima Dossa, MD, of the University of Toronto, and her associates compared 667 patients with T1 to 2N+ or T3 to 4N0/+ rectal adenocarcinoma who received adjuvant chemotherapy with 667 patients who did not. They used propensity-score matching to account for measurable differences between groups that might influence the receipt of adjuvant treatment. They also conducted a subgroup analysis to determine if treatment effects depended on whether patients initially had node-positive disease.

After a median follow-up of 3.1 years (interquartile range, 1.9-4.4 years), adjuvant therapy was associated with significantly improved overall survival (hazard ratio, 0.44; 95% confidence interval, 0.28-0.70), Dr. Dossa and her coinvestigators said. However, the effect was limited to patients with pretreatment, node-positive disease (HR, 0.24; 95% CI, 0.10-0.58).

“Although this study suggests a beneficial effect of adjuvant treatment on survival in patients with pathologic[al] complete response, these results are limited by the presence of potential unmeasured confounding in this nonrandomized study,” Dr. Dossa and her associates wrote in JAMA Oncology. A pathological complete response signifies a good prognosis in locally advanced rectal cancer, and any additional survival benefit from adjuvant chemotherapy has to be weighed against the risk of chemotoxicity, they stressed. (In their study, 5-year overall survival rates were 95% in the adjuvant group and 88% in the observation-only group).

In the second study, Patricio M. Polanco, MD, of the University of Texas, Dallas, and his associates also used propensity-score matching to compare 741 patients with clinical TNM stages T1 to 2N+ or T3 to 4N0/+ rectal adenocarcinoma who received adjuvant chemotherapy with 741 patients who underwent observation only. Once again, after a median follow-up of 3.2 years, adjuvant chemotherapy was associated with significantly improved overall survival (HR, 0.50; 95% CI, 0.32-0.79). Estimated 5-year overall survival rates were 95% and 88%, respectively (P = .05). Subgroup analyses showed that adjuvant chemotherapy had the strongest apparent effect in the setting of stage T3/T4 and node-positive disease.

Current U.S. guidelines recommend treating stage T3 or higher or node-positive rectal cancer with neoadjuvant chemoradiation therapy plus 6 months of perioperative chemotherapy. Each of these studies attempted to address the lack of evidence clearly supporting adjuvant chemotherapy for these patients, the researchers noted.

Dr. Fossa and her associates reported no specific funders or conflicts of interests. Dr. Polanco disclosed support from the VA North Texas New Investigator Program, Department of Veterans Affairs. He and his associates reported no conflicts of interest.

SOURCES: Dossa F et al. JAMA Oncol. 2018 Apr 19. doi: 10.1001/jamaoncol.2017.5597; Polanco PM et al. JAMA Oncol. 2018 Apr 19. doi: 10.1001/jamaoncol.2018.0231.

For adults whose stage T3 or greater rectal cancer shows a pathological complete response to neoadjuvant chemoradiation and resection, perioperative adjuvant therapy was associated with significantly improved outcomes, according to the results of two observational cohort studies of the National Cancer Database.

In the first study, Fahima Dossa, MD, of the University of Toronto, and her associates compared 667 patients with T1 to 2N+ or T3 to 4N0/+ rectal adenocarcinoma who received adjuvant chemotherapy with 667 patients who did not. They used propensity-score matching to account for measurable differences between groups that might influence the receipt of adjuvant treatment. They also conducted a subgroup analysis to determine if treatment effects depended on whether patients initially had node-positive disease.

After a median follow-up of 3.1 years (interquartile range, 1.9-4.4 years), adjuvant therapy was associated with significantly improved overall survival (hazard ratio, 0.44; 95% confidence interval, 0.28-0.70), Dr. Dossa and her coinvestigators said. However, the effect was limited to patients with pretreatment, node-positive disease (HR, 0.24; 95% CI, 0.10-0.58).

“Although this study suggests a beneficial effect of adjuvant treatment on survival in patients with pathologic[al] complete response, these results are limited by the presence of potential unmeasured confounding in this nonrandomized study,” Dr. Dossa and her associates wrote in JAMA Oncology. A pathological complete response signifies a good prognosis in locally advanced rectal cancer, and any additional survival benefit from adjuvant chemotherapy has to be weighed against the risk of chemotoxicity, they stressed. (In their study, 5-year overall survival rates were 95% in the adjuvant group and 88% in the observation-only group).

In the second study, Patricio M. Polanco, MD, of the University of Texas, Dallas, and his associates also used propensity-score matching to compare 741 patients with clinical TNM stages T1 to 2N+ or T3 to 4N0/+ rectal adenocarcinoma who received adjuvant chemotherapy with 741 patients who underwent observation only. Once again, after a median follow-up of 3.2 years, adjuvant chemotherapy was associated with significantly improved overall survival (HR, 0.50; 95% CI, 0.32-0.79). Estimated 5-year overall survival rates were 95% and 88%, respectively (P = .05). Subgroup analyses showed that adjuvant chemotherapy had the strongest apparent effect in the setting of stage T3/T4 and node-positive disease.

Current U.S. guidelines recommend treating stage T3 or higher or node-positive rectal cancer with neoadjuvant chemoradiation therapy plus 6 months of perioperative chemotherapy. Each of these studies attempted to address the lack of evidence clearly supporting adjuvant chemotherapy for these patients, the researchers noted.

Dr. Fossa and her associates reported no specific funders or conflicts of interests. Dr. Polanco disclosed support from the VA North Texas New Investigator Program, Department of Veterans Affairs. He and his associates reported no conflicts of interest.

SOURCES: Dossa F et al. JAMA Oncol. 2018 Apr 19. doi: 10.1001/jamaoncol.2017.5597; Polanco PM et al. JAMA Oncol. 2018 Apr 19. doi: 10.1001/jamaoncol.2018.0231.

For adults whose stage T3 or greater rectal cancer shows a pathological complete response to neoadjuvant chemoradiation and resection, perioperative adjuvant therapy was associated with significantly improved outcomes, according to the results of two observational cohort studies of the National Cancer Database.

In the first study, Fahima Dossa, MD, of the University of Toronto, and her associates compared 667 patients with T1 to 2N+ or T3 to 4N0/+ rectal adenocarcinoma who received adjuvant chemotherapy with 667 patients who did not. They used propensity-score matching to account for measurable differences between groups that might influence the receipt of adjuvant treatment. They also conducted a subgroup analysis to determine if treatment effects depended on whether patients initially had node-positive disease.

After a median follow-up of 3.1 years (interquartile range, 1.9-4.4 years), adjuvant therapy was associated with significantly improved overall survival (hazard ratio, 0.44; 95% confidence interval, 0.28-0.70), Dr. Dossa and her coinvestigators said. However, the effect was limited to patients with pretreatment, node-positive disease (HR, 0.24; 95% CI, 0.10-0.58).

“Although this study suggests a beneficial effect of adjuvant treatment on survival in patients with pathologic[al] complete response, these results are limited by the presence of potential unmeasured confounding in this nonrandomized study,” Dr. Dossa and her associates wrote in JAMA Oncology. A pathological complete response signifies a good prognosis in locally advanced rectal cancer, and any additional survival benefit from adjuvant chemotherapy has to be weighed against the risk of chemotoxicity, they stressed. (In their study, 5-year overall survival rates were 95% in the adjuvant group and 88% in the observation-only group).

In the second study, Patricio M. Polanco, MD, of the University of Texas, Dallas, and his associates also used propensity-score matching to compare 741 patients with clinical TNM stages T1 to 2N+ or T3 to 4N0/+ rectal adenocarcinoma who received adjuvant chemotherapy with 741 patients who underwent observation only. Once again, after a median follow-up of 3.2 years, adjuvant chemotherapy was associated with significantly improved overall survival (HR, 0.50; 95% CI, 0.32-0.79). Estimated 5-year overall survival rates were 95% and 88%, respectively (P = .05). Subgroup analyses showed that adjuvant chemotherapy had the strongest apparent effect in the setting of stage T3/T4 and node-positive disease.

Current U.S. guidelines recommend treating stage T3 or higher or node-positive rectal cancer with neoadjuvant chemoradiation therapy plus 6 months of perioperative chemotherapy. Each of these studies attempted to address the lack of evidence clearly supporting adjuvant chemotherapy for these patients, the researchers noted.

Dr. Fossa and her associates reported no specific funders or conflicts of interests. Dr. Polanco disclosed support from the VA North Texas New Investigator Program, Department of Veterans Affairs. He and his associates reported no conflicts of interest.

SOURCES: Dossa F et al. JAMA Oncol. 2018 Apr 19. doi: 10.1001/jamaoncol.2017.5597; Polanco PM et al. JAMA Oncol. 2018 Apr 19. doi: 10.1001/jamaoncol.2018.0231.

Tailoring chemoradiation therapy while minimizing anthracycline exposure produced strong survival results in stage IV favorable histology Wilms tumor (FHWT), according to new results from the Children’s Oncology Group AREN0533 study.

In the new regimen, patients whose isolated lung nodules completely respond to 6 weeks of vincristine/dactinomycin/doxorubicin (DD4A) therapy continue DD4A and forgo lung radiation therapy (RT), explained David B. Dix, MBChB, of British Columbia Children’s Hospital, Vancouver, B.C., and his associates. Incomplete responders and patients with loss of heterozygosity at chromosomes 1p/16q receive lung RT plus boosted chemotherapy consisting of DD4 plus four cycles of cyclophosphamide/etoposide (Regimen M).

Among 133 assessable complete responders who received the DD4A regimen and were followed for a median of 4.7 years, 4-year event-free survival (EFS) was 79.5% (95% confidence interval, 71%-88%) and 4-year overall survival (OS) was 96% (95% CI, 92%-100%), Dr. Dix and his associates wrote. The report was published in the Journal of Clinical Oncology.

Among 159 incomplete responders receiving Regimen M, 4-year EFS was 88.5% (95% CI, 82%-95%) and 4-year OS was 95% (95% CI, 91%-100%). Regimen M produced superior EFS and OS (P less than .001 for both comparisons) than the protocol used in the National Wilms Tumor Study (NWTS) 5 study, in which all patients with lung metastases received DD4A plus RT, regardless of lung nodule response. “These results provide a benchmark for future studies,” Dr. Dix and his associates concluded.

Most patients with FHWT have pulmonary metastases and historically have fared worse than peers with localized disease. Until now, patients have had two main treatment options. The Society of Pediatric Oncology (SIOP) protocol focuses on pre-nephrectomy DD4A and forgoes lung RT if chemotherapy or surgical resection achieves lung nodule CR. Patients in the most recently reported SIOP trial (93-01) received a high cumulative anthracycline dose of 350 mg/m² and had 5-year EFS of 77% and 5-year OS of 87%. The second option – the NWTS protocol – more than halves the cumulative doxorubicin dose (150 mg/m²), but all patients undergo lung RT.

In contrast, the AREN0533 protocol involved cumulative doxorubicin doses of 150 mg/m² for DD4A and 195 mg/m² for Regimen M. Among complete responders, the expected event rate was 15% and the actual rate was 20% (P = .05). Among incomplete responders, observed and expected event rates were 25% and. 12%, respectively (P less than .001). The higher-than-expected event rates might stem from lower chemotherapy doses, but the SIOP study also did not include central image review and may have defined CR less stringently, Dr. Dix and his coinvestigators said.

They concluded that AREN0533 showed “excellent” survival results for patients with CR and that certain late risks of Regimen M – including an increased risk of leukemia from exposure to cyclophosphamide and etoposide – should be balanced against its superior 4-year EFS.

SOURCE: Dix DB et al. J Clin Oncol. 2018 Apr 11. doi: 10.1200/JCO. 2017.77.1931.

Tailoring chemoradiation therapy while minimizing anthracycline exposure produced strong survival results in stage IV favorable histology Wilms tumor (FHWT), according to new results from the Children’s Oncology Group AREN0533 study.

In the new regimen, patients whose isolated lung nodules completely respond to 6 weeks of vincristine/dactinomycin/doxorubicin (DD4A) therapy continue DD4A and forgo lung radiation therapy (RT), explained David B. Dix, MBChB, of British Columbia Children’s Hospital, Vancouver, B.C., and his associates. Incomplete responders and patients with loss of heterozygosity at chromosomes 1p/16q receive lung RT plus boosted chemotherapy consisting of DD4 plus four cycles of cyclophosphamide/etoposide (Regimen M).

Among 133 assessable complete responders who received the DD4A regimen and were followed for a median of 4.7 years, 4-year event-free survival (EFS) was 79.5% (95% confidence interval, 71%-88%) and 4-year overall survival (OS) was 96% (95% CI, 92%-100%), Dr. Dix and his associates wrote. The report was published in the Journal of Clinical Oncology.

Among 159 incomplete responders receiving Regimen M, 4-year EFS was 88.5% (95% CI, 82%-95%) and 4-year OS was 95% (95% CI, 91%-100%). Regimen M produced superior EFS and OS (P less than .001 for both comparisons) than the protocol used in the National Wilms Tumor Study (NWTS) 5 study, in which all patients with lung metastases received DD4A plus RT, regardless of lung nodule response. “These results provide a benchmark for future studies,” Dr. Dix and his associates concluded.

Most patients with FHWT have pulmonary metastases and historically have fared worse than peers with localized disease. Until now, patients have had two main treatment options. The Society of Pediatric Oncology (SIOP) protocol focuses on pre-nephrectomy DD4A and forgoes lung RT if chemotherapy or surgical resection achieves lung nodule CR. Patients in the most recently reported SIOP trial (93-01) received a high cumulative anthracycline dose of 350 mg/m² and had 5-year EFS of 77% and 5-year OS of 87%. The second option – the NWTS protocol – more than halves the cumulative doxorubicin dose (150 mg/m²), but all patients undergo lung RT.

In contrast, the AREN0533 protocol involved cumulative doxorubicin doses of 150 mg/m² for DD4A and 195 mg/m² for Regimen M. Among complete responders, the expected event rate was 15% and the actual rate was 20% (P = .05). Among incomplete responders, observed and expected event rates were 25% and. 12%, respectively (P less than .001). The higher-than-expected event rates might stem from lower chemotherapy doses, but the SIOP study also did not include central image review and may have defined CR less stringently, Dr. Dix and his coinvestigators said.

They concluded that AREN0533 showed “excellent” survival results for patients with CR and that certain late risks of Regimen M – including an increased risk of leukemia from exposure to cyclophosphamide and etoposide – should be balanced against its superior 4-year EFS.

SOURCE: Dix DB et al. J Clin Oncol. 2018 Apr 11. doi: 10.1200/JCO. 2017.77.1931.

Tailoring chemoradiation therapy while minimizing anthracycline exposure produced strong survival results in stage IV favorable histology Wilms tumor (FHWT), according to new results from the Children’s Oncology Group AREN0533 study.

In the new regimen, patients whose isolated lung nodules completely respond to 6 weeks of vincristine/dactinomycin/doxorubicin (DD4A) therapy continue DD4A and forgo lung radiation therapy (RT), explained David B. Dix, MBChB, of British Columbia Children’s Hospital, Vancouver, B.C., and his associates. Incomplete responders and patients with loss of heterozygosity at chromosomes 1p/16q receive lung RT plus boosted chemotherapy consisting of DD4 plus four cycles of cyclophosphamide/etoposide (Regimen M).

Among 133 assessable complete responders who received the DD4A regimen and were followed for a median of 4.7 years, 4-year event-free survival (EFS) was 79.5% (95% confidence interval, 71%-88%) and 4-year overall survival (OS) was 96% (95% CI, 92%-100%), Dr. Dix and his associates wrote. The report was published in the Journal of Clinical Oncology.

Among 159 incomplete responders receiving Regimen M, 4-year EFS was 88.5% (95% CI, 82%-95%) and 4-year OS was 95% (95% CI, 91%-100%). Regimen M produced superior EFS and OS (P less than .001 for both comparisons) than the protocol used in the National Wilms Tumor Study (NWTS) 5 study, in which all patients with lung metastases received DD4A plus RT, regardless of lung nodule response. “These results provide a benchmark for future studies,” Dr. Dix and his associates concluded.

Most patients with FHWT have pulmonary metastases and historically have fared worse than peers with localized disease. Until now, patients have had two main treatment options. The Society of Pediatric Oncology (SIOP) protocol focuses on pre-nephrectomy DD4A and forgoes lung RT if chemotherapy or surgical resection achieves lung nodule CR. Patients in the most recently reported SIOP trial (93-01) received a high cumulative anthracycline dose of 350 mg/m² and had 5-year EFS of 77% and 5-year OS of 87%. The second option – the NWTS protocol – more than halves the cumulative doxorubicin dose (150 mg/m²), but all patients undergo lung RT.

In contrast, the AREN0533 protocol involved cumulative doxorubicin doses of 150 mg/m² for DD4A and 195 mg/m² for Regimen M. Among complete responders, the expected event rate was 15% and the actual rate was 20% (P = .05). Among incomplete responders, observed and expected event rates were 25% and. 12%, respectively (P less than .001). The higher-than-expected event rates might stem from lower chemotherapy doses, but the SIOP study also did not include central image review and may have defined CR less stringently, Dr. Dix and his coinvestigators said.

They concluded that AREN0533 showed “excellent” survival results for patients with CR and that certain late risks of Regimen M – including an increased risk of leukemia from exposure to cyclophosphamide and etoposide – should be balanced against its superior 4-year EFS.

SOURCE: Dix DB et al. J Clin Oncol. 2018 Apr 11. doi: 10.1200/JCO. 2017.77.1931.

Rheumatoid arthritis, psoriatic arthritis, and axial spondyloarthritis were linked to similarly increased risks of major adverse cardiovascular events in a large population-based cohort study.

Inflammation itself drives this relationship and “adequate control of disease activity is needed to lower cardiovascular risk,” wrote Kim Lauper, MD, of Geneva University Hospitals, and her coinvestigators.

Major adverse cardiovascular events (MACE) also were significantly associated with traditional cardiovascular risk factors such as smoking, hypertension, and hyperlipidemia, “stressing the importance of [their] detection and management,” the researchers wrote in Arthritis Care and Research.

Previous studies linked inflammatory arthritis to a 40%-50% increase in risk of cardiovascular events, such as MI and acute coronary syndrome. Inflammatory arthritis also increases the risk of cerebrovascular disease, and traditional cardiovascular risk factors alone do not explain these associations, the researchers noted. Mounting data suggest that inflammation underlies the pathogenesis of atherosclerosis. Other studies have documented the cardioprotective effect of disease-modifying antirheumatic drugs (DMARDs) in patients with rheumatoid arthritis and psoriasis.

Dr. Lauper and her coinvestigators examined the prevalence and incidence of MACE, including MI, transient or permanent cerebrovascular events, or cardiovascular deaths among patients with rheumatoid arthritis, psoriatic arthritis, or spondyloarthritis. The 5,315 patients in the study were part of the Swiss Clinical Quality Management registry, which longitudinally tracks individuals throughout Switzerland who receive biologic DMARDs.

The investigators also asked rheumatologists to supply missing data and used a questionnaire to survey patients about cardiovascular events and associated risk factors. These efforts produced more than 66,000 patient-years of follow-up data, more than half of which were for rheumatoid arthritis and less than 10,000 of which were for psoriatic arthritis.

Among all patients, independent risk factors for MACE included older age (P less than .001), disease duration (P = .002), male gender (P less than .001), family history of MACE (P = .03), personal history of hyperlipidemia (P less than .001), and hypertension (P = .04). In contrast, there was no link between MACE and use of NSAIDs. “Similarly, a recent Taiwanese nationwide study did not find an increase in coronary disease in patients taking etoricoxib or celecoxib after adjustment for gender, age, comorbidities, hypertension, hyperlipidemia, and DMARDs,” the researchers wrote.Dr. Lauper reported having no conflicts of interest. The senior author and two coinvestigators disclosed ties to Roche, Abbvie, Pfizer, and several other pharmaceutical companies.

SOURCE: Lauper K et al. Arthritis Care Res. 2018 Apr 2. doi: 10.1002/acr.23567.

Rheumatoid arthritis, psoriatic arthritis, and axial spondyloarthritis were linked to similarly increased risks of major adverse cardiovascular events in a large population-based cohort study.

Inflammation itself drives this relationship and “adequate control of disease activity is needed to lower cardiovascular risk,” wrote Kim Lauper, MD, of Geneva University Hospitals, and her coinvestigators.

Major adverse cardiovascular events (MACE) also were significantly associated with traditional cardiovascular risk factors such as smoking, hypertension, and hyperlipidemia, “stressing the importance of [their] detection and management,” the researchers wrote in Arthritis Care and Research.

Previous studies linked inflammatory arthritis to a 40%-50% increase in risk of cardiovascular events, such as MI and acute coronary syndrome. Inflammatory arthritis also increases the risk of cerebrovascular disease, and traditional cardiovascular risk factors alone do not explain these associations, the researchers noted. Mounting data suggest that inflammation underlies the pathogenesis of atherosclerosis. Other studies have documented the cardioprotective effect of disease-modifying antirheumatic drugs (DMARDs) in patients with rheumatoid arthritis and psoriasis.

Dr. Lauper and her coinvestigators examined the prevalence and incidence of MACE, including MI, transient or permanent cerebrovascular events, or cardiovascular deaths among patients with rheumatoid arthritis, psoriatic arthritis, or spondyloarthritis. The 5,315 patients in the study were part of the Swiss Clinical Quality Management registry, which longitudinally tracks individuals throughout Switzerland who receive biologic DMARDs.

The investigators also asked rheumatologists to supply missing data and used a questionnaire to survey patients about cardiovascular events and associated risk factors. These efforts produced more than 66,000 patient-years of follow-up data, more than half of which were for rheumatoid arthritis and less than 10,000 of which were for psoriatic arthritis.

Among all patients, independent risk factors for MACE included older age (P less than .001), disease duration (P = .002), male gender (P less than .001), family history of MACE (P = .03), personal history of hyperlipidemia (P less than .001), and hypertension (P = .04). In contrast, there was no link between MACE and use of NSAIDs. “Similarly, a recent Taiwanese nationwide study did not find an increase in coronary disease in patients taking etoricoxib or celecoxib after adjustment for gender, age, comorbidities, hypertension, hyperlipidemia, and DMARDs,” the researchers wrote.Dr. Lauper reported having no conflicts of interest. The senior author and two coinvestigators disclosed ties to Roche, Abbvie, Pfizer, and several other pharmaceutical companies.

SOURCE: Lauper K et al. Arthritis Care Res. 2018 Apr 2. doi: 10.1002/acr.23567.

Rheumatoid arthritis, psoriatic arthritis, and axial spondyloarthritis were linked to similarly increased risks of major adverse cardiovascular events in a large population-based cohort study.

Inflammation itself drives this relationship and “adequate control of disease activity is needed to lower cardiovascular risk,” wrote Kim Lauper, MD, of Geneva University Hospitals, and her coinvestigators.

Major adverse cardiovascular events (MACE) also were significantly associated with traditional cardiovascular risk factors such as smoking, hypertension, and hyperlipidemia, “stressing the importance of [their] detection and management,” the researchers wrote in Arthritis Care and Research.

Previous studies linked inflammatory arthritis to a 40%-50% increase in risk of cardiovascular events, such as MI and acute coronary syndrome. Inflammatory arthritis also increases the risk of cerebrovascular disease, and traditional cardiovascular risk factors alone do not explain these associations, the researchers noted. Mounting data suggest that inflammation underlies the pathogenesis of atherosclerosis. Other studies have documented the cardioprotective effect of disease-modifying antirheumatic drugs (DMARDs) in patients with rheumatoid arthritis and psoriasis.

Dr. Lauper and her coinvestigators examined the prevalence and incidence of MACE, including MI, transient or permanent cerebrovascular events, or cardiovascular deaths among patients with rheumatoid arthritis, psoriatic arthritis, or spondyloarthritis. The 5,315 patients in the study were part of the Swiss Clinical Quality Management registry, which longitudinally tracks individuals throughout Switzerland who receive biologic DMARDs.

The investigators also asked rheumatologists to supply missing data and used a questionnaire to survey patients about cardiovascular events and associated risk factors. These efforts produced more than 66,000 patient-years of follow-up data, more than half of which were for rheumatoid arthritis and less than 10,000 of which were for psoriatic arthritis.

Among all patients, independent risk factors for MACE included older age (P less than .001), disease duration (P = .002), male gender (P less than .001), family history of MACE (P = .03), personal history of hyperlipidemia (P less than .001), and hypertension (P = .04). In contrast, there was no link between MACE and use of NSAIDs. “Similarly, a recent Taiwanese nationwide study did not find an increase in coronary disease in patients taking etoricoxib or celecoxib after adjustment for gender, age, comorbidities, hypertension, hyperlipidemia, and DMARDs,” the researchers wrote.Dr. Lauper reported having no conflicts of interest. The senior author and two coinvestigators disclosed ties to Roche, Abbvie, Pfizer, and several other pharmaceutical companies.

SOURCE: Lauper K et al. Arthritis Care Res. 2018 Apr 2. doi: 10.1002/acr.23567.

CHICAGO – Adjuvant pembrolizumab for resected high-risk melanoma slowed the rate of recurrence or death by 43% compared with placebo in a phase 3 trial of 1,519 patients.

After 15 months of follow-up, 12-month rates of recurrence-free survival (RFS) were 75% for pembrolizumab and 61% for placebo (hazard ratio, 0.57; P less than .001), Alexander M.M. Eggermont, MD, PhD, reported at the annual meeting of the American Association for Cancer Research.

By 18 months, the RFS difference between the arms had widened even more (71% versus 53%), Dr. Eggermont and his associates said at the meeting. The report was published simultaneously in the New England Journal of Medicine.

Adjuvant pembrolizumab was effective irrespective of PD-L1 tumor expression status. In a subgroup of more than 800 patients with PD-L1-positive tumors, 12-month RFS rates were 77% for pembrolizumab and 63% for placebo (HR, 0.54; 95% CI, 0.42 to 0.69; P less than .001). Among 116 patients who were PD-L1-negative, these rates were 72% and 52%, respectively (HR, 0.47; P = .01).

Treatment produced no new safety signals, said Dr. Eggermont of Gustave Roussy Cancer Campus Grand Paris and University Paris-Saclay, Villejuif, France. Grade 3 or higher toxicities affected 15% of pembrolizumab patients. Myositis caused one pembrolizumab-related death.

The findings bolster data suggesting that adjuvant therapy can stop or delay recurrence in resected high-risk melanoma. Previously, adjuvant ipilimumab was approved after significantly extending RFS and overall survival in the placebo-controlled European Organization for Research and Treatment of Cancer 18071 trial. More recently, adjuvant dabrafenib plus trametinib reduced the risk of recurrence compared with placebo in completely resected stage III melanoma with BRAF mutations (COMBI-AD), and adjuvant nivolumab significantly improved RFS and was less toxic than was ipilimumab in patients with advanced resected BRAF-mutated and BRAF-wild-type melanomas (CheckMate 238).

SOURCE: Eggermont AMM et al. AACR Annual Meeting Abstract CT001.

CHICAGO – Adjuvant pembrolizumab for resected high-risk melanoma slowed the rate of recurrence or death by 43% compared with placebo in a phase 3 trial of 1,519 patients.

After 15 months of follow-up, 12-month rates of recurrence-free survival (RFS) were 75% for pembrolizumab and 61% for placebo (hazard ratio, 0.57; P less than .001), Alexander M.M. Eggermont, MD, PhD, reported at the annual meeting of the American Association for Cancer Research.

By 18 months, the RFS difference between the arms had widened even more (71% versus 53%), Dr. Eggermont and his associates said at the meeting. The report was published simultaneously in the New England Journal of Medicine.

Adjuvant pembrolizumab was effective irrespective of PD-L1 tumor expression status. In a subgroup of more than 800 patients with PD-L1-positive tumors, 12-month RFS rates were 77% for pembrolizumab and 63% for placebo (HR, 0.54; 95% CI, 0.42 to 0.69; P less than .001). Among 116 patients who were PD-L1-negative, these rates were 72% and 52%, respectively (HR, 0.47; P = .01).

Treatment produced no new safety signals, said Dr. Eggermont of Gustave Roussy Cancer Campus Grand Paris and University Paris-Saclay, Villejuif, France. Grade 3 or higher toxicities affected 15% of pembrolizumab patients. Myositis caused one pembrolizumab-related death.

The findings bolster data suggesting that adjuvant therapy can stop or delay recurrence in resected high-risk melanoma. Previously, adjuvant ipilimumab was approved after significantly extending RFS and overall survival in the placebo-controlled European Organization for Research and Treatment of Cancer 18071 trial. More recently, adjuvant dabrafenib plus trametinib reduced the risk of recurrence compared with placebo in completely resected stage III melanoma with BRAF mutations (COMBI-AD), and adjuvant nivolumab significantly improved RFS and was less toxic than was ipilimumab in patients with advanced resected BRAF-mutated and BRAF-wild-type melanomas (CheckMate 238).

SOURCE: Eggermont AMM et al. AACR Annual Meeting Abstract CT001.

CHICAGO – Adjuvant pembrolizumab for resected high-risk melanoma slowed the rate of recurrence or death by 43% compared with placebo in a phase 3 trial of 1,519 patients.

After 15 months of follow-up, 12-month rates of recurrence-free survival (RFS) were 75% for pembrolizumab and 61% for placebo (hazard ratio, 0.57; P less than .001), Alexander M.M. Eggermont, MD, PhD, reported at the annual meeting of the American Association for Cancer Research.

By 18 months, the RFS difference between the arms had widened even more (71% versus 53%), Dr. Eggermont and his associates said at the meeting. The report was published simultaneously in the New England Journal of Medicine.

Adjuvant pembrolizumab was effective irrespective of PD-L1 tumor expression status. In a subgroup of more than 800 patients with PD-L1-positive tumors, 12-month RFS rates were 77% for pembrolizumab and 63% for placebo (HR, 0.54; 95% CI, 0.42 to 0.69; P less than .001). Among 116 patients who were PD-L1-negative, these rates were 72% and 52%, respectively (HR, 0.47; P = .01).

Treatment produced no new safety signals, said Dr. Eggermont of Gustave Roussy Cancer Campus Grand Paris and University Paris-Saclay, Villejuif, France. Grade 3 or higher toxicities affected 15% of pembrolizumab patients. Myositis caused one pembrolizumab-related death.

The findings bolster data suggesting that adjuvant therapy can stop or delay recurrence in resected high-risk melanoma. Previously, adjuvant ipilimumab was approved after significantly extending RFS and overall survival in the placebo-controlled European Organization for Research and Treatment of Cancer 18071 trial. More recently, adjuvant dabrafenib plus trametinib reduced the risk of recurrence compared with placebo in completely resected stage III melanoma with BRAF mutations (COMBI-AD), and adjuvant nivolumab significantly improved RFS and was less toxic than was ipilimumab in patients with advanced resected BRAF-mutated and BRAF-wild-type melanomas (CheckMate 238).

SOURCE: Eggermont AMM et al. AACR Annual Meeting Abstract CT001.

Neoadjuvant nivolumab did not delay surgery and produced at least 90% tumor regression in nearly half of early-stage, resectable non–small cell lung cancers (NSCLC), according to the results of a 21-patient pilot trial.

Eighty percent of patients were alive and recurrence-free a year after surgery, said Patrick M. Forde, MBBCh, and his colleagues from Johns Hopkins University, Baltimore. The only grade 3 or higher adverse event was treatment-related pneumonia, which did not prevent surgery. The findings were reported at the annual meeting of the American Association for Cancer Research and simultaneously in the New England Journal of Medicine.

©Sebastian Kaulitzki/Thinkstock

SOURCE: Forde PM. AACR Annual Meeting 2018. Forde PM et al. N Engl J Med. 2018 Apr 16. doi: 10.1056/NEJMoa1716078.

Neoadjuvant nivolumab did not delay surgery and produced at least 90% tumor regression in nearly half of early-stage, resectable non–small cell lung cancers (NSCLC), according to the results of a 21-patient pilot trial.

Eighty percent of patients were alive and recurrence-free a year after surgery, said Patrick M. Forde, MBBCh, and his colleagues from Johns Hopkins University, Baltimore. The only grade 3 or higher adverse event was treatment-related pneumonia, which did not prevent surgery. The findings were reported at the annual meeting of the American Association for Cancer Research and simultaneously in the New England Journal of Medicine.

©Sebastian Kaulitzki/Thinkstock

SOURCE: Forde PM. AACR Annual Meeting 2018. Forde PM et al. N Engl J Med. 2018 Apr 16. doi: 10.1056/NEJMoa1716078.

Neoadjuvant nivolumab did not delay surgery and produced at least 90% tumor regression in nearly half of early-stage, resectable non–small cell lung cancers (NSCLC), according to the results of a 21-patient pilot trial.

Eighty percent of patients were alive and recurrence-free a year after surgery, said Patrick M. Forde, MBBCh, and his colleagues from Johns Hopkins University, Baltimore. The only grade 3 or higher adverse event was treatment-related pneumonia, which did not prevent surgery. The findings were reported at the annual meeting of the American Association for Cancer Research and simultaneously in the New England Journal of Medicine.

©Sebastian Kaulitzki/Thinkstock

SOURCE: Forde PM. AACR Annual Meeting 2018. Forde PM et al. N Engl J Med. 2018 Apr 16. doi: 10.1056/NEJMoa1716078.