Day: 01/11/2024

Efanesoctocog Alfa Shows Promise for Severe Hemophilia A Therapy

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Among the benefits of treatment with this recombinant factor VIII product were fewer bleeding episodes, improved joint health, and reduced treatment burden.

Replacement with factor VIII concentrates remains the standard of care for hemophilia A but requires frequent infusions and imposes a significant therapy burden. Efforts to extend factor VIII half-life though factor VIII modification are under way to reduce the therapy burden.

Researchers evaluated the safety, efficacy, and pharmacokinetics of efanesoctocog alfa, an investigational molecule composed of recombinant factor VIII protein with additional modifications — a von Willebrand D’D3 fragment and Fc portion of IgG — that extend its half-life up to 5 days. In the multinational, open-label, phase 3 trial, previously treated patients with severe hemophilia A (≥150 factor VIII exposure days) ages 12 years and older received either once weekly prophylaxis with intravenous efanesoctocog alfa (50 IU per kg) for 52 weeks (group A, n=133) or on-demand efanesoctocog alfa for 26 weeks followed by once-weekly prophylaxis for 26 weeks (group B, n= 26).

The mean annualized bleeding rate (ABR) in group A — the primary endpoint — was 0.71. Patients in group A had a significant reduction in mean ABR from 2.96 pre-study to 0.69 post-study. The median ABR was 0 (interquartile range, 0 to 1.04). There were 362 bleeding episodes, most in group B, and 97% resolved with one dose of efanesoctocog alfa. With weekly prophylaxis, mean factor VIII activity was >40 IU/dL for roughly 4 days and was 15 IU/dL at day 7.

Patients in group A also experienced significantly improved physical health, pain intensity, and joint health. In the overall study population, efanesoctocog alfa had an acceptable side-effect profile, and no patients developed factor VIII inhibitors.

Comment

This comprehensive study shows that once-weekly efanesoctocog alfa offers a promising alternative to currently available factor VIII products for prophylaxis and treatment of severe hemophilia A. Major weaknesses of the study are (1) it was not a randomized clinical trial and (2) the incidence of alloantibodies against factor VIII — a serious complication of factor VIII therapy — could not be evaluated.

Sublobar Resection Is Now Standard of Care for Some Patients with Early-Stage NSCLC

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Sublobar resection is noninferior to lobectomy in patients with carefully staged, peripheral cT1aN0 NSCLC and should be offered to them.

To determine whether sublobar resection (wedge resection or segmentectomy) is noninferior to lobar resection in early-stage stage non–small-cell lung cancer (NSCLC), researchers conducted an international phase 3 trial. Nearly 700 patients with histologically confirmed stage IA node-negative NSCLC were randomized to lobar resection (357 patients) or sublobar resection (340 patients). Node status was confirmed by frozen section examination of level 10 lymph nodes and at least 2 mediastinal stations.

At a median follow-up of 7 years, the primary endpoint — disease-free survival (DFS) — did not differ significantly between groups (hazard ratio, 1.01; 90% CI, 0.83–1.24). The 5-year DFS was 63.6% in the sublobar-resection arm and 64.1% in the lobar-resection arm. There were no significant differences in DFS between the arms in subgroup analyses by tumor size or sites of recurrence. Overall survival (OS) also did not differ significantly between arms (HR, 0.95; 95% CI, 0.72–1.26). The 5-year OS was 80.3% with sublobar resection and 78.9% with lobar resection. There were no significant differences between the arms in lung cancer–related deaths (HR, 0.99) or deaths from other causes (HR, 1.12).

At 6 months, there was a greater reduction from baseline in the median percentage of predicted forced expiratory volume in 1 second (FEV1)in the lobar-resection arm (−6.0; 95% CI, −8.0 to −5.0) than in the sublobar-resection arm (−4.0; 95% CI, −5.0 to −2.0). The reduction in the median percentage of predicted forced vital capacity (FVC) was also greater in the lobar-resection arm (−5.0; 95% CI, −7.0 to −3.0) than in the sublobar resection arm (−3.0; 95% CI, −4.0 to −1.0).

Comment

A recent trial from Japan showed that segmentectomy was noninferior to lobectomy in patients with T1a/bN0 NSCLC (NEJM JW Oncol Hematol May 9 2022 and Lancet 2022; 399:1607). Together, these trials provide conclusive evidence that sublobar resection is the standard of care for patients with small, peripheral, node-negative NSCLC. As computed tomography screening for lung cancer becomes more widespread, the proportion of patients who meet these criteria will continue to increase. As noted by an editorialist, although many patients are cured of their first NSCLC, the risk for metachronous primary tumors remains quite high. Sublobar resection allows more treatment options for these patients.

PET-Adapted Treatment of Hodgkin Lymphoma

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Patients with bulky stage I–II disease were safely spared radiation therapy if they were PET-negative following two cycles of induction chemotherapy.

Combined-modality treatment — chemotherapy plus radiotherapy — has been a standard of care for patients with limited-stage bulky Hodgkin lymphoma. Investigators now report a single-arm, multicenter, phase 2 trial in which patients with stage I–II bulky disease received two cycles of ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine) followed by interim restaging positron emission tomography scan (PET2). Patients with negative scans (Deauville score 1–3) then received four additional ABVD cycles, while patients with positive scans (Deauville score 4–5) received four cycles of escalated BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone) followed by 30 Gy involved-field radiation therapy. PET scans were centrally reviewed.

Of 94 evaluable patients, median age was 30 (range, 18–58) and most had stage II disease; 78% were PET2-negative and 22% were PET2-positive. Three-year progression-free survival (PFS; the primary endpoint) was 93.1% in the PET2-negative group and 89.7% in the PET2-positive group. Toxicities, including neutropenia and febrile neutropenia, were as expected for these regimens.

Comment

This PET-adapted study met the objective of maintaining ongoing remissions in PET2-negative patients treated with chemotherapy only without the addition of radiation therapy. Of note, similar durable response was achieved via chemotherapy intensification plus involved-field radiation therapy in PET2-positive patients, an improvement from prior studies of patients in this population not undergoing risk-adapted treatment escalation. The authors recommend eliminating bleomycin from cycles three to six in PET2-negative patients, consistent with current practice. The avoidance of radiotherapy is an important achievement that will decrease incident cardiovascular and second primary cancer events in the decades following curative treatment.

Importantly, a just-reported European trial in children and adolescents with early-stage classical Hodgkin lymphoma also showed that PET2-negative patients can be spared radiotherapy while maintaining very high 5-year event-free survival (Lancet Oncol 2023; 24:252. opens in new tab).

In addition, another newly reported phase 2 trial showed 100% PFS with the addition of the immune checkpoint inhibitor nivolumab to four AVD cycles in patients with early-stage unfavorable Hodgkin lymphoma, although all patients in this study received 30 Gy involved-site radiation

Bevacizumab Added to FTD-TPI in Third-Line Therapy for Metastatic Colorectal Cancer

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A phase 3, randomized, placebo-controlled trial shows benefits, including in overall survival and progression-free survival.

Trifluridine-tipiracil (FTD-TPI) is an approved late-line therapy in chemotherapy-refractory metastatic colorectal cancer. Bevacizumab is combined with first- and second-line chemotherapy, but its continued use in later-line therapy has not been clearly supported in clinical trials. Investigators now report results of the SUNLIGHT trial, a global, open-label, industry-sponsored, randomized, phase 3 trial evaluating the use of standard-regimen FTD-TPI, given with or without bevacizumab (5 mg/kg) every 2 weeks, in chemotherapy-refractory colorectal cancer.

Of the 492 patients treated, 72% had left-sided primary tumors, 92% had received two prior chemotherapy regimens, 72% had received prior anti–vascular endothelial growth factor (VEGF) therapy, 20% received bevacizumab as part of first- and second-line chemotherapy, and of the 31% with RAS wild-type cancers, 94% had received prior epidermal growth factor (EGFR)–targeted therapy.

At a median follow-up of 14 months, the primary endpoint of median overall survival was significantly longer with the addition of bevacizumab (10.8 vs. 7.5 months; hazard ratio, 0.61). Overall survival at 6 months and at 12 months were also better with bevacizumab added (77% vs. 61% and 43% vs. 30%, respectively). Progression-free survival was significantly longer with bevacizumab (5.6 vs. 2.4 months; HR for disease progression or death, 0.44), and response rate was also better (6.1% vs. 1.2%). No new safety signals were observed; hypertension and neutropenia were more common with bevacizumab.

Comment

The SUNLIGHT trial is practice changing and indicates that bevacizumab should be continued into late-line treatment with FTD-TPI, as the addition of bevacizumab was associated with clinically meaningful improvements in all treatment endpoints. Although a cleaner trial comparison would have included only patients with prior first- and second-line bevacizumab therapy, most patients received at least two lines of prior chemotherapy, and nearly all had prior treatment with EGFR or anti-VEGF agents.

Capivasertib for Advanced ER+/HER2− Breast Cancer

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Adding the investigational AKT inhibitor capivasertib to fulvestrant improved progression-free survival overall and in patients with AKT pathway alterations.

Aberrant AKT signaling, through the PI3K–AKT–PTEN pathway, is often present in tumor cells that develop endocrine resistance. Capivasertib, an investigational oral, small-molecule inhibitor of AKT, has antiproliferative properties and demonstrated synergy with endocrine therapy. A phase 2 trial (FAKTION) previously showed fulvestrant plus capivasertib improved progression-free survival (PFS) and overall survival (OS) over fulvestrant alone in postmenopausal patients with ER-positive/HER2-negative breast cancer who previously received endocrine therapy (Lancet Oncol 2020; 21:345).

Now, the industry-sponsored phase 3 CAPItello-291 trial evaluated fulvestrant plus capivasertib in pre-, peri-, and postmenopausal patients with ER-positive/HER2-negative metastatic breast cancer who had relapse or progression following treatment with an aromatase inhibitor with or without a CDK4/6 inhibitor. A total of 708 patients were randomized to fulvestrant (500 mg intramuscularly every 14 days for three injections and every 28 days thereafter) plus either capivasertib (400 mg orally twice daily for 4 days each week) or matching placebo; 41% had AKT pathway alterations and 69% had previously received a CDK/6 inhibitor.

Median PFS was 7.2 months in the capivasertib group compared with 3.6 months in the placebo group (hazard ratio for progression or death, 0.60; P<0.001). In patients with AKT pathway alterations, the median PFS was 7.3 versus 3.1 months, respectively (HR, 0.50; P<0.001). The most frequent grade 3 or higher adverse events with capivasertib were rash (12.1% vs. 0.3% with placebo) and diarrhea (9.3% vs. 0.3%, respectively). Baseline global health status and quality of life were maintained longer in the capivasertib arm than the placebo arm.

Comment

Capivasertib may offer yet another partner for endocrine therapy following treatment with a CDK4/6 inhibitor. The FDA is considering capivasertib for approval in this setting. Alpelisib combined with fulvestrant is available for treating patients with PIK3CA mutations; however, capivasertib appears to have a better toxicity profile than alpelisib and is effective even in patients without a mutation in the AKT pathway.

Preoperative Chemotherapy Without Radiotherapy for Locally Advanced Rectal Cancer

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Patients with clinical stage T2N1 or T3N0–1 rectal cancers who are eligible for sphincter-sparing surgery might be able to avoid preoperative radiotherapy if given induction FOLFOX prior to surgery.

Total neoadjuvant therapy for patients with locally advanced rectal cancer — whereby chemoradiotherapy and chemotherapy are administered prior to surgery — offers the potential for enhanced treatment tolerance and delivery, improvements in pathologic response at surgery, and nonoperative management for colostomy candidates who achieve a clinical complete response. However, for patients with high- or mid-rectal cancers undergoing total mesorectal excision, the role of neoadjuvant radiotherapy has been increasingly questioned.

To test the concept of avoiding neoadjuvant radiotherapy in this setting, investigators conducted a multicenter, noninferiority, randomized, phase 3 trial (PROSPECT) involving 1128 patients with clinical stage T2N1 or T3N0–1 high- or mid-rectal cancer who were candidates for sphincter-sparing surgery. Most patients were male, half had T3N1 cancers, 91% had T3N0–1 cancers, and 64% had cancers 5 to 10 cm from the anal verge. Half of patients received conventional neoadjuvant chemoradiotherapy, surgery, and adjuvant chemotherapy. The other half received induction chemotherapy with 6 cycles of FOLFOX, and those with a ≥20% reduction in the primary tumor proceeded to surgery without radiotherapy and received adjuvant chemotherapy.

At 5 years, disease-free survival was noninferior with induction FOLFOX versus chemoradiotherapy (80.8% vs. 78.6%; hazard ratio, 0.92, P=0.005), meeting the primary endpoint. Rates of local recurrence were similar with FOLFOX or chemoradiotherapy (1.8% and 1.6%, respectively), as were 5-year overall survival (89.5% and 90.2%) and pathologic complete response (21.9% and 24.3%). Nearly 90% of patients treated with FOLFOX avoided radiotherapy; 9.1% required neoadjuvant chemoradiotherapy after FOLFOX, and 1.4% required postoperative chemoradiotherapy. No new safety signals were observed.

Comment

The large, well-conducted trial indicates that the vast majority of patients with clinical stage T2N1 or T3N0–1 rectal cancers who are eligible for sphincter-sparing surgery can avoid the use of preoperative radiotherapy if given induction FOLFOX. This trial will change practice. The use of radiotherapy preoperatively will increasingly be relegated to more advanced rectal cancers or to patients requiring a permanent colostomy.

Perioperative Nivolumab and Chemotherapy in Stage III NSCLC

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The addition of nivolumab to platinum-based chemotherapy improved pathologic complete response rates in patients with resectable stage IIIA or IIIB NSCLC.

Approximately 20% of patients with non–small-cell lung cancer (NSCLC) have stage III disease. Although therapeutic intent is curative for patients with locally advanced disease, historically, treatment outcomes have been poor, and there is lack of consensus on the most appropriate management.

In the industry-sponsored, open-label, multicenter, phase 2 NADIM II trial, 86 treatment-naive patients with resectable stage IIIA or IIIB NSCLC were randomized 2:1 to receive either neoadjuvant nivolumab and paclitaxel plus carboplatin (experimental group) or paclitaxel plus carboplatin alone (control group), followed by surgery. Patients in the experimental group who had R0 resections received adjuvant nivolumab for 6 months.

Pathologic complete response (pCR), the primary endpoint, occurred in 37% of patients in the experimental group compared with 7% in the control group (relative risk, 5.34; 95% CI 1.34–21.23; P=0.02). Progression-free survival at 24 months was 67.2% in the experimental group and 40.9% in the control group (hazard ratio for disease progression, disease recurrence, or death, 0.47; 95% CI, 0.25–0.88).

During neoadjuvant treatment, grade 3 or 4 adverse events occurred in 19% of patients in the experimental group compared with 10% in the control group, most commonly febrile neutropenia (5%) and diarrhea (4%). A higher percentage of patients in the experimental group underwent surgery (93% vs. 69%); there were no delays in surgery due to adverse events. All patients who attained pCR were free from progression at the time of data cutoff.

Comment

In the NADIM II trial, patients with stage IIIA or stage IIIB NSCLC who were treated with neoadjuvant nivolumab and paclitaxel plus carboplatin achieved a higher rate of pCR and longer survival than those treated with chemotherapy alone. These findings add further support for a neoadjuvant chemo-immunotherapy strategy as demonstrated in CheckMate 816 (NEJM JW Oncol Hematol Apr 14 2022 and N Engl J Med 2022; 386:1973) and in KEYNOTE 677 (NEJM JW Oncol Hematol Jun 20 2023 and N Engl J Med 2023 Jun 3; [e-pub]) in a restricted population of patients with stage III NSCLC.

Safely Omitting Breast Radiation Therapy

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Some women aged 55 and older with early-stage breast cancer may omit radiation therapy after breast conserving surgery.

Breast radiation to reduce risk of local recurrence has been a standard of care for women undergoing breast conserving surgery for invasive cancer. Certain subsets of patients, including older women, have been identified who may be able to avoid radiation therapy, with no compromise in overall outcome (NEJM JW Oncol Hematol Feb 12 2023 and N Engl J Med 2023; 388:585). Another approach being explored is identifying molecular subsets of breast cancer that may not require radiation therapy in the setting of breast conservation.

The LUMINA prospective cohort study enrolled 500 women ≥55 years old with T1N0, luminal A-subtype breast cancer who had undergone breast-conserving surgery. Patients received adjuvant endocrine therapy with no radiation therapy. Eligible tumors were estrogen receptor-positive (≥1%), progesterone receptor-positive (>20%), and HER2-negative, and had Ki-67 index ≤13.25%. Ductal, tubular, and mucinous histology was allowed, whereas lobular carcinoma was not.

Patients were followed clinically every 6 months for 2 years and annually thereafter. Annual mammograms were obtained, and patients were interviewed about adherence to adjuvant endocrine therapy. Patients’ median age was 67 years; only 12% were aged 75 and older. The median tumor size was 1.1 cm. Adjuvant endocrine therapy was an aromatase inhibitor in 59% of patients and tamoxifen in 41%.

At 5 years, the rate of local recurrence in the ipsilateral breast was 2.3% (10 patients), which met the trial’s prespecified boundary of ≤5%.

Comment

This study identifies a group of patients with early-stage breast cancer with favorable features who can safely defer radiation therapy. The study included younger patients than prior studies, thus expanding the population of patients with favorable features who can safely avoid radiation therapy. Inevitably, with longer follow-up there will be additional ipsilateral recurrences, but these results support a more refined approach to adjuvant radiation therapy.

Olanzapine Improves Weight Gain in Patients with Advanced Cancer on Chemotherapy

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Among patients with newly diagnosed advanced gastric, hepatopancreaticobiliary, or lung cancers starting chemotherapy, low-dose daily olanzapine improved appetite and weight gain.

Patients with advanced cancer often present with anorexia and weight loss. Poor nutritional status is associated with myriad adverse outcomes in this population. Medical management options have been limited, although corticosteroids and progesterone analogs (e.g., megestrol acetate) are commonly used. These investigators evaluated olanzapine — an antipsychotic agent that increases appetite and decreases nausea — for the treatment of chemotherapy-related anorexia in patients with locally advanced or metastatic gastric, hepatopancreaticobiliary, or lung cancer.

In the randomized, double-blind study, 124 adult patients received olanzapine (2.5 mg daily) or placebo for 12 weeks, starting on the first day of the first chemotherapy cycle. A significantly higher percentage of patients in the olanzapine arm than the placebo arm had weight gain >5% (60% vs. 9%; P<.001) and improved appetite (43% vs. 13%; P<.001) — the primary outcomes. The olanzapine arm also had significantly improved quality of life and nutritional status, as well as less chemotoxicity ≥ grade 3 (12% vs. 37%; P=.002). Adverse events attributable to olanzapine included mild, limited drowsiness.

Comment

This study fills an important gap in the literature, helping clinicians better support patients with advanced cancer who have cancer-associated weight loss and anorexia.

As noted in a recent ASCO Guideline Rapid Recommendation Update on cancer cachexia, daily low-dose olanzapine should be offered to patients with advanced cancer to support appetite and weight gain, along with nutritional support (J Clin Oncol 2023; 41:4178). For patients unable to tolerate olanzapine, a short-term trial of a corticosteroid or progesterone analog may be considered. Although the Update applies to all adult patients with advanced cancer, the majority of evidence derives from patients with gastrointestinal or lung malignancies and those receiving cytotoxic chemotherapy.

The use of mirtazapine for cancer-associated weight loss and anorexia should be limited, as a recent study found it to be no better than placebo (J Pain Symptom Manage 2021; 62:1207). Importantly, there are no FDA-approved medications for cancer cachexia.

Levetiracetam vs. Lamotrigine in Women with Idiopathic Generalized Epilepsy

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The risk for treatment failure is lower in women using levetiracetam instead of lamotrigine for first-line treatment of juvenile myoclonic epilepsy.

Levetiracetam and lamotrigine are considered the least teratogenic among antiseizure medications (ASMs) that are effective for idiopathic generalized epilepsy (IGE), but little evidence is available to guide initial ASM selection in women of childbearing age. In a multicenter, retrospective cohort study including 543 women with IGE who received either levetiracetam or lamotrigine as initial monotherapy, investigators assessed time from ASM prescription to treatment failure due to ineffectiveness or adverse effects. Two authors report receiving fees from the manufacturer of levetiracetam for work unrelated to the study.

Compared with lamotrigine use, levetiracetam use was associated with lower risk for treatment failure and a higher likelihood of seizure freedom at 12 months, after adjustment for all baseline variables. In secondary analyses, levetiracetam use had a lower risk for ineffectiveness than lamotrigine use, but no difference in ASM withdrawal due to adverse effects alone or ASM retention (ineffectiveness plus adverse-effect withdrawals) despite more frequently reported adverse effects with levetiracetam. Behavioral symptoms and drowsiness were more frequent with levetiracetam, whereas dermatologic symptoms were more frequent with lamotrigine. Among IGE subsyndromes, levetiracetam performed better than lamotrigine only for juvenile myoclonic epilepsy. Clinicians more commonly noted worsening myoclonic seizures in women using lamotrigine. Time to treatment failure did not differ between the two ASMs for absence epilepsy or generalized tonic-clonic seizures.

Comment

Study strengths include the inclusion of patients from primary, secondary, and tertiary care settings, and epilepsy syndrome classification according to International League Against Epilepsy criteria. Limitations include insufficient sample size for subanalysis by IGE syndrome and selection bias due to the retrospective design. As the study population was mainly white and no other information was collected about race and ethnicity, generalizability of the findings for nonwhite women is unclear. Still, evidence supporting the superiority of levetiracetam over lamotrigine in juvenile myoclonic epilepsy will help clinicians treating women of childbearing age.