publication date: Sep. 28, 2018

Clinical Roundup

CT screening reduces lung cancer mortality, NELSON study finds

Findings from the NELSON study demonstrate that the use of computed tomography screening among asymptomatic men at high risk for lung cancer led to a 26 percent (9-41%, 95% CI) reduction in lung cancer deaths at 10 years of study follow-up (at 86% compliance).

In the smaller subset of women, the rate-ratio of dying from lung cancer varied between 0.39 and 0.61 in different years of follow-up, indicating an even significant and larger reduction in lung cancer mortality than in men.

Harry De Koning, Erasmus MC, Rotterdam, Netherlands, presented these findings at the International Association for the Study of Lung Cancer’s 19th World Conference on Lung Cancer in Toronto. The NELSON study was a population-based, controlled trial that enrolled 15,792 individuals, who were randomized 1:1 to either the study arm or control arm.

“These findings show that CT screenings are an effective way to assess lung nodules in people at high risk for lung cancer, often leading to detection of suspicious nodules and subsequent surgical intervention at relatively low rates and with few false positives, and can positively increase the chances of cure in this devastating disease,” De Koning said in a statement. “It is the second largest trial in the world, with an even more favorable outcome than the first trial, the NLST, showed. These results should be used to inform and direct future CT screening in the world.”

Study arm participants were offered CT screenings at baseline, one, three and five and one-half years after randomization. No screenings were offered to control arm participants. Participants’ records were linked to national registries with 100 percent coverage regarding cancer diagnosis (Netherlands Cancer Registry), date of death (Centre for Genealogy) and cause of death (Statistics Netherlands).

An expert panel reviewed 65 percent of cases. The follow-up period comprised a minimum of 10 years, unless deceased, for 93.7 percent of enrolled participants. The results of the study showed an 86 percent average CT screening compliance rate, encompassing 29,736 scans. In 9.3 percent of participants, additional CT scans were performed within two months to estimate nodule volume doubling time, leading to an overall referral rate of 2.3 percent for suspicious nodules.

Detection rates across the rounds varied between 0.8 and 1.1 percent, and 69 percent of screen-detected lung cancers were detected at Stage 1A or 1B. A total of 261 lung cancers (52 interval cancers) were detected before the fourth round of follow ups. In a subset of analyzed patients, surgical treatment was three times significantly more prevalent in study lung cancer patients than in control arm patients (67.7 percent versus 24.5 percent, p<0.001).

 

Imfinzi significantly improves OS in unresectable, stage III NSCLC

Imfinzi (durvalumab) reduced the risk of death by nearly one-third compared to placebo in the phase III PACIFIC trial.

Results from the phase III PACIFIC trial in patients with unresectable stage III non-small cell lung cancer whose disease had not progressed following chemoradiation showed that Imfinzi significantly improved OS, the second primary endpoint of the trial, compared to placebo regardless of PD-L1 expression, reducing the risk of death by 32 percent (HR 0.68, 99.73% CI 0.47-0.997; p=0.0025).

Updated data reaffirm unprecedented improvement in progression-free survival of more than 11 months. AstraZeneca and MedImmune, its global biologics research and development arm, have presented data on overall survival in the phase III PACIFIC trial of Imfinzi (durvalumab) during the Presidential Symposium of the IASLC 19th World Conference on Lung Cancer hosted by the International Association for the Study of Lung Cancer in Toronto, Canada. Results were published simultaneously in the New England Journal of Medicine.

“The five-year survival rate in this setting has historically been around 15 percent after concurrent chemoradiation therapy,” said Scott Antonia, chair of the Thoracic Oncology Department at Moffitt Cancer Center and principal investigator in the PACIFIC trial. “The significant survival benefit observed using the PACIFIC regimen provides confidence and clear rationale for a new standard of care.”

Summary of primary endpoints:

  • The data cut-off date for first-planned OS analysis and updated PFS analysis was March 22, 2018.

  • Stratified by sex, age, and smoking history.

  • Confidence interval adjusted for interim analysis.

  • Criteria for statistical significance at the interim analysis of OS was a p-value ≤ 0.00274 for OS (using Lan DeMets spending function approximating O’Brien Fleming boundary).

  • Not Reached.

  • Assessed by Blinded Independent Central Review according to RECIST v1.1.

  • No formal statistical comparison was made because the study had achieved significance for PFS at the first planned interim analysis (data cutoff of Feb 13, 2017).

The safety and tolerability profile for Imfinzi was consistent with that reported at the time of the previous progression-free survival analysis. Imfinzi can cause serious, potentially fatal adverse reactions.

Imfinzi is currently approved in the U.S. for the treatment of patients with unresectable stage III NSCLC whose disease has not progressed following concurrent platinum-based chemotherapy and radiation therapy, based on the PACIFIC trial. It is also approved in the EU, Canada, Switzerland, India, Japan and Brazil. Other global health authority reviews and submissions are ongoing.

 

Tecentriq + chemo significantly improves OS as initial treatment for ES-SCLC

Genentech announced positive results from the phase III IMpower133 study of Tecentriq (atezolizumab) plus carboplatin and etoposide for the initial treatment of people with previously-untreated extensive-stage small cell lung cancer.

Genentech is a member of the Roche Group.

The analysis showed that Tecentriq and chemotherapy helped people live significantly longer compared with chemotherapy alone (overall survival = 12.3 versus 10.3 months; hazard ratio = 0.70, 95 percent CI: 0.54-0.91; p=0.0069) in the intention-to-treat population.

The Tecentriq-based combination also significantly reduced the risk of disease worsening or death (progression-free survival) compared with chemotherapy alone (PFS=5.2 versus 4.3 months; HR=0.77, 95 percent CI: 0.62-0.96; p=0.017). Safety for the Tecentriq and chemotherapy combination appeared consistent with the known safety profile of the individual medicines, and no new safety signals were identified with the combination.

The data was presented at the International Association for the Study of Lung Cancer 2018 World Conference on Lung Cancer Presidential Symposium. The data will be simultaneously published in the New England Journal of Medicine.

IMpower133 is a phase III, multicenter, double-blinded, randomized placebo-controlled study evaluating the efficacy and safety of Tecentriq in combination with chemotherapy (carboplatin and etoposide) versus chemotherapy (carboplatin and etoposide) alone in chemotherapy-naïve people with ES-SCLC.

The study enrolled 403 people who were randomized equally (1:1) to receive:

  • Tecentriq in combination with carboplatin and etoposide (Arm A), or

  • Placebo in combination with carboplatin and etoposide (Arm B, control arm)

During the treatment-induction phase, people received treatment on 21-day cycles for four cycles, followed by maintenance with Tecentriq or placebo until progressive disease as assessed by the investigator using Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1). Treatment could be continued until persistent radiographic PD or symptomatic deterioration was observed.

The co-primary endpoints were:

  • PFS as determined by the investigator using RECIST v1.1 in the ITT population

  • OS in the ITT population

Safety for the Tecentriq and chemotherapy combination appeared consistent with the known safety profile of the individual medicines, and no new safety signals were identified with the combination. Grade III-IV treatment-related adverse events were reported in 56.6 percent of people receiving Tecentriq plus chemotherapy compared to 56.1 percent of people receiving chemotherapy alone.

 

Atezolizumab + carboplatin & pemetrexed improves PFS in stage IV non-squamous NSCLC

Findings from a recent study demonstrate that the use of atezolizumab, a PD-L1 inhibitor, in combination with carboplatin plus pemetrexed as first-line therapy and pemetrexed as maintenance therapy improves progression free survival in patients with stage IV non-squamous non-small cell lung cancer.

Vassiliki Papadimitrakopoulou, chief of the Section of Thoracic Medical Oncology at MD Anderson Cancer Center, presents these findings at the International Association for the Study of Lung Cancer’s 19th World Conference on Lung Cancer in Toronto, Canada.

IMpower132 is a global, randomized, open-label, phase III study of 578 chemotherapy-naïve patients with stage IV non-squamous NSCLC. Eligibility criteria included measurable disease by Response Evaluation Criteria in Solid Tumors guidelines v1.1 and Eastern Cooperative Oncology Group Performance Status 0-1.

Exclusion criteria included tumors known to harbor epidermal growth factor receptor or anaplastic lymphoma kinase driver mutations, untreated central nervous system metastases, autoimmune disease and prior exposure to immunotherapy.

Patients were randomized 1:1 to receive four or six cycles of carboplatin area under the curve 6 mg/mL/min or cisplatin 75 mg/m2 plus pemetrexed 500 mg/m2 Q3W, followed by pemetrexed as maintenance therapy (Arm B), or carboplatin-pemetrexed or cisplatin-pemetrexed plus atezolizumab 1200 mg, followed by pemetrexed plus atezolizumab as maintenance therapy (Arm A).

Results of the study showed that the atezolizumab plus pemetrexed—based chemotherapy (Arm A) resulted in improvement in PFS (median 7.6 months versus 5.2 months for the control group) associated with 40 percent reduction in risk for progression (HR 0.60, 95 CI :0.49, 072) in all patients and across key clinical subgroups, including Asian patients (HR 0.42;95% CI:0.28-0.63), never smokers (HR 0.49; 95% CI 0.28-0.87), current and former smokers (HR 0.61; 95% CI 0.50-0.74.

Also, at this interim OS analysis, this atezolizumab plus pemetrexed-based chemotherapy demonstrated a numerical improvement in OS of 4.5 months over pemetrexed-based chemotherapy alone (HR 0.46; 95% CI :0.22-0.96).

These IMpower132 study results are significant because it further supports the use of atezolizumab plus chemotherapy with or without Avastin (bevacizumab) in chemotherapy-naïve NSCLC.

 

Myriad’s Variant Reclassification Study published in JAMA

Myriad Genetics announced that results from a landmark study of variant classifications following hereditary cancer genetic testing were published in the Journal of the American Medical Association.

This was a retrospective study of individuals who had genetic testing from 2006-2016 at Myriad Genetics. Genetic variants were classified as Benign, Likely Benign, Variant of Uncertain Significance, Likely Pathogenic, or Pathogenic. The primary objective of this study was to measure the frequency and types of variant reclassification.

The results showed that 1.45 million individuals had genetic testing in the 10-year time period and 59,955 amended reports were issued due to variant reclassification. Importantly, 25 percent of all reported variants of uncertain significance were reclassified, with 91 percent downgraded to Benign/Likely Benign and 9 percent upgraded to Pathogenic/Likely Pathogenic.

“The implications of this study are three-pronged,” said Theodora Ross, senior author of the study and professor of Internal Medicine at UT Southwestern Medical Center. “Physicians need to be aware of how rapidly knowledge about gene variants is advancing and that reclassifications are common. Labs need to review gene variant information on a regular basis and alert physicians to changes. Finally, patients and their family members need to be made aware of reclassifications by their physicians so they can make well-informed choices.”

 

Alunbrig improves PFS by over 50% vs. crizotinib in first-line advanced ALK+ NSCLC

Takeda Pharmaceutical Co. Ltd. announced results from the phase III ALTA-1L (ALK in lung cancer trial of BrigAtinib in 1st Line) trial, demonstrating that Alunbrig reduced the risk of disease progression or death, known as progression-free survival, as assessed by a blinded independent review committee, by more than 50 percent compared to crizotinib in adults with anaplastic lymphoma kinase-positive locally advanced or metastatic non-small cell lung cancer who had not received a prior ALK inhibitor.

Findings from the first interim analysis of the ALTA-1L trial was presented during the Presidential Symposium at the International Association for the Study of Lung Cancer 19th World Conference on Lung Cancer in Toronto. The data were also simultaneously published online in The New England Journal of Medicine. Alunbrig is currently not approved as first-line therapy for advanced ALK+ NSCLC.

ALTA-1L is a global, randomized, open-label, comparative, multicenter trial, which enrolled 275 patients with ALK+ locally advanced or metastatic NSCLC who have not received prior treatment with an ALK inhibitor but may have received up to one prior regimen of chemotherapy in the advanced setting.

Patients were eligible for study entry on the basis of locally determined ALK testing. Patients received either Alunbrig, 180 mg once daily with seven-day lead-in at 90 mg once daily, or crizotinib, 250 mg twice daily.

Treatment with Alunbrig resulted in superior PFS compared to crizotinib as assessed by a blinded independent review committee (hazard ratio = 0.49 [95 percent confidence interval, 0.33 to 0.74]; log-rank p=0.0007), corresponding to a 51 percent reduction in the risk of disease progression or death. The safety profile associated with Alunbrig was generally consistent with the existing U.S. prescribing information.

Research at the University of Colorado Cancer Center and lead investigator of ALTA-1L,include:

  • A total of 275 patients were randomized to either brigatinib (n=137) or crizotinib (n=138). The median age was 59 years (Brigatinib, 58; Crizotinib, 60) and 55 percent of patients in the trial were female (Brigatinib, 50%; Crizotinib, 59%). Twenty-nine percent had brain metastases at baseline (Brigatinib, 29%; Crizotinib, 30%), with comparable pre-enrollment CNS radiotherapy rates. Overall, 27 percent of patients had prior chemotherapy in the locally advanced or metastatic setting (Brigatinib, 26%; Crizotinib, 27%).

  • At the data cutoff for the first interim analysis (February 19, 2018), at a median follow-up period of 11.0 and 9.3 months in the Brigatinib arm and Crizotinib arm, respectively, 95 patients (69%) in the brigatinib arm and 59 patients (43%) in the crizotinib arm remained on study treatment.

  • The trial has met the pre-specified threshold for superiority in the primary endpoint at the first interim analysis. With a total of 99 events, BIRC-assessed PFS with brigatinib was superior to crizotinib (hazard ratio, 0.49 [95% confidence interval, 0.33 to 0.74]; log-rank p=0.0007).

  • The safety profile associated with ALUNBRIG was generally consistent with the existing U.S. prescribing information.

The phase III ALTA-1L (ALK in Lung Cancer Trial of BrigAtinib in 1st Line) trial of ALUNBRIG in adults is a global, ongoing, randomized, open-label, comparative, multicenter trial, which enrolled 275 patients with ALK+ locally advanced or metastatic NSCLC who have not received prior treatment with an ALK inhibitor.

Patients received either ALUNBRIG, 180 mg once daily with seven-day lead-in at 90 mg once daily, or crizotinib, 250 mg twice daily. Blinded Independent Review Committee-assessed progression-free survival was the primary endpoint.

Secondary endpoints included objective response rate per RECIST v1.1, intracranial ORR, intracranial PFS, overall survival, safety and tolerability. A total of approximately 198 PFS events are planned at the final analysis of the primary endpoint in order to demonstrate a minimum of six months PFS improvement over crizotinib. The trial is designed with two pre-specified interim analyses for the primary endpoint – one at approximately 50 percent of planned PFS events and one at approximately 75 percent of planned PFS events.

 

Cancer patients have lower risk of opioid-related death than general public

Opioid use among cancer patients does not appear to be leading to the steep increase of overdoses seen in the general public, according to a study by Duke Cancer Institute researchers.

The study, presented to the ASCO Quality Care Symposium in Phoenix, found that death from opioids are 10 times less likely to occur in cancer patients compared to the general population.

During a 10-year period from 2006-16, the researchers found that opioid deaths in the general population increased from 5.33 to 8.97 per 100,000 people. For cancer patients, the rate rose from 0.52 to 0.66 per 100,000.

In all, 895 cancer patients died as a result of opioids over that period, compared to 193,500 in the non-cancer population.

Researchers used de-identified death certificate data from the National Center for Health Statistics, which cites one underlying cause of death and up to 20 contributing causes, as well as demographic data.

All deaths due to opioids were included from 2006-2016; if present, cancer was noted as a contributing cause. Opioid death incidence was calculated from both the U.S. and estimated cancer survivor population.

 

Breast cancer patients prefer knowing costs prior to starting treatment

Even when they had good health insurance coverage, women with breast cancer reported having financial worries related to their care, and the vast majority said they preferred to know about treatment costs at the time of diagnosis.

The findings from a study by Duke Cancer Institute researchers highlight the importance of considering medical costs as women face breast cancer treatment decisions.

The vast majority of women—eight out of 10—said they preferred knowing the costs of treatment prior to embarking on cancer care. And 40 percent preferred that doctors consider costs when making treatment recommendations.

In the study, the Duke team surveyed more than 750 women after breast cancer from the Army of Women and Sisters Network, national organizations of women after breast cancer. All were women with a median age of about 50. Most had either private health insurance or Medicare, and had annual household income of more than $74,000.

Even within this group—financially better off than many cancer patients—nearly 16 percent reported significant to catastrophic financial burden.

Median reported out-of-pocket costs were $3,500, although 5 percent of women faced out-of-pocket costs over $30,000.

 

CIMAvax-EGF well tolerated for NSCLC, initial findings show

Initial results from the first North American clinical study of CIMAvax-EGF show that this Cuban-developed immunotherapy is safe, well tolerated and worthy of further study. Principal Investigator Grace Dy, of Roswell Park Comprehensive Cancer Center, presented the findings at the International Association for the Study of Lung Cancer’s 19th World Conference on Lung Cancer in Toronto, Canada.

The poster presentation reports results from the first portion of an ongoing phase I/II study of CIMAvax, an epidermal growth factor-depleting immunotherapy, in combination with the checkpoint inhibitor nivolumab (brand name Opdivo) in 13 patients with advanced non-small cell lung cancer. Nivolumab is an anti-PD1 antibody and is a standard therapeutic option in many countries, including the U.S., for patients with treatment-resistant or recurrent NSCLC.

No patients experienced life-threatening side effects attributable to the combination. One patient — representing 7 percent of this small study sample — experienced an on-target grade III side effect, myocarditis, attributed to nivolumab.

Earlier studies from Cuba have demonstrated a survival benefit for patients with advanced NSCLC who received maintenance doses of CIMAvax therapy in advanced NSCLC. While this initial dose-escalation portion of the ongoing Roswell Park study did not set out to evaluate efficacy, further examinations are underway.

Dy’s study was presented in collaboration with scientists from the Centro de Inmunología Molecular and Innovative Immunotherapy Alliance, a new company spun off from both Roswell Park and the CIM — the first-ever U.S.-Cuban biotech venture.

Copyright (c) 2018 The Cancer Letter Inc.