Cetuximab plus carboplatin and paclitaxel with or without bevacizumab versus carboplatin and paclitaxel with or without bevacizumab in advanced NSCLC (SWOG S0819): a randomised, phase 3 study.


Abstract

EGFR antibodies have shown promise in patients with advanced non-small-cell lung cancer (NSCLC), particularly with squamous cell histology. We hypothesised that EGFR copy number by fluorescence in-situ hybridisation (FISH) can identify patients most likely to benefit from these drugs combined with chemotherapy and we aimed to explore the activity of cetuximab with chemotherapy in patients with advanced NSCLC who are EGFR FISH-positive.

We did this open-label, phase 3 study (SWOG S0819) at 277 sites in the USA and Mexico. We randomly assigned (1:1) eligible patients with treatment-naive stage IV NSCLC to receive paclitaxel (200 mg/m2; every 21 days) plus carboplatin (area under the curve of 6 by modified Calvert formula; every 21 days) or carboplatin plus paclitaxel and bevacizumab (15 mg/kg; every 21 days), either with cetuximab (250 mg/m2 weekly after loading dose; cetuximab group) or without (control group), stratified by bevacizumab treatment, smoking status, and M-substage using a dynamic-balancing algorithm. Co-primary endpoints were progression-free survival in patients with EGFR FISH-positive cancer and overall survival in the entire study population. We analysed clinical outcomes with the intention-to-treat principle and analysis of safety outcomes included patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov (number NCT00946712).

Between Aug 13, 2009, and May 30, 2014, we randomly assigned 1313 patients to the control group (n=657; 277 with bevacizumab and 380 without bevacizumab in the intention-to-treat population) or the cetuximab group (n=656; 283 with bevacizumab and 373 without bevacizumab in the intention-to-treat population). EGFR FISH was assessable in 976 patients and 400 patients (41%) were EGFR FISH-positive. The median follow-up for patients last known to be alive was 35·2 months (IQR 22·9-39·9). After 194 progression-free survival events in the cetuximab group and 198 in the control group in the EGFR FISH-positive subpopulation, progression-free survival did not differ between treatment groups (hazard ratio [HR] 0·92, 95% CI 0·75-1·12; p=0·40; median 5·4 months [95% CI 4·5-5·7] vs 4·8 months [3·9-5·5]). After 570 deaths in the cetuximab group and 593 in the control group, overall survival did not differ between the treatment groups in the entire study population (HR 0·93, 95% CI 0·83-1·04; p=0·22; median 10·9 months [95% CI 9·5-12·0] vs 9·2 months [8·7-10·3]). In the prespecified analysis of EGFR FISH-positive subpopulation with squamous cell histology, overall survival was significantly longer in the cetuximab group than in the control group (HR 0·58, 95% CI 0·36-0·86; p=0·0071), although progression-free survival did not differ between treatment groups in this subgroup (0·68, 0·46-1·01; p=0·055). Overall survival and progression-free survival did not differ among patients who were EGFR FISH non-positive with squamous cell histology (HR 1·04, 95% CI 0·78-1·40; p=0·77; and 1·02, 0·77-1·36; p=0·88 respectively) or patients with non-squamous histology regardless of EGFR FISH status (for EGFR FISH-positive 0·88, 0·68-1·14; p=0·34; and 0·99, 0·78-1·27; p=0·96; respectively; and for EGFR FISH non-positive 1·00, 0·85-1·17; p=0·97; and 1·03, 0·88-1·20; p=0·69; respectively). The most common grade 3-4 adverse events were decreased neutrophil count (210 [37%] in the cetuximab group vs 158 [25%] in the control group), decreased leucocyte count (103 [16%] vs 74 [20%]), fatigue (81 [13%] vs 74 [20%]), and acne or rash (52 [8%] vs one [<1%]). 59 (9%) patients in the cetuximab group and 31 (5%) patients in the control group had severe adverse events. Deaths related to treatment occurred in 32 (6%) patients in the cetuximab group and 13 (2%) patients in the control group.

Although this study did not meet its primary endpoints, prespecified subgroup analyses of patients with EGFR FISH-positive squamous-cell carcinoma cancers are encouraging and support continued evaluation of anti-EGFR antibodies in this subpopulation.

National Cancer Institute and Eli Lilly and Company.

Advertisements

Nanoparticle albumin-bound paclitaxel for second-line treatment of metastatic urothelial carcinoma: a single group, multicentre, phase 2 study.


Background

No standard treatment exists for patients with platinum-refractory urothelial cancer. Taxanes and vinflunine are commonly used, but response is less than 20% with no survival benefit. In this phase 2 study, we assessed efficacy and tolerability of nanoparticle albumin-bound (nab) paclitaxel in platinum-refractory urothelial cancer.

Methods

We did an open-label, single-group, two-stage study at five centres in Canada. We enrolled patients aged at least 18 years with histologically confirmed, locally advanced, or metastatic measurable urothelial cancer, with documented progression on or within 12 months of treatment with one previous platinum-containing regimen. Patients received nab-paclitaxel at 260 mg/m2 intravenously every 3 weeks. Treatment continued until disease progression or occurrence of unacceptable toxic effects. The primary endpoint was objective tumour response, defined by a complete response (CR) or partial response (PR) according to Response Evaluation Criteria In Solid Tumors (version 1.0) criteria. Tumour response and safety were assessed in all patients who received at least one cycle of nab-paclitaxel. This study is registered with ClinicalTrials.gov, numberNCT00683059.

Findings

We enrolled 48 patients between Oct 16, 2008, and June 23, 2010. Patients received a median of six cycles (range one to 15). 47 patients were evaluable; one (2·1%) had a CR and 12 (25·5%) had PRs, resulting in an overall response of 27·7% (95% CI 17·3—44·4). The most frequently recorded adverse events of any grade were fatigue (38 of 48; 79%), pain (37 of 48; 77%), alopecia (34 of 48; 71%), and neuropathy (30 of 48; 77%). The most frequently recorded adverse events of grade 3 or higher were pain (11 of 48; 23%), fatigue (five of 48; 23%), hypertension (three of 48; 6%), neuropathy (three of 48, 6%), and joint stiffness or pain (two of 48; 4%).

Interpretation

Nab-paclitaxel was well tolerated in this population of patients with pretreated advanced urothelial cancer with an encouraging tumour response. These results warrant further study of nab-paclitaxel in second-line treatment of urothelial cancer.

Source: Lancet

For Multiple Heart Blockages, Bypass Surgery or Stents?


Study Compares Pain, Quality of Life After Drug-Coated Stents or Coronary Artery Bypass Surgery

For patients who have several blocked arteries around their heart, the gold standard treatment has long been coronary artery bypass surgery.
Now a large clinical trial suggests that drug-coated stents, springy lattice tubes used to prop open clogged arteries, may also work well in patients with multiple blockages. And in some patients, the stents produce equally good results with faster recovery times.

The caveats, experts say, are that people with daily or weekly chest pain from advanced coronary artery disease will probably experience slightly better relief from bypass surgery compared to stenting; but they can also count on waiting to get the full benefit of that procedure weeks to months longer than people who get stents.
Experts say the study, which is published in The New England Journal of Medicine, brings to light important trade-offs that people with complex coronary artery disease need to weigh before making a decision between the two procedures.

“I think the message here, therefore, is not a simple one — that there’s a clear winner — but that patients will need to choose based on their own priorities and values,” says study researcher David J. Cohen, MD, a cardiologist at St. Luke’s Mid America Heart Institute in Kansas City, Mo.
Independent experts agree.
“If you take the 50,000-mile view, it looks like these procedures got about the same results,” says A. Marc Gillinov, MD, cardiac surgeon at the Sydell and Arnold Miller Family Heart & Vascular Institute at Cleveland Clinic, in Ohio. “But if you really dig down and look at the clinical circumstances going in, you’ll see there are important differences. So the real value in this study is that it can help patients and doctors make informed decisions on an individual basis.”

A Visual Guide to Heart Disease
Comparing the Effectiveness of Stents vs. Bypass

For the study, researchers at 85 medical centers around the world randomly assigned 1,800 patients with at least three clogged arteries around their hearts, or alternatively, a clogged left main coronary artery — the vessel that carries the lion’s share of blood to the heart’s primary pumping chamber — to one of two treatments: coronary artery bypass graft (CABG) surgery or percutaneous coronary intervention (PCI).
In CABG, surgeons typically saw through the breast bone and open the rib cage, a procedure that, in and of itself, requires significant downtime for recovery. Doctors usually also need to make incisions in other parts of the body, often the legs, to harvest healthy vessels that can be used to bypass blockages.
PCI, a catheter is threaded through an artery in the groin up to the heart, where a doctor uses a video monitor and radioactive dye to locate the blockages within arteries. The doctor then inflates a balloon to compress the buildup against the artery walls and places a stent to hold the spot open.

The stents in this trial were coated with the drug paclitaxel, which is thought to help prevent the formation of scar tissue around the site of stent implantation, a problem called restenosis.
Before any procedure was performed, an interventional cardiologist and a cardiac surgeon consulted together on each case. If there was mutual agreement that the blocked vessels might be effectively opened using either procedure, the patient was cleared to enter the study.

Before patients were assigned to one procedure or the other, doctors asked patients questions about how often and how strongly they’d been feeling angina, or chest pain, their physical limitations and general quality of life. Based upon the answers, patients were scored on a scale of 1 to 100, with higher scores indicating fewer symptoms and better health status.

Those questions were asked again one month, six months, and 12 months after their procedures.

A disease severity score was also determined at study entry for each patient. This score is dependent upon the degree and extent of blockages as demonstrated on the initial angiogram, with higher scores indicating more complex disease. For subsequent analysis purposes, the patients in the study were divided into three subgroups depending upon their disease severity scores (0 to 22, 23 to 32, and 33 to 83).

In all, 903 patients received stents, while 897 had bypass surgery. In both cases, doctors tried to open all the arteries that were at least 50% blocked.

In the first phase of the study, which was published in 2009, researchers looked primarily at the risk of having a major event, like a heart attack, stroke, or having to reopen an artery that had clogged a second time. After one year, there were about 5% fewer total events in the bypass group compared to the stent group, 12.4% compared to 17.8% respectively.

More patients needed to have clogged arteries reopened in the PCI group than in the CABG group, 13.9% vs. 5.9%, respectively.

After one year, the rate of heart attack or death was similar between the two groups, while stroke was more likely to occur in the bypass group (2.2%) compared to the stent group (0.6%).
Looking at Quality of Life

When researchers looked at angina and quality of life in study participants, overall, both groups fared well. In fact, slightly more than half of people in both groups reported substantial improvement in angina as early as one month after their procedures.

But when investigators looked at those measures across various time points, and in people with more and less severe disease, differences emerged.

As was expected, people who got stents generally felt better faster, compared to the group that had bypass surgery, probably because there was less healing time required after the less invasive procedure.

But by six and 12 months after their procedures, both groups reported nearly equal improvements in physical functioning, pain, vitality, and social and mental health.

And after six months, researchers say people that went into the study with daily or weekly chest pain experienced greater relief after CABG than did those who got PCI.

“Angina relief at six months and a year was better with bypass surgery, though the difference was small,” says Cohen. “But there were clear differences in the early quality of life on a wide range of dimensions that clearly favored PCI, but those benefits were transient,” he says.

The study was sponsored by Boston Scientific, which produces paclitaxel-coated stents.

source: webMD