Prophylactic cranial irradiation fails to improve overall survival in NSCLC

Dr Alex Sun.

An updated 10-year analysis of the RTOG 0214 trial showed that the use of prophylactic cranial irradiation (PCI) improved disease-free survival (DFS) and reduced brain metastases, but failed to improve overall survival (OS) in patients with locally advanced non-small-cell lung carcinoma (LA-NSCLC).

The results of the 10-year follow-up of this phase III study, done from September 2001 to August 2007 in 356 patients with stage III A/B LA-NSCLC (median age, 60), showed that PCI did not improve OS rate vs observation alone (17.6 percent vs 13.3 percent; hazard ratio [HR], 1.23; 95 percent confidence interval [CI], 0.95 to 1.59; p=0.124)  [Sun A, et al, WCLC 2018 abstract OA01.01]

Patients who underwent PCI, however, experienced better DFS (12.6 percent vs 7.5 percent; HR, 1.32; 95 percent CI, 1.03 to 1.69; p=0.0298) and less central nervous system (CNS) metastasis (16.7 percent vs 28.3 percent; HR, 2.33; 95 percent CI, 1.31 to 4.15; p=0.0298) vs those who were just observed.

“There was only 45 percent power to detect the hypothesized difference [HR=1.25], and if we were able to accrue the targeted number, there may have been a benefit in OS,” said study investigator Dr Alex Sun from the University of Toronto, Toronto, Ontario, Canada.

“As compared with previous trials, PCI employing delivery of 30 Gy in 15 fractions as used in the RTOG 0214 study might also be too low a dose to exert its desirable effects,” commented discussant Dr John Armstrong of St Luke’s Radiation Oncology Network, Dublin, Ireland. [Radiat Oncol 2016;11:67]

“However, a subgroup analysis among 225 patients who did not have surgery as primary treatment showed that patients who underwent PCI had better OS [p=0.026] and DFS [p=0.014] and a lower incidence of brain metastases [p=0.003],” said Sun.

Most patients in the study experienced grade 1 (14.6 percent) or grade 2 (35 percent) acute toxicities or grade 1 (12.7 percent) or grade 2 (8.7 percent) late toxicities, with neurocognitive-associated toxicities being the most commonly reported.

“The most probable reason why we do not do much PCI is due to concerns about its reported toxicities such as somnolence, cognitive disturbances, neuropathy, memory impairment and dizziness. It is difficult to convince patients to undergo a procedure which will unlikely alter their survival,” said Armstrong. [J Clin Oncol 2018;36:2366-2377]

A previous study in 113 cancer patients with brain metastases showed that hippocampus-sparing intensity-modulated radiation therapy (IMRT) is associated with a significantly lower decline in Hopkins Verbal Learning Test-Revised Delayed Recall scores vs historical controls (p<0.001). [J Clin Oncol 2014;32:3810-3816]

In the future, PCI in NSCLC is foreseen to involve identification of ultra-high-risk individuals and performance of research which can be used for profiling patients who will experience brain metastases. For these patients, aggressive surveillance with volumetric MRI and early intervention with stereotactic surgery should be performed.

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.


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 (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.

Clinical Translation and Validation of a Predictive Biomarker for Patritumab, an Anti-human Epidermal Growth Factor Receptor 3 (HER3) Monoclonal Antibody, in Patients With Advanced Non-small Cell Lung Cancer


  • High heregulin levels predict benefit from patritumab treatment in patients with NSCLC.

    A prospective–retrospective approach provisionally validated a predictive biomarker.

    Post hoc analyses can be used to test underlying assumptions in biomarker validation.

    The median may be a reasonable initial cutoff for a unimodal continuous biomarker.



During early clinical development, prospective identification of a predictive biomarker and validation of an assay method may not always be feasible. Dichotomizing a continuous biomarker measure to classify responders also leads to challenges. We present a case study of a prospective–retrospective approach for a continuous biomarker identified after patient enrollment but defined prospectively before the unblinding of data. An analysis of the strengths and weaknesses of this approach and the challenges encountered in its practical application are also provided.


HERALD (NCT02134015) was a double-blind, phase 2 study in patients with non-small cell lung cancer (NSCLC) randomized to erlotinib with placebo or with high or low doses of patritumab, a monoclonal antibody targeted against human epidermal growth factor receptor 3 (HER3). While the primary objective was to assess safety and progression-free survival (PFS), a secondary objective was to determine a single predictive biomarker hypothesis to identify subjects most likely to benefit from the addition of patritumab. Although not identified as the primary biomarker in the study protocol, on the basis of preclinical results from 2 independent laboratories, expression levels of the HER3 ligand heregulin (HRG) were prospectively declared the predictive biomarker before data unblinding but after subject enrollment. An assay to measure HRG mRNA was developed and validated. Other biomarkers, such as epidermal growth factor receptor (EGFR) mutation status, were also evaluated in an exploratory fashion. The cutoff value for high vs. low HRG mRNA levels was set at the median delta threshold cycle. A maximum likelihood analysis was performed to evaluate the provisional cutoff. The relationship of HRG values to PFS hazard ratios (HRs) was assessed as a measure of internal validation. Additional NSCLC samples were analyzed to characterize HRG mRNA distribution.


The subgroup of patients with high HRG mRNA levels (“HRG-high”) demonstrated clinical benefit from patritumab treatment with HRs of 0.37 (P = 0.0283) and 0.29 (P = 0.0027) in the high- and low-dose patritumab arms, respectively. However, only 102 of the 215 randomized patients (47.4%) had sufficient tumor samples for HRG mRNA measurement. Maximum likelihood analysis showed that the provisional cutoff was within the optimal range. In the placebo arm, the HRG-high subgroup demonstrated worse prognosis compared with HRG-low. A continuous relationship was observed between increased HRG mRNA levels and lower HR. Additional NSCLC samples (N = 300) demonstrated a similar unimodal distribution to that observed in this study, suggesting that the defined cutoff may be applicable to future NSCLC studies.


The prospective–retrospective approach was successful in clinically validating a probable predictive biomarker. Post hoc in vitro studies and statistical analyses permitted further testing of the underlying assumptions. However, limitations of this analysis include the incomplete collection of adequate tumor tissue and a lack of stratification. In a phase 3 study, findings are being confirmed, and the HRG cutoff value is being further refined.


Genetic Testing in New NSCLC: Worth the Effort?

“If you build it, they will come,” the saying goes, but has that been the case with genetic/genomic testing in patients with newly diagnosed non-small cell lung cancer (NSCLC)? After all, research has shown that about 40% of patients with NSCLC have one of these molecular alterations in their tumor, and using these tests can help sort out those who have KRAS-mutated disease, versus epidermal growth factor receptor (EGFR) mutations, versus ALK, ROS1, or RET translocations, guiding patients to the most effective targeted therapy.

A recent international survey of oncologists revealed that while the use of genetic/genomic is on the rise, many clinicians are either bypassing testing altogether, or if the patient did undergo testing, the results were not used to make treatment decisions.

 Overall, genetic testing can help clinicians get a better handle on the subtype of NSCLC they are contending with, based on specific molecular alterations. This improved disease description will give patients a better chance of receiving the most effective treatment with the least toxicity and, ideally, at the right price point.

For instance, EGFR mutations are currently the most common genomically classified subgroup of NSCLC. These mutations tend to be more prevalent in tumors with adenocarcinoma histology, in patients who have never smoked tobacco, in patients of East Asian race, and women. Results of genetic/genomic testing can then set patients up for treatment with agents such as gefitinib (Iressa) and erlotinib (Tarceva).

Guidelines established by specialty groups, including the College of American Pathologists and the International Association for the Study of Lung Cancer, recommend testing for EGFR mutations (along with testing for ALK mutations) in patients with advanced-stage disease. Whether early-stage patients should undergo the same is uncertain.

“The question of whether or not to test a diagnostic specimen in early-stage disease is a local decision that must be made in conjunction with each institution’s oncology care team, as insufficient published evidence supports a universal recommendation,” according to 2013 guidelines from the groups mentioned above. “The benefits of testing all early-stage disease patients must be balanced against the cost of performing testing that may not be used to select therapy for the patients who never have relapse.”

But genetic screening in early NSCLC isn’t out of the question, wrote Jean-Charles Soria, MD, PhD, of Gustave Roussy Cancer Center in Villejuif, France, in an email to MedPage Today. He pointed out that there is a debate over the risk of relapse in stage I-II cancer, but even if that risk is over a 5-year period, it “reaches 50%, so I also believe it could help.”

 Even in early-stage NSCLC, molecular testing can serve as a decisive factor in the choice of therapeutic strategies for patients, explained Frédérique Nowak, PhD, of the French National Cancer Institute (INCa) in Boulogne-Billancourt, France in an email to MedPage Today.

For example, early testing can rule out if a patient is simply ineligible for treatment with gefitinib, an EGFR tyrosine kinase inhibitor (TKI). Nowak cited a 2012 study that she and Soria co-authored that found that EGFR testing avoided a median of 8 weeks of administration of gefitinib for EGFR-negative patients.

An added benefit to testing? The potential for a significant reduction in treatment costs. “In France in 2010, about 15,000 of the 16,834 patients with lung cancer who benefited from EGFR screening were EGFR-mutation negative and thus were ineligible for TKI-EGFR treatment,” Nowak stated.

“As 8 weeks of gefitinib treatment costs €4,600 per patient in France [about $5,000], this would mean overall savings of €69 million [about $74 million]. According to the numbers of EGFR tests performed in 2011, the spared costs should be even greater,” she added.

Seven years ago, INCa, along with the French Ministry of Health, launched a campaign to implement molecular testing for all cancer patients across the French national healthcare system. The network is made up of 28 regional molecular genetic centers that perform tests for free for all patients in their regions.

 Nowak reported that the network now “is fully deployed in the country. For lung cancer, the tumors of more than 24,000 patients were screened for EGFR mutation and ALK rearrangement in 2014. It roughly corresponds to all non-epidermoid NSCLC patients at a metastatic stage in France.”

Back to the survey results, which revealed that one of the impediments to implementing genetic testing in newly diagnosed patients may be the wait for the results – the turnaround time for test findings can range from 1 to 2 weeks. About a quarter of U.S.-based survey respondents stating that was too long.

In general, lung cancer takes some time to develop before a diagnosis is made; a few extra days of waiting for test results that can have a major impact on treatment course and patient outcomes shouldn’t be that onerous, noted survey leader James Spicer, PhD, MBBS, of King’s College London.

“Personally — and I think this is a fairly common viewpoint — turnaround within 1 week — 5 working days — would definitely be acceptable; 2 weeks or more becomes a problem,” he said.

While Spicer told MedPage Today that he wasn’t surprised by the survey results, his group also did not find any evidence that clinicians were skeptical about EGFR testing overall. Instead, it may be a matter of continual education to emphasize the benefits of genetic testing in NSCLC patients across the board.

“We should be aiming for every suitable NSCLC patient to be tested, and every patient receiving an appropriate treatment for their type of lung cancer,” Spicer said in a written statement about the survey results. He added that “there is still work to be done in emphasizing the importance of obtaining EGFR test results prior to the initiation of treatment, and using this vital information to select optimum therapy.”

NSCLC patients with uncommon EGFR mutations respond poorly to EGFR-TKIs

Advanced non-small cell lung cancer (NSCLC) patients with uncommon mutations did not respond as well to first generation epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) as those with more common mutations, according to a small, retrospective Japanese study presented at the IASLC Asia Pacific Lung Conference (APLCC) 2016, held recently in Chiang Mai, Thailand.

NSCLC patients with common EGFR mutations, such as exon 19 deletions or L858R mutations, respond well to standard EGFR-TKI therapy but the efficacy for patients with less common mutations is unknown.

Using a patient database from the Kinki-chuo Chest Medical Center and Osaka Prefectural Medical Center for Respiratory and Allergic Diseases in Osaka, Japan, researchers selected 41 NSCLC patients with uncommon mutations who had been treated with the first-generation EGFR-TKIs gefitinib or erlotinib as monotherapy between 2007 and 2014. Median patient age was 71 years. [APLCC 2016, abstract PA25]

The researchers identified the uncommon G719X, L861Q, and S768I EGFR mutations (in single and complex combinations) for inclusion in the experimental arm of the study.

Median progression-free survival (PFS), defined as the interval between first EGFR-TKI initiation and the date when progressive disease or death was first documented, was 3.5 months among all patients with uncommon mutations. Median overall survival (OS), defined as from the date of first anti-tumour agent initiation until the date of death, or the last follow-up visit, was 6.3 months.

Among NSCLC patients with common EGFR mutations, PFS tends to be longer, about 10 months, than those without such mutations, though OS seems unaffected, making them good predictive biomarkers for EGFR-TKI therapy. [N Engl J Med 2010;362:2380-2388; J Thorac Oncol 2009;4:22-29]

Treatment response varied among patients with uncommon mutations, with L861Q and G719A mutations responding better than those with G719B or G719C mutations. In fact, G719C-mutated patients responded notably worse compared to the rest of the patients with other uncommon mutations, the researchers said.

Doublet therapy may be best treatment option for elderly patients with NSCLC

Platinum-based doublet chemotherapy may be the best treatment option for elderly patients with advanced non-small cell lung cancer (NSCLC) who are fit, whereas monotherapy using either gemcitabine, vinorelbine, or taxanes should be a valid option for those who are less fit, according to an expert who spoke at the Asia Pacific Lung Cancer Conference 2016 held recently in Chiang Mai, Thailand.

To prove this point, Dr. Silvia Novello, assistant professor at the Department of Oncology, University of Turin in Turin, Italy reviewed  findings from a well-known French trial that examined the effects of using carboplatin plus paclitaxel versus vinorelbine or gemcitabine monotherapy in a cohort of 451 patients aged 79 to 89 years with stage III to IV NSCLC. Primary endpoint was overall survival, and analysis was done by intention to treat.

Platinum-based doublet chemotherapy provided significant survival benefits compared with vinorelbine or gemcitabine monotherapy. Median overall survival was 10.3 months for doublet and 6.2 months for single-agent chemotherapy (p<0.0001), with 1-year survival rate of 44.5 and 25.4 percent, respectively. Toxicity was higher with doublet chemotherapy than with monotherapy. [Lancet 2011;378:1079-88]

The survival curves are impressive, Novello said. “There is a statistical significance, but there is also a difference in terms of toxicity profile.”

Greater toxicity may be an issue in immunotherapy when considering treatment options outside doublet chemotherapy regimens. Novello cited an unplanned analysis of data on fit elderly patients (aged ≥70 years) with advanced NSCLC from the Eastern Cooperative Oncology Group Trial 4599 who were randomized to paclitaxel plus carboplatin with bevacizumab (PCB) or PC only.

In the subset of elderly NSCLC patients, PCB versus PC did not result in improved survival and was further associated with a higher degree of toxicity, she said. Grade 3 to 5 toxicities occurred in 87 percent of elderly patients in the PCB arm compared to 61 percent in the PC arm, with treatment-related deaths of 7 and 1, respectively. [J Clin Oncol 2008;26:60-65]

“What is more important is that when comparing the toxicity between the elderly and younger population, there is a statistically significant difference in the PCB arm that is not true for the arm without bevacizumab,” she said.

In elderly patients with epidermal growth factor receptor (EGFR)-activating mutations, EGFR tyrosine kinase inhibitors (TKIs) are recommended as a first-line treatment, with gefitinib being the least toxic, said Novello.

Moreover, in those who failed previous chemotherapy, “there is a room to administer EGFR TKI as a second-line treatment because the efficacy is more or less the same compared to younger patients,” she added.

“[The approach to take when treating elderly patients with advanced NSCLC] is a choice, and we can make this choice by making the right screening in elderly patients.”

Dr. Silvia Novello from the University of Turin (APLCC 2016)

Dr. Silvia Novello from the University of Turin (APLCC 2016)

Novello underlined several factors must be taken into account in the management of lung cancer in this particular population. These include the absence of an agreement on the definition of “elderly,” existence of comorbid conditions, underrepresentation in clinical trials, limited social and financial resources, and adoption of biological rather than chronological age to guide medical decision.

However, she noted that it is difficult to ascertain the biological age as there are no specific biomarker or test to properly detect the maturity of the cells.

In addition, changes occurring with age should also be considered, such as increased body fat, decreased total body water, altered gastrointestinal system, and reduced renal, hepatic, and hematopoietic function, she said.

“This at the end means a different pharmacodynamics, especially with drugs requiring conversion to active metabolites, and increase in terms of toxicity not only related to chemotherapy,” Novello noted.

She proposed classifying elderly patients into three clinically meaningful categories, as follows: fit patients (functionally independent and without relevant comorbidity) who can receive full dose treatment; intermediate or vulnerable patients (dependent in one or more instrumental activities of daily living [IADLs] and/or have one or two significant comorbid conditions) who should receive special treatment precautions such as initial dose reduction and adequate home care; and frail patients (dependent on one or more ADLs, with three or more severe comorbidities, one or more geriatric syndromes, and aged >80 to 85 years) who are best suited for palliative and supportive care.

“We have to spend time, and the calculation in different publications is more or less 20 to 25 years to properly define elderly patients. In this way, we can probably better define the biological age, define which patients are good for clinical trials or for standard treatment or only for best supportive care,” she said.

FDA Approves First Immunotherapy-Companion Diagnostic Combo for Lung Cancer

On the heels of the U.S. Food and Drug Administration’s approval of acombination of immune checkpoint inhibitors for unresectable and metastatic melanoma comes yet another immunotherapy approval. This time it is pembrolizumab (Keytruda), an immune checkpoint inhibitor, being approved for patients with metastatic non-small cell lung cancer (NSCLC) that has progressed after other treatments, and whose tumors express the protein PD-L1.

Lung cancer cell
Illustration of lung cancer cell during cell division.

This is the first immunotherapeutic to be approved in conjunction with a companion diagnostic test, the PD-L1 IHC 22C3 pharmDx test, which can detect the presence of the protein PD-L1 in non-small cell lung tumors.

Pembrolizumab is the second drug in the class of immune checkpoint inhibitors to be approved for NSCLC, the first being nivolumab, which was approved for treating squamous NSCLC in March this year. Pembrolizumab works by blocking the PD-1/PD-L1 pathway that cancer cells sometimes engage in order to apply “brakes” on cancer-fighting T cells, preventing the T cells from doing their job. Blocking the PD-1/PD-L1 pathway releases the brakes on T cells and enables them to fight cancer cells.

The FDA’s approval is based on the results of a randomized clinical trial of 550 patients with advanced NSCLC. In a subgroup of patients who received pembrolizumab after their lung cancer progressed following chemotherapy or targeted therapy and whose tumors had PD-L1, the overall response rate was 41 percent, and the treatment effect lasted between 2.1 and 9.1 months.

Early results from this trial were presented in April at the AACR Annual Meeting 2015. At that time, describing the promising data from the study, Edward B. Garon, MD, associate professor of medicine at the David Geffen School of Medicine at the University of California, Los Angeles, said in a press release, “Neither the drug nor the biomarker test is approved for use in this setting at this time, but if I had a patient whose tumor had PD-L1 expression on at least half of the cells and if pembrolizumab was available, I think that I would find the data compelling to look at the drug as the treatment option for that patient.” The results of this study were published in the New England Journal of Medicine.

The Diagnostic Tests Dilemma

While immune checkpoint inhibitors are one of the most promising classes of drugs to be tested and approved in recent years, their use is not without challenges.

As individual pharmaceutical companies continue to develop diagnostic tests to identify patients most likely to benefit from the immune checkpoint inhibitor they are each developing, and as more and more therapeutics from this class of drugs are approved by the FDA for a range of cancer types, identifying the right drug in a reasonable timeframe and making it a cost-effective endeavor poses challenges for both the patient and his or her physician.

Recognizing the challenges and in an effort to develop some solutions, the FDA, the AACR, and the American Society of Clinical Oncology (ASCO) held a one-dayworkshop in March this year in Washington, D.C., titled “Complexities in Personalized Medicine: Harmonizing Companion Diagnostics across a Class of Targeted Therapies.”

A significant development to emerge from the workshop was a commitment from six companies to work together in the pre-competitive space and analytically characterize the performance of their individual PD-1/PD-L1 companion diagnostic test systems. The project is continuing to make strides, and results are expected to help build an evidence base for post-approval studies that will help inform patients, physicians, pathologists, and others on how best to use the tests to determine treatment decisions.

Targeted therapies for NSCLC underused

Nearly a quarter of patients with advanced non-small-cell lung cancer (NSCLC) in Europe, Asia and North America are started on first-line therapy before their EGFR mutation testing results are available, which compromises their access to individualized treatment.

The data, presented at the  European Lung Cancer Conference (ELCC) 2015 held recently in Geneva, Switzerland, came from an international survey that looked at the treatment practices of 562 treating physicians from 10 countries (Canada, France, Germany, Italy, Japan, Korea, Spain, Taiwan, UK and USA). [ELCC 2015, abstract LBA2_PR]

Mutation testing rate was similar in all three regions (82 percent in Asia, 77 in Europe and 76 in NA). “That’s suboptimal, as international guidelines recommend that all advanced NSCLC patients with nonsquamous histology should be tested, so they can receive appropriate treatment according to their mutation status,” remarked Dr. James Spicer of Guy’s hospital, London, UK, who reported the results.

The main reasons for not testing all patients, aside from tumour histology, are insufficient tissue, poor performance status, smoking, and long turnaround time for test results.

“In Asia, more patients are being tested for EGFR mutations and getting the results in a timely manner. Only 10 percent of Asian patients do not have the results before treatment decisions are made, vs 21 percent in North America and 26 percent in Europe,” noted Spicer.

The most important factor in the choice of first-line treatment across all regions was a clinically relevant increase in overall survival, but the survey showed that prescribing practices for EGFR-positive patients vary among regions.

“Physicians in North America and Asia offer significantly more first-line EGFR tyrosine kinase inhibitors [TKIs] than those in Europe [83, 81 and 76 percent, respectively]. Even when available, the use of mutation status to inform treatment decisions is variable, and a significant minority of EGFR-positive patients worldwide receive chemotherapy first, contrary to established guidelines,” he pointed out.

According to Spicer, the reasons why many patients with EGFR mutations receive chemotherapy first need to be understood. “Not being tested or being tested but not given a treatment associated with significant benefits affects patient outcomes,” he concluded.

The discussant, Professor Tony Mok of the Chinese University of Hong Kong, pointed out the survey’s limitations, including the small sample size, selection bias, and differences between types of physicians between continents.

“We don’t know whether the respondents were academic oncologists or private physicians, which may affect their access to EGFR analysis facilities,” he said. “Moreover, we don’t know whether testing or treatment selection had any financial implications for the patient or the physician. For example, were the respondents paid? Are testing and TKI therapy reimbursed?”

Mok also pointed out that a 2011 survey on EGFR mutation testing in Asia showed that overall, only 32 percent of Asian patients were tested, ranging from 18 percent in China to 65 in Japan. “The good news is that the proportion of those tested has been increasing steadily in the past few years,” he said.

“As for the choice of first-line therapy, I don’t think Europe is that different from Asia and North America,” he added.

Immune Checkpoint Drug Active in NSCLC

Tumors with at least 50% PD-L1 expression associated with unexpected improvement..

Patients with advanced non-small cell lung cancer (NSCLC) had almost a 50% response rate to an immune checkpoint inhibitor if their tumors tested positive for the checkpoint protein, according to data reported here.

Overall response to pembrolizumab (Keytruda) was 45.2% in patients whose tumors exhibited PD-L1 (programmed death-ligand 1) expression in at least 50% of cells. Patients who received the PD-L1 inhibitor as initial therapy had a 50% response rate.

The response rate fell off dramatically (17% or less) in tumors that had lower levels of PD-L1 expression, Edward B. Garon, MD, of the University of California Los Angeles, said at the American Association for Cancer Research (AACR) meeting. A fourth of the tumors met the 50% cutoff for PD-L1 expression.

“I think that, with this data, we can now confidently say that in previously treated patients, who have PD-L1 expression in at least half of their cells … pembrolizumab is associated with superior clinical outcomes, clearly, than would be anticipated with cytotoxic chemotherapy,” Garon said during an AACR press briefing.

“The outcomes in patients with lesser degrees of staining, in certain clinical scenarios, may also be better than what is seen with comparators, but complete data on that will require data from randomized studies.”

The results were reported simultaneously in the New England Journal of Medicine.

The PD-1 (L1) receptor/ligand system has a braking effect on immune function, specially T-cell function. Tumor cells that express PD-L1 effectively block the immune system’s ability to attack the tumor. In describing immune checkpoint inhibitors, such as pembrolizumab, researchers have often used the analogy of “taking the foot off the brakes” of the immune system and “giving it the gas.”

Approved in 2014 for advanced melanoma, pembrolizumab has demonstrated activity in multiple types of solid tumors, including NSCLC. Garon reported findings from a phase I study to examine the safety and efficacy of the PD-L1 inhibitor only in patients with advanced NSCLC and to validate PD-L1 expression as a biomarker to identify patients who are more likely to respond to the drug.

Investigators enrolled and treated 495 patients with one of three doses of pembrolizumab and subsequently randomized them to a training group (n=182) or a validation group (n=313) for the biomarker analysis. PD-L1 expression was determined from immunohistochemical staining of tumor samples, and results were reported as the proportion of tumor cells that stained positive for membranous PD-L1.

The training cohort comprised 171 previously treated patients and 11 with no prior therapy. After exclusions, 129 patients remained for PD-L1 expression cutoff values. In the validation cohort, 223 patients had received prior therapy, 90 had no prior treatment, and 156 were included in the PD-L1 expression analysis.

Overall, 19.4% of the patients had objective responses to treatment with pembrolizumab. The patients had a median duration of response was 12.5 months, median progression-free survival (PFS) of 3.7 months, and median overall survival (OS) of 12.0 months. None of the outcomes differed appreciably by dosage.

In the validation cohort, patients whose tumors had at least 50% staining for PD-L1 had an response rate of 45.2%, including 50% in patients with no prior therapy. Patients with PD-L1 expression in 1% to 49% of tumor cells had a response rate of 16.5% (19.2% in untreated patients), and the response rate declined to 10.7% for patients with <1% of cells that expressed PD-L1.

PD-L1 expression ≥50% was associated with a median PFS of 6.3 months, almost double the PFS associated with 1% to 49% expression (3.3 months) and nearly triple the PFS of patients whose tumors had the least PD-L1 expression (2.3 months). Patients with no prior treatment and ≥50% PD-L1 expression had a median PFS of 12.5 months.

Median OS has yet to be reached in the patients with ≥50% PD-L1 expression, regardless of treatment history. For patients with 1% to 49% PD-L1 expression, median OS was 7.3 months in previously treated patients and 16.2 months in the previously untreated subgroup. For the lowest level of PD-L1 expression, median survival was 8.6 and 10.4 months in the previously treated and untreated patients, respectively.

Garon said pembrolizumab was well tolerated. The most common adverse event was fatigue, occurring in about 20% of all patients (all grades). About 10% of patients developed pruritus and decreased appetite. No other adverse event occurred in as many as 10% of patients. Most adverse events were mild or moderate in severity.

Noting that three-fourths of the patients in the study had progressed on prior therapy, press briefing moderator Suzanne Topalian, MD, of Johns Hopkins Medicine in Baltimore, said pembrolizumab exceeded conventional expectations for second- and third-line therapy in advanced NSCLC.

“This is a very difficult-to-treat patient population where the impact of second- and third-line agents is generally not expected to prolong survival,” she said. “These results are especially impressive in this particular treatment setting.”

Topalian pointed out that the PD-L1 expression data are clear-cut, given that patients with less than 50% expression “still had notable response rates.” Garon agreed and said that one of the shortfalls of research on PD-L1 expression has been the inability to identify groups of patients who clearly will not respond to PD-L1 inhibition.

“The data are exciting and will be valuable for practitioners and patients to stratify their likelihood of benefiting,” he added.

Gene Involved in Lung Tumor Growth Identified.

Lung cancer researchers at St. Joseph’s Hospital and Medical Center in Phoenix, Ariz., in collaboration with researchers at the Translational Genomics Research Institute and other institutions, have identified a gene that plays a role in the growth and spread of non-small cell lung cancer tumors, opening the door for potential new treatment options.

The study, titled “Elevated Expression of Fn14 in Non-Small Cell Lung Cancer Correlates with Activated EGFR and Promotes Tumor Cell Migration and Invasion,” was published in the May 2012 issue of The American Journal of Pathology. Landon J. Inge, PhD, is the lead scientist in the thoracic oncology laboratory at St. Joseph’s Center for Thoracic Disease and Transplantation and was a member of the study’s research team.

Lung cancer is the leading cause of cancer deaths worldwide, and approximately 85 percent of these cancers are non-small cell lung cancers (NSCLC). Patients with NSCLC frequently have tumors with mutations in the epidermal growth factor receptor (EGFR) gene. When activated, this mutated gene leads to tumor development and growth. By studying lung cancer samples from patients who had undergone tumor resection, the researchers discovered that many patients with EGFR mutations also exhibited higher than normal levels of the gene fibroblast growth factor-inducible 14 (Fn14). The researchers believe that activation of EGFR can lead to increased expression and activity of the Fn14 gene.

The research team also discovered that while over-expression of Fn14 enhances lung tumor formation and metastasis, suppression of Fn14 reduces metastasis in NSCLC.

“Our data suggest that Fn14 levels can contribute to NSCLC cell migration and invasion,” says Dr. Inge. “Thus, tumor suppression through the targeting of Fn14 may prove to be a therapeutic intervention in NSCLC and other tumor types.”

The Fn14 gene has been found to be elevated in other types of tumors, as well, including glioblastoma and certain types of breast cancer, suggesting that Fn14 may be a therapeutic target for multiple cancer therapies.


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