Lung Cancer in the News

November is National Lung Cancer Awareness Month. It started in 1995 as Lung Cancer Awareness Day and expanded as the lung cancer community grew and awareness of the disease increased. In this issue, we explore some of the lung cancer–related highlights from the European Cancer Congress (ESMO/ECCO/ESTRO), held September 27-October 1, 2013, in Amsterdam, the Netherlands.

Second-Generation ALK Inhibitor Regresses CNS Metastases in NSCLC

A novel ALK/EGFR (anaplastic lymphoma kinase/epidermal growth factor receptor) inhibitor—AP26113 (ARIAD Pharmaceuticals, Inc.)—achieved good responses in crizotinib-resistant and crizotinib-naive patients with non-small cell lung cancer (NSCLC) as well as radiographic regression of central nervous system (CNS) metastases in these patients. The results of the first-in-human phase 1/2 dose-finding study of AP26113 were presented by D. Ross Camidge, MD, University of Colorado, Denver.

Half of all ALK-positive patients with NSCLC who develop crizotinib resistance become resistant in the brain, suggesting that crizotinib has inadequate CNS exposure. Systemic progression typically occurs later in the course of disease.

Phase 1 was a 3x3 dose escalation study in 30 to 60 patients with various advanced malignancies. In phase 2, there were 5 cohorts—4 with NSCLC (n = 85 total) and 1 with other cancers amenable to ALK inhibition (n = 20).

The identified dose of 180 mg/day was used in phase 2 initially, but some patients developed pulmonary symptoms at that level, which resolved with steroids over 1 week. The decision was made to use a step-up approach of 90 mg/day for the first week on drug, and then move to 180 mg/day, Camidge said.

Other adverse events included gastrointestinal disturbances, and these were mainly mild. Elevated liver enzymes were reported in 12% of patients. Treatment-emergent grade 3 or higher adverse events were reported in 2% to 4% of patients across all dose levels.

Objective response rate was 65%. Response rate in patients previously treated with crizotinib was 61%; all 3 crizotinib-naive patients responded (100%), 1 with a complete response.
Eight of 10 patients with CNS metastasis had radiographic evidence of regression, and this improvement lasted from 8 to 40 weeks.

Responses were seen in some patients with the T790M mutation who were treated with the drug. Among 12 treated patients with the T790M mutation, 5 had stable disease, 4 had progressive disease, and 3 discontinued the study before receiving treatment.

These data are preliminary. More experience is needed to determine if the drug will be an improvement on crizotinib. At least 2 other second-generation ALK inhibitors are in development, and these drugs also appear to achieve radiographic regression in CNS metastases.

Reference
Camidge DR, Bazhenova L, Salgia R, et al. Updated results of a first-in-human dose-finding study of the ALK/EGFR inhibitor AP26113 in patients with advanced malignancies. Presented at: 2013 European Cancer Congress; September 27-October 1, 2013; Amsterdam, the Netherlands. Abstract 3401.

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Disappointing Results of Vaccine

Maintenance therapy with a therapeutic tumor cell vaccine (belagenpumatucel-L [Lucanix], NovaRx Corporation) failed to improve survival compared with placebo in a phase 3 study of patients with stage IIIA/B and IV non-small cell lung cancer (NSCLC).

The vaccine is composed of 4 different, allogeneic NSCLC cell lines genetically modified to block transforming growth factor beta (TGF-b). The cells are irradiated and cryopreserved until the vaccine is used.

“Most tumors use TGF-b to evade the immune system. Activated T and B cells are refractory to TGF-b inhibition,” explained lead author Giuseppe Giaccone, MD, associate director of clinical research at the Lombardi Comprehensive Cancer Center at Georgetown University in Washington, DC (formerly of the National Cancer Institute).

The trial took place in 8 countries at 73 clinical sites and enrolled 532 patients (42 stage IIIA and 490 stage IIIB/IV) with no disease progression after up to 6 cycles of frontline therapy. Four to 17 weeks after chemotherapy, patients were randomized in a 1:1 ratio to receive double-blind therapy with either the vaccine or placebo as maintenance therapy.

Vaccine treatment consisted of 18 monthly injections followed by 2 quarterly injections. The primary end point of the trial was overall survival (OS).

Median OS in this group of patients is usually about 10.4 months. The investigators were hoping to achieve 14 months of survival with the vaccine.

At 6 months of follow-up, OS was 20.3 months in the vaccine arm versus 17.8 months in the placebo arm, which was much higher than anticipated for placebo. An exploratory subgroup analysis showed that patients enrolled within 12 weeks of chemotherapy had a trend toward improved survival in the vaccine arm.

Stage IIIB/IV patients had significantly improved survival in the placebo arm if they received radiation, Giaccone said.

“In this study, progression-free survival did not correlate with overall survival,” he said.
The rate of serious adverse events was low, with only 5 patients experiencing 1 of these events. The most common adverse events were immune related and included injection site reaction, erythema, induration, rash, and local effects.

Prospective studies are planned in stage IIIB/IV patients, he said.

“This is a negative study. The expected difference in survival favoring the vaccine is 3.5 months, but the actual difference between the vaccine and placebo is only 2.5 months,” said formal discussant Rolf A. Stahel, MD, University Hospital Zurich, Switzerland.

“This is another example where a promising phase 2 trial does not have phase 3 confirmation,” he added.

Reference
Giaccone G, Bazhenova L, Nemunaitis J, et al. A phase III study of belagenpumatucel-L therapeutic tumor cell vaccine for non-small cell lung cancer (NSCLC). Presented at: 2013 European Cancer Congress; September 27-October 1, 2013; Amsterdam, the Netherlands. Late-Breaking Abstract 2.

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QOL Improved With Crizotinib Versus Chemotherapy

In the ongoing phase 3 PROFILE 1007 study of patients with previously treated anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer, crizotinib improved quality of life (QOL) and key lung cancer symptoms compared with chemotherapy (investigator’s choice: pemetrexed or docetaxel). Crizotinib was associated with a significantly higher improvement rate in global QOL compared with chemotherapy in all domains, said Vera Hirsh, MD, McGill University, Montreal, Canada.

“These improvements in QOL are particularly impor-tant for this palliative group of patients. Our findings support the improvement in PFS [progression-free survival] seen in the trial with crizotinib,” she said.

The QOL study randomized 172 patients to receive crizotinib and 171 to standard-of-care chemotherapy with either pemetrexed or docetaxel. Patient-reported outcomes were assessed at baseline, on day 1 of each cycle, and at the end of treatment using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) and lung cancer module QLQ-LC13. Scores on these instruments ranged from 0 to 100, with higher scores reflecting higher symptom severity or better functioning/QOL, depending on the instrument and question.

A 10-point or greater change from baseline was deemed clinically meaningful for either improvement or worsening.

As of March 30, 2012, 162 patients in the crizotinib arm and 151 in the chemotherapy arm completed at least 1 question at baseline, and this population was analyzed for QOL.
Baseline scores were well balanced between the 2 arms and were relatively low. Crizotinib achieved significantly greater improvement in global QOL versus chemotherapy (42.6% vs 20.7%, respectively; P <.001). Crizotinib also significantly improved physical functioning (27.2% vs 11.9%; P <.001), role functioning (30.9% vs 14.6%; P <.001), and emotional functioning (37.0% vs 24.0%; P <.05).

Lung cancer symptoms were significantly improved in the crizotinib arm versus chemotherapy (P <.001 for all comparisons): fatigue (46.3% vs 20.5%, respectively), pain (43.8% vs 20.5%), cough (55.3% vs 33.3%), dyspnea (39.1% vs 17.3%), chest pain (40.0% vs 22.3%), and pain in arm or shoulder (33.5% vs 19.5%).

Domains significantly worsened on crizotinib (P <.001 for both comparisons) were constipation (44.4% vs 22.5%) and diarrhea (41.4% vs 19.2%).

“Deterioration was slowed in a significantly greater proportion of patients in the crizotinib arm versus chemotherapy,” Hirsh reported.

The study was supported by Pfizer Inc.

Reference
Blackhall F, Hirsh V, Kim DW, et al. Impact of crizotinib on patient-reported symptoms and global quality of life (QoL) compared with chemotherapy in a phase III study of advanced alk-positive non-small cell lung cancer (NSCLC). Presented at: 2013 European Cancer Congress; September 27-October 1, 2013; Amsterdam, the Netherlands. Abstract 3400.

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MPDL3280A in Advanced NSCLC

For the first time, a therapy for non-small cell lung cancer (NSCLC) has achieved more responses in smokers than nonsmokers. The antibody MPDL3280A also achieved good responses in the squamous and adenoma histologic types of NSCLC.

These phase 1 study results in patients with metastatic NSCLC were so encouraging that experts suggested bypassing phase 2 and going directly to phase 3 studies.

Genentech’s development program for the monoclonal antibody includes ongoing recruitment for phase 2 and 3 trials in NSCLC.

“We are at the beginning of a new era. After 30 years of research in immunotherapy for lung cancer, we have one that works, and it works in smokers,” said lead author Jean-Charles Soria, MD, Institut Gustave Roussy, Paris, France, at the European Cancer Congress. “In this study, smokers responded much better than nonsmokers. This is great news for lung cancer patients—the majority are current or former smokers. The data are preliminary, but the trends are extremely promising,” Soria added.

The study results were based on 85 patients (53 evaluable for efficacy) who received treatment with an intravenous infusion of MPDL3280A every 3 weeks for a median duration of 106 days (range, 1-450 days). Median duration of therapy was 48 weeks.

Of the 85 patients with NSCLC, 55% were heavily pretreated with 3 or more previous therapies and the majority were smokers or ex-smokers (81%); 19% never smoked.

MPDL3280A was considered safe. Most adverse events were mild. No dose-limiting toxicities were identified in this trial, nor was any grade 3 to 5 pneumonitis or diarrhea reported. Grade 3 and 4 adverse events were reported in 34%, but these were not necessarily treatment related, as some were cancer related (ie, dyspnea, fatigue).

Objective response rate (ORR) was 24% in the overall population and 23% in patients with NSCLC; 17% of responders were stable over 24 weeks.

The 24-week progression-free survival rate was 44% in squamous cell NSCLC and 46% in nonsquamous cell NSCLC.

PD-L1 expression (the target of MPDL3280A) was directly correlated with response, with the best response seen in those with the highest expression of PD-L1 on immunohistochemistry (IHC 3). Those with IHC 3 also had less progressive disease. Although based on very small numbers of patients, ORR was 46% in patients with PD-L1 IHC 2 and IHC 3, and 86% in those with IHC 3.
Responses were sustained over time in all patients except one, Soria said.

Smoking status was a predictor of response; former/current smokers had an ORR of 26% (n = 43) compared with 10% in never-smokers (n = 10).

Reference
Soria JC, Cruz C, Bahleda R, et al. Clinical activity, safety and biomarkers of PD-L1 blockade in non-small cell lung cancer (NSCLC): additional analyses from a clinical study of the engineered antibody MPDL3280A (anti-PDL1). Presented at: 2013 European Cancer Congress; September 27-October 1, 2013; Amsterdam, the Netherlands. Abstract 3408.

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Who Should Get CT Screening

Computed tomography (CT) screening is expensive and should be targeted to high-risk patients when the benefits exceed the harms. A late-breaking abstract used modeling based on a hypothetical US cohort of 100,000 people from an analysis by the National Lung Screening Trial. That study found a 20% reduction in mortality with CT screening of high-risk populations.

In 100,000 people, the most efficient use of annual lung cancer CT screening was for those individuals between the ages of 55 and 80 with at least 30 pack-years of smoking and who quit within 15 years, reported Harry J. de Koning, MD, Erasmus Medical Center, Rotterdam, the Netherlands.

“If you go above that strategy, you exceed the harms, with more radiation exposure, more overdiagnosis and overtreatment, and higher cost,” he said.

De Koning and his coinvestigators used 5 different models to estimate the harms and benefits in this population born in 1950 and followed up from ages 45 to 90 years. They evaluated 576 possible scenarios and found that triennial screening programs reduced lung cancer mortality by 5% to 6%, biennial screening programs by 7% to 10%, and annual screening programs by 11% to 21%.

If screening were limited to the group they identified (age 55-80 years; 30 pack-years, quitting within the past 15 years), this would result in 19.3% of the cohort being screened at least once, 287,000 CT screens, 1971 screen-detected cases, 50% of lung cancers being detected at an early and treatable stage, a 14% reduction in lung cancer mortality (avoiding 520 deaths), and 5500 life-years gained. To avoid 1 lung cancer death, 550 screens are needed.

These benefits must be balanced against 330,000 CT exams, 66,000 false-positive results, and an estimated overdiagnosis rate of 4% (190 lung cancers), as well as 24 deaths due to radiation exposure.
Formal discussant of this trial, Dirk de Ruysscher, MD, University Hospitals Leuven, Belgium, said that lung cancer survivors are also in the highest risk group, even after 18 years of survivorship.

“Five years later, survivors are in the highest risk group of developing lung cancer. After 10 years, 23% of those survivors will die of lung cancers [probably a second primary]; after 15 years, 35% will die of lung cancer; and after 18 years, 40% will die of lung cancer. That is about 2% per year,” de Ruysscher said.
Perhaps this type of modeling could be used to follow up patients treated for primary lung cancer, and be extended to survivors, he suggested.

Reference
De Koning HJ, Plevritis SK, Meza R, et al. Benefits and harms of computed tomography lung cancer screening programs for high risk populations—using evidence from the 2 largest randomized controlled trials on lung cancer screening worldwide. Presented at: 2013 European Cancer Congress; September 27-October 1, 2013; Amsterdam, the Netherlands. Late-Breaking Abstract 14.