Howard West

Gefitinib therapy in advanced bronchioloalveolar carcinoma: Southwest Oncology Group Study S0126.

PURPOSE Advanced bronchioloalveolar carcinoma (BAC) is a distinct subtype of non-small-cell lung cancer (NSCLC) for which there is currently no optimal therapy. Based on preclinical and clinical data suggesting relevance of the epidermal growth factor receptor (EGFR) axis in BAC, the Southwest Oncology Group initiated a phase II trial (S0126) to evaluate the EGFR tyrosine kinase inhibitor gefitinib in chemotherapy-naïve and chemotherapy-pretreated patients with advanced BAC. METHODS A total of 136 eligible and assessable patients (101 untreated, 35 previously treated) received gefitinib 500 mg daily until progression or prohibitive toxicity. RESULTS The median age was 68.0 years (range, 34.3 to 88.6); 51% were female; 89% had a performance status (PS) of 0% or 1% and 11% had a PS of 2. The Response Evaluation Criteria in Solid Tumors response rate was 17%, with 6% complete responses (CRs) among 69 previously untreated patients with measurable disease, and 9% with no CRs among 22 pretreated patients. Median survival was 13 months for both chemo-naïve (95% CI, 8 to 18) and previously treated patients (95% CI, 6 to 17). Overall survival at 3 years was 23% (95% CI, 14% to 32%). Toxicity consisted mainly of rash and diarrhea, but 2% of patients died of presumed interstitial lung disease. Exploratory subset analyses revealed improved survival among women (P = .031), patients developing a rash (P = .003), never-smokers (P = .061), and patients with a PS of 0 or 1 (P = .015). CONCLUSION Gefitinib is an active agent in advanced stage BAC. Several subsets demonstrate significantly improved clinical outcomes.

Brigatinib in Patients With Crizotinib-Refractory Anaplastic Lymphoma Kinase–Positive Non–Small-Cell Lung Cancer: A Randomized, Multicenter Phase II Trial

Purpose Most crizotinib-treated patients with anaplastic lymphoma kinase gene ( ALK)-rearranged non-small-cell lung cancer (ALK-positive NSCLC) eventually experience disease progression. We evaluated two regimens of brigatinib, an investigational next-generation ALK inhibitor, in crizotinib-refractory ALK-positive NSCLC. Patients and Methods Patients were stratified by brain metastases and best response to crizotinib. They were randomly assigned (1:1) to oral brigatinib 90 mg once daily (arm A) or 180 mg once daily with a 7-day lead-in at 90 mg (180 mg once daily [with lead-in]; arm B). Investigator-assessed confirmed objective response rate (ORR) was the primary end point. Results Of 222 patients enrolled (arm A: n = 112, 109 treated; arm B: n = 110, 110 treated), 154 (69%) had baseline brain metastases and 164 of 222 (74%) had received prior chemotherapy. With 8.0-month median follow-up, investigator-assessed confirmed ORR was 45% (97.5% CI, 34% to 56%) in arm A and 54% (97.5% CI, 43% to 65%) in arm B. Investigator-assessed median progression-free survival was 9.2 months (95% CI, 7.4 to 15.6) and 12.9 months (95% CI, 11.1 to not reached) in arms A and B, respectively. Independent review committee-assessed intracranial ORR in patients with measurable brain metastases at baseline was 42% (11 of 26 patients) in arm A and 67% (12 of 18 patients) in arm B. Common treatment-emergent adverse events were nausea (arm A/B, 33%/40%), diarrhea (arm A/B, 19%/38%), headache (arm A/B, 28%/27%), and cough (arm A/B, 18%/34%), and were mainly grades 1 to 2. A subset of pulmonary adverse events with early onset (median onset: day 2) occurred in 14 of 219 treated patients (all grades, 6%; grade ≥ 3, 3%); none occurred after escalation to 180 mg in arm B. Seven of 14 patients were successfully retreated with brigatinib. Conclusion Brigatinib yielded substantial whole-body and intracranial responses as well as robust progression-free survival; 180 mg (with lead-in) showed consistently better efficacy than 90 mg, with acceptable safety.

Bronchioloalveolar Carcinoma: The Case for Two Diseases

By current criteria, bronchioloalveolar carcinoma (BAC) is a subtype of pulmonary adenocarcinoma, developing from terminal bronchiolar and acinar epithelia and progressing in a lepidic and/or aerogenous manner on intact alveolar walls but without stromal, vascular, or pleural invasion. Evidence suggests that the 2 main cytologic types of BAC, ie, nonmucinous and mucinous, have some differing characteristics. The more frequent nonmucinous BAC directly evolves from the terminal respiratory unit cells, the type II pneumocyte, and Clara cells. This form predominates in smokers, presents more frequently as a ground-glass opacity, and frequently harbors epidermal growth factor receptor (EGFR) polysomy/mutations, believed to be the driver of its malignant process. The less frequent mucinous BAC, on the other hand, derived from metaplasia of bronchiolar epithelia, presents more frequently as a pneumonic-type infiltrate, rarely demonstrates EGFR polysomy/mutations, and much more frequently harbors and is driven by a K-ras mutation. These mutational oncogenic differences could lead to different therapeutic responses: nonmucinous BAC has been found to be sensitive to EGFR tyrosine kinase inhibitors, while mucinous BAC might be more responsive to taxane-based chemotherapy. In fact, there might be more differences than similarities, suggesting 2 distinct phenotypes that might need to be treated differently in order to optimize our management of the range of clinical disease that is often currently broadly classified as BAC.

Bronchioloalveolar Carcinoma: A Model for Investigating the Biology of Epidermal Growth Factor Receptor Inhibition

Bronchioloalveolar carcinoma (BAC) is a previously uncommon subset of non-small cell lung cancer (NSCLC) with unique epidemiology, pathology, clinical features, radiographic presentation, and natural history compared with other NSCLC subtypes. Recent data suggest that the incidence of BAC is increasing, notably in younger nonsmoking women. Despite reports of prolonged survival after repeated surgical resection of multifocal lesions and slow growth kinetics, advanced bilateral or recurrent diffuse BAC remains incurable, with the vast majority of patients dying of respiratory failure or intercurrent pneumonia within 5 years. Limited data suggest that chemotherapy may yield poor results in BAC. However, anecdotal reports of prolonged complete response to tyrosine kinase inhibitors of the epidermal growth factor receptor (EGFR), a member of the human epidermal growth factor receptor (erbB) family, have raised considerable interest in studying this NSCLC subset. Here we present clinical data and preliminary results of correlative science studies analyzing human epidermal growth factor receptor pathways from the following two prospective Southwest Oncology Group clinical trials performed in advanced stage BAC: S9714 testing a 96-h continuous infusion of paclitaxel (Taxol) and S0126 evaluating the small molecule EGFR inhibitor gefitinib (ZD1839 or Iressa). These studies provide a biological rationale for investigating BAC as a model of predictive markers of EGFR inhibition.

Systemic therapy of bronchioloalveolar carcinoma: results of the first IASLC/ASCO consensus conference on bronchioloalveolar carcinoma.

Introduction: Bronchioloalveolar carcinoma (BAC) is a subtype of adenocarcinoma of the lung with unique pathological, clinical, and molecular characteristics. Methods: This consensus conference group reviewed studies performed specifically in BAC and data from patients with BAC who were included in clinical trials of all non–small-cell lung cancer (NSCLC) subtypes. Results: Although BAC as defined by the World Health Organization represents less than 5% of adenocarcinomas, as many as 20% of adenocarcinomas have BAC features. These latter tumors are more likely to have mutations in the epidermal growth factor receptor (EGFR) gene and to be sensitive to the EGFR tyrosine kinase inhibitors gefitinib and erlotinib. Although most patients are men and have a history of smoking cigarettes, proportionally more are women and never smokers. Patients with BAC are routinely treated with drugs and regimens appropriate for patients with all subtypes of adenocarcinoma of the lung; four studies have been performed specifically in this disease. Conclusions: There is insufficient evidence to confirm or refute the assertion that the sensitivity of BAC to chemotherapy is different from that of other lung cancer histologic types. The unique clinical and molecular characteristics associated with BAC led this panel to conclude that future clinical trials should be designed specifically for persons with BAC. Recommendations for trial design and research questions are proposed.

Denosumab for Prevention of Skeletal-Related Events in Patients With Bone Metastases From Solid Tumors: Incremental Benefit, Debatable Value

Bone metastases are both frequent and morbid complications in many cancers. Most common in patients with advanced breast, prostate, and lung cancers, bone metastases are also seen in patients with other malignancies. Although the exact incidence of bone metastases in the broad population is not precisely known, it is estimated that skeletal involvement is present in more than half of those deaths resulting from advanced cancer. 1 Bone metastases may impact survival, and they also often compromise quality of life in the form of several complications that have emerged as a collection of defined skeletal-related events (SREs), including pathologic fractures, spinal cordcompression,theneedforsurgeryorradiationforasymptomatic

Patients With Advanced Non–Small-Cell Lung Cancer and Marginal Performance Status: Walking the Tight Rope Towards Improved Survival

An Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 2, alternatively termed as “marginal PS” or “poor risk,” is defined as being “ambulatory and capable of all self-care but unable to carry out any work activities; up and about more than 50% of waking hours.” While this characterizes 30% to 40% of the patients with lung cancer who present to our cancer clinics, this population has historically been woefully understudied in the field of lung cancer, commonly excluded from clinical trials based on the observation based on the finding that PS is a strong independent predictor of survival in lung cancer, with PS 2 patients demonstrating poor survival and sometimes prohibitive toxicity in early combination chemotherapy studies. Some studies have pooled PS2 patients with the elderly, most commonly defined as being older than 70 years. For instance, the Elderly Lung Cancer Vinorolbine Italian Study (ELVIS) confirmed a benefit for monotherapy with a typically well-tolerated agent like vinorelbine (Vin), while doublet therapy with a combination of Vin with gemcitabine (Gem) demonstrated no improvement in clinical outcomes compared with Vin or Gem alone. Though based on relatively scant data from small trials that pooled PS2 and fit elderly patients, the prevailing wisdom favored single-agent chemotherapy for these populations. However, emerging data from the last several years have consistently demonstrated that elderly and PS2 patients are distinct populations. Fit elderly patients with a PS of 0 to 1 on the ECOG/ Zubrod scale consistently benefit from a platinum doublet-based regimen relative to single-agent chemotherapy and typically enjoy clinical outcomes comparable to fit younger patients with a median overall survival (OS) in the 7 to 9 month (mo) range in subset analyses of elderly patients enrolled in doublet chemotherapy trials. A recent trial specifically for chemotherapy-naive patients 70 to 89 years old with advanced non–small-cell lung cancer (NSCLC) revealed a significant survival benefit for recipients of a carboplatin (Cb)/paclitaxel (Pac) doublet compared with Vin or Gem monotherapy (10.3 v 6.2 mos; hazard ratio [HR] 0.64; 95% CI, 0.52 to 0.78; P .001). In contrast, subset analyses of trials for patients with advanced NSCLC with eligibility ranging from PS 0 to 2 have historically shown that PS2 patients experience a much shorter survival, in the range of 3 to 4 mos, highlighting the potential value of studying this population as a distinct clinical entity for which different treatment recommendations may be appropriate. The field then witnessed the first large trials specifically focusing on PS2 patients with advanced NSCLC, which also raised important questions about the reliability of patient assignment as PS2. Arguably the most notable result in the global Selected Targeted Efficacy in Lung Cancer to Lower Adverse Reactions 3 (STELLAR 3) trial of Cb with paclitaxel poliglumex (PPX) or conventional Pac, which showed no benefit for either arm, was that PS2 patients enrolled from the United States, Western Europe, or Canada demonstrated a median overall survival (OS) of approximately 6.5 months, while those enrolled from Eastern Europe (who represented the majority of patients on the trial) had a median OS of approximately 9 months. This observation led Langer et al to offer the caveat that “PS designation remains highly subjective and open to debate,” a conclusion corroborated by the finding of the exact same pattern of conspicuously higher median OS in Eastern European patients enrolled on a parallel trial of PS2 patients randomized to single agent PPX or either Vin or Gem. Importantly, the patients from the United States, Canada, and Western Europe did not underperform compared with historical benchmarks, instead demonstrating outcomes modestly superior to those expected based on historical patterns from subset analyses of PS2 patients enrolled in other studies. In contrast, patients enrolled from Eastern Europe demonstrated an unprecedented survival for PS2 patients, far more in keeping with the outcomes expected for fit patients with advanced NSCLC. Though unexplained by obvious differences in other demographic parameters, this systematic difference in outcomes for patients ostensibly sharing the same eligibility features highlights that interpretation of PS represents an obvious opportunity for subjectivity. Independent of the geographic variability in the outcomes for patients characterized as PS2 around the world, another pattern that has been notable has been that PS2 patients enrolled on trials for which patients with a broad range of PS are eligible have demonstrated a median OS that is several months lower than those seen in trials designed for PS2 patients only. Even in trials led by common investigators, we have seen that that the subset of PS2 patients in the Cancer and Leukemia Group B 9730 trial for PS 0 to 2 patients by Lilenbaum et al had a median OS of 4.7 months with the Cb/Pac doublet, JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 31 NUMBER 23 AUGUST 1

Novel targeted agents for lung cancer.

It has been quite challenging to demonstrate significant improvements in survival for patients with non-small-cell lung cancer (NSCLC) over the past decade, but targeted therapies such as epidermal growth factor receptor (EGFR) inhibitors and angiogenesis inhibitors have been associated with benefits sufficient to alter our treatment standards. In addition to variations within these classes and combinations of such agents, several novel targeted therapy strategies have been introduced and are now emerging with encouraging results in early clinical trials for patients with advanced NSCLC. Immunotherapies targeting the MUC1 protein, MAGE-A3, and EGFR have shown early evidence of clinical benefits. Belagenpumatucel-L is a nonspecific allogeneic vaccine derived from multiple lung cancer cell lines, and the agent talactoferrin alfa might improve clinical outcomes based on broad immune system activation and stimulation. Other approaches that inhibit insulin-like growth factor receptor or heat-shock protein, both involved with multiple pathways involved with cell growth and survival, have shown activity in early trials and are moving forward in trials that specifically focus on patients with advanced NSCLC. This article reviews current data and future directions for each of these approaches.

Bronchioloalveolar Carcinoma: Not as Easy as “BAC”

In this issue, Cadranel et al.1 on behalf of the Intergroupe Francophone de Cancérologie Thoracique (IFCT) describe their experience of administering the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) gefitinib as single-agent, first-line treatment to 88 patients with advanced bronchioloalveolar carcinoma (BAC) or adenocarcinoma with BAC features (IFCT-0401). Similar to other studies in this setting,2,3 the authors note its significant activity, but this work also highlights in a clinical report the highly clinically relevant variable of BAC subtype. Mucinous BAC (M BAC) arises from mucinous metaplasia of bronchiolar cells and demonstrates strong intraand extracellular mucosecretion.4,5 This form is more often associated with aerogenous spread, advanced disease, bronchorrhea, and a relatively rapid disease course.4 In contrast, nonmucinous BAC (NM BAC) can arise from either of two similar terminal cell types that are often detected in the same tumor: Clara cells and type II pneumocytes. NM BAC is most often detected at an early and resectable stage, is typically asymptomatic for a prolonged period, and its course is more likely to be indolent.6 Although the NM BAC subtype is generally noted to be more common and represent 50 to 60% of cases compared with about 30 to 40% with M BAC and the remainder to be mixed,7–9 the IFCT trial by Cadranel notes an even split between the two subtypes in unresectable disease. In addition to distinctive cells of origin and natural histories, there is an emerging body of data that illustrates specific molecular profiles that correlate with very different responses to our common systemic therapies. Diastase resistant periodic acid Schiff stains M BAC essentially uniformly but is seen in only a small minority of NM BAC tumors.10 In contrast, thyroid transcription factor-1 is expressed consistently in lung adenocarcinomas with terminal respiratory unit morphology11 and is nearly uniformly expressed in NM BAC tumors but is uncommon in patients with M BAC.6 EGFR activating mutations, consistently associated with profound and prolonged responses to EGFR TKIs, have been seen in anywhere from 19 to 88% of patients with NM BAC tumors but have only been very rarely been reported in cases with M BAC (reviewed in Ref. 12). In contrast, V-Ki-ra2 Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations, seen in the great majority of M BAC cases TKI,13,14 are associated with a very low likelihood of a radiographic response to an EGFR. The EGFR TKIs are commonly used as an early treatment for patients with unresectable BAC, but the current limited evidence strongly supports recognition of the distinction between the two major BAC subtypes, in accordance with the molecular features described earlier. The IFCT-0401 trial reported here demonstrates a significantly higher disease control rate with gefitinib among those patients with NM BAC. In fact, no responses to an EGFR TKI have been reported in the literature for any patient with M BAC, as favorable results with this line of treatment seem limited to patients with NM

Impact of the ASCO 2007 Presentation of HOG Lun 01-24/USO-023 on the Prescribing Plans of American Medical Oncologists for Patients with Stage IIIB Non-small Cell Lung Cancer

Introduction: Nonoperative treatment of stage III non-small cell lung cancer has evolved over the past 30 years. The current approach in the Unites States most often includes concurrent chemoradiotherapy. Methods: We have used live, case-based research events to document prescribing plans among American medical oncologists for first-line therapy in patients with N3 stage IIIB non-small cell lung cancer. Changes in prescribing plans documented before and after the 2007 American Society of Clinical Oncology (ASCO) presentation of a Hoosier Oncology Group trial testing the role of consolidation docetaxel chemotherapy in this setting are presented. Results: Data from 2007 show a post-ASCO shift away from plans for docetaxel consolidation, increased use of concurrent chemoradiotherapy alone, and stable to increased plans for concurrent chemoradiation followed by additional cycles of the chemotherapy used during concurrent management (20%). Preliminary data from 2008 confirm the durability of these changes. Conclusions: The findings of the Hoosier Oncology Group trial support a transition away from docetaxel consolidation. A trend in this direction among American medical oncologists is clear from our data. However, nearly 20% of oncologists studied in 2008 still plan to use docetaxel consolidation. Furthermore, a majority of those studied after ASCO 2007 continue to report plans to use more than two cycles of chemotherapy as part of their preferred treatment recommendation despite no level I evidence to support this approach.