Originally published as JCO Early Release 10.1200/JCO.2008.20.4859 on February 17 2009

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The "Lazarus Response" in Treatment-Naïve, Poor Performance Status Patients With Non–Small-Cell Lung Cancer and Epidermal Growth Factor Receptor Mutation

Thoracic Oncology, Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA

BACKGROUND: PERFORMANCE STATUS 2 PATIENTS WITH NON–SMALL-CELL LUNG CANCER

In a series of more than 500 non–small-cell lung cancer (NSCLC) patients evaluated by Cella and colleagues in quality of life studies, the prevalence of poor performance status (PS; 2 to 4) among lung cancer patients was 34% when estimated by providers and 48% when determined by patients themselves; these findings strongly suggest that physicians and nurses tend to underestimate the degree of compromise in PS.¹ Unfortunately, there is no standard therapy in advanced NSCLC patients with very poor performance status (PS 3 to 4). Median survival (MS) without therapy, which is the norm, is typically fewer than 2 to 3 months in such individuals, whether the compromise in PS is due to disease burden or comorbidity.^2,3

The optimal nature of treatment for PS 2 patients with advanced NSCLC remains controversial.^3–7 Data from prospective phase III trials isolating the role of platinum suggest an improvement in survival for those receiving third generation platinum-based combinations compared to the constituent, nonplatinum single agent.^8,9 Lilenbaum et al, in a phase III trial, isolated the role of carboplatin in combination with paclitaxel compared to single-agent paclitaxel. They demonstrated an increase in survival for PS 2 patients receiving the combination, but the results were still dismal: 4.7 months MS for those receiving the combination compared to 2.4 months for those receiving single-agent therapy with 1-year survival rates of 19% and 10%, respectively. Virtually no PS 2 patients were alive on the single-agent arm at 2 years.⁸ More recent studies suggest that modern combination regimens may be able to generate MS times of 6 to 8 months in PS 2 individuals, but seldom higher.^10,11 In Eastern Cooperative Oncology Group (ECOG) 2598, chemotherapy-naïve PS 2 patients with advanced NSCLC receiving either dose-attenuated paclitaxel and carboplatin or gemcitabine and cisplatin realized MS of 6.2 and 6.9 months, respectively, with 1-year survival rates of 19% and 25%.¹⁰ A much larger phase III trial enrolling more than 400 patients and restricted to a PS 2 population evaluated carboplatin in combination with either paclitaxel or polyglutamated paclitaxel. The results from this trial—and, to date, the "best" results in this population—showed a MS of 7.9 months and 8.0 months, respectively, for standard versus polyglutamated paclitaxel and identical 1-year survival rates of 31%.¹²

Baseline comorbidities and anticipated toxicities are a major impediment to more aggressive therapy in poor PS patients with NSCLC. For example, work by LeChevalier et al comparing vinorelbine, either alone or in combination with cisplatin, to vindesine and cisplatin, not only failed to demonstrate a significant survival advantage in PS 2 patients receiving the cisplatin and vinorelbine combination, but also showed substantially more severe toxicity compared to the single agent.¹³ Current trials are emphasizing the role of less toxic agents in the PS 2 population; but none to date, with the exception of the work by Inoue and colleagues,¹⁴ highlighted in this issue of the Journal of Clinical Oncology, have assessed customized therapy based on epidermal growth factor receptor (EGFr) mutation status.

GEFITINIB IN TREATMENT-NAïVE POOR PS PATIENTS WITH NSCLC

In this small phase II study in poor PS patients with advanced, chemotherapy-naïve NSCLC, Inoue et al report a median survival of 17.8 months for first-line EGFr tyrosine kinase inhibition (TKI) in patients with mutated tumors,¹⁴ most of whom, by traditional criteria, would not have received systemic therapy.^1,2,3 This article is remarkable in that it included PS 3 and 4 patients, not just PS 2. Despite the fact that most of these patients had aggressive disease, treatment with gefitinib in this setting yielded a median survival three- to four-fold higher than that generally observed with conventional cytotoxics. Moreover, PS consistently improved in these patients over the course of treatment. One would assume that quality of life (QOL) also improved, although confirmatory QOL data are not provided. The authors also make it clear that a substantial proportion of those with EGFr mutation did not fit the typical clinical profile; in other words, they were not necessarily female, nonsmokers with adenocarcinoma histology. The relatively low percentage of patients who went on to receive second-line therapy with conventional cytotoxics at the time of disease progression seems curious, if not bothersome, particularly when these individuals, whether they received additional treatment or not, lived an average of one year beyond the time of documented progressive disease (PD). Assuming there is no under-reporting of second-line treatment, this observation would suggest that refractory or resistant tumor at the point of PD might consist of slower growing clone(s) distinct from the original tumor that responded to EGFr TKI. In addition, the authors do not state the turnaround time for mutation testing. This is crucial in a population with rapidly progressive cancer and fulminant symptomatology, where time delays are critical; a delay in turnaround would have potentially biased the results toward a more favorable outcome, effectively excluding patients with more aggressive cancers and arguably worse survival.

This effort is further noteworthy in that it helps to substantiate the role of first-line EGFr TKI in patients with mutated tumors, and this observation is likely to have far broader implications beyond those advanced NSCLC patients with compromised PS. These data have been validated, in part, by a number of phase II trials^15,16,17,18 which have demonstrated promising single-agent activity with high response rates and encouraging progression-free survival (PFS) and, in some instances, OS for first line EGFr TKIs in patients with mutations, and generally good PS (Table 1). More importantly, it has been reinforced by recent phase III data from the I-PASS (open-label, randomized parallel group, multicenter, phase III study to assess efficacy, safety, and tolerability of gefitinib [Iressa] versus carboplatin/paclitaxel as first-line treatment in selected patients with stage IIIB/IV NSCLC) trial presented by Mok et al (Table 2).¹⁹ Although the study was performed in never smokers and light former smokers—and independent of EGFr status—gefitinib, in an embedded subanalysis of treatment-naïve patients with EGFr mutation, yielded a statistically significant and clinically meaningful PFS advantage compared to first-line chemotherapy with carboplatin and paclitaxel. The hazard ratio (HR) for improvement in PFS in mutation-positive patients receiving gefitinib was 0.48 (P < .0001). The response rate in mutation-positive patients receiving gefitinib was 71%, compared to 1% in mutation-negative patients. Conversely, in mutation-negative patients, chemotherapy upfront yielded superior PFS compared to gefitinib with a HR of 2.85 (P < .0001). However, the PFS benefit for gefitinib in mutation-positive patients did not translate into an obvious survival benefit. Preliminary survival results from the I-PASS study have not yet shown an advantage for EGFr TKI upfront. One suspects that second-line therapy with EGFr TKI in mutation-positive patients with disease progression after treatment on the chemotherapy control arm may have nullified any emerging survival advantage for mutation-positive patients receiving upfront EGFr TKI therapy. There are also data to suggest that mutation-positive patients undergoing treatment have an intrinsically better survival. In contrast, poor PS patients with declining functional status and advanced NSCLC typically have only one shot at therapeutic redemption. Under these circumstances, one wonders if a survival advantage, had it emerged in the I-PASS trial, would have been more readily appreciated in a poor PS cohort, where the efficacy of systemic chemotherapy upfront is clearly limited and where the likelihood of receiving salvage therapy is far less common. Then again, a reduction of symptoms with an effective EGFr TKI in mutation-positive patients might have led to improvements in PS and functional status and an enhanced likelihood of receiving and benefiting from salvage chemotherapy at the time of disease progression.

The applicability of these results beyond East Asia is limited. In the United States and Northern Europe, the average incidence of EGFr mutations is 10% to 12% at most, far lower than the 30% to 40% rates reported in Japan, China, and Korea.^20,21,22 Consequently, the pool of treatment-naïve patients likely to benefit from this approach upfront is very likely limited. Moreover, trials evaluating the role of EGFr TKI in the treatment-naïve setting in the United States and Northern Europe have largely been conducted in patients with good PS. There are at least two ongoing prospective, randomized, phase III trials comparing EGFr TKI to standard chemotherapy in mutation-positive, chemotherapy-naïve patients with advanced NSCLC.²³ Outside of an endemic population where the mutation rate is much higher, the accrual rate to such trials is expected to be quite slow.

Cogent data regarding the utility of EGFr TKI in unselected, treatment-naive PS 2 patients has emerged from the work of Lilenbaum and colleagues.²⁴ Enrollees in this randomized phase II trial were assigned to either single-agent erlotinib or to combination paclitaxel and carboplatin (PCb). The MS for those receiving the PCb combination was 9.7 months compared to 6.6 months for patients receiving erlotinib upfront. Although marker analysis was not required for entry into this trial, EGFr mutations, when evaluated, were confined to those on the PCb arm; ironically, not one enrollee on the erlotinib arm actually had an EGFr mutation at baseline. The three-fold difference in MS in poor PS patients between those receiving erlotinib on the Lilenbaum trial and poor PS patients with mutations receiving gefitinib on the Inoue trial strongly suggests that EGFr mutation status in this population trumps PS, and that the efficacy of agents that target such mutations may overcome the deleterious effects of compromised function in these patients. However, this hypothesis cannot be automatically assumed. There may be subtle pharmacogenomic or ethnic differences which result in better outcome in Japanese patients, which extend beyond mutation status and which make these agents relatively more active in mutation positive patients from East Asia compared to their North American or European counterparts. In contrast, the existence of mutations, in the setting of active therapy, regardless of its nature, may actually confer a survival benefit. Of the 10 patients on the Lilenbaum trial receiving PCb who were tested for mutation status, five proved positive. MS in this small cohort was 17 months, not too dissimilar to the results seen with gefitinib in the Inoue trial. The notion then that the outcome in the Inoue trial is too good to be true is disputed by historic data. On behalf of the Southwest Oncology Group, Hesketh and colleagues evaluated single-agent erlotinib in the first-line setting in PS 2 patients.²⁵ Results in this effort were similar to those observed by Lilenbaum et al, and very different from those observed by Inoue et al (Table 3).

The empiric addition of EGFr TKI to chemotherapy has failed to yield an improvement in survival compared to chemotherapy alone.^26,27,28,29 It has been speculated that concurrent therapy with cytotoxic agents and targeted agents may lead to therapeutic antagonism. But pharmacodynamic separation or intercalation of EGFr TKI and chemotherapy may facilitate the integration of these two approaches. However, this strategy has not been tested specifically in poor PS patients or in those exclusively harboring mutations. The recently completed randomized phase II FASTACT (a phase II, randomized, double-blind trial of sequential erlotinib and chemotherapy as first-line treatment in patients with stage IIIB/IV NSCLC) trial in China, in which chemotherapy-naïve patients received either chemotherapy with cisplatin and gemcitabine (alone) or chemotherapy followed 2 weeks later by "intercalated" gefitinib, yielded an improvement in response rate and PFS in the "intercalated" cohort.³⁰ Survival data from this effort are pending.

If never smoker status is a potential surrogate for mutation status, then the posthoc subanalysis of the TRIBUTE (phase III trial of erlotinib hydrochloride combined with carboplatin and paclitaxel chemotherapy in advanced NSCLC) trial in never smokers is illustrative. Although the trial overall was negative, never smokers receiving paclitaxel, carboplatin, and erlotinib had a MS of 22.5 months compared to 10.1 months in the control group receiving chemotherapy and placebo (hazard ratio, 0.49; 95% CI, 0.28 to 0.85).²⁶ The Cancer and Leukemia and Group B is currently investigating this tactic in a randomized phase II trial evaluating erlotinib alone or erlotinib plus chemotherapy in both never smokers and light former smokers (< 10 pack-years).²⁴ Tissue correlatives are mandated as part of this protocol, which is nearing completion. In a separate trial in never smokers, ECOG is about to initiate a prospective randomized phase II trial of standard treatment (chemotherapy alone with or without bevacizumab) or standard treatment plus erlotinib. Patients whose disease progresses on standard treatment will be crossed over to erlotinib. However, in North America, at least, there are no ongoing randomized, prospective phase III trials comparing EGFr TKI alone or combination chemotherapy and TKI to chemotherapy alone in either mutation positive or never smoker populations. Such trials may be moot if the final results of I-PASS¹⁹ and other ongoing phase III first-line trials in mutation-positive patients show a consistent improvement in both PFS and OS for upfront single-agent EGFr TKIs.

IS EGFR MUTATION THE OPTIMAL MARKER FOR BENEFIT?

It is clear that EGFr mutations identify a cohort of patients with the highest likelihood of responding to EGFr TKIs.^20–22 Moreover, the presence of mutation may help us select patients for treatment who do not demonstrate the classical clinical phenotype for response to this class of compounds, including smokers, men, and even those with squamous histology. In the Inoue trial, seven patients were smokers and six were male.

It is unclear if either fluorescence in situ hybridization (FISH) testing or EGFr assessment by immunohistochemical (IHC) staining warrants use in this setting. Older studies suggest that 40% to 70% of patients with NSCLC are EGFr positive by IHC^31,32; but in the recently reported FLEX (first-line trial for patients with EGFR-expressing advanced NSCLC [comparing chemotherapy with cisplatin and vinorelbine to chemotherapy plus cetuximab]) trial, which required EGFr positivity by IHC for enrollment and which showed a survival advantage for the monoclonal antibody cetuximab targeting EGFr in combination with chemotherapy compared to chemotherapy alone, more than 80% of those screened proved positive.³³ In the second- and third-line setting, in the BR21 study, EGFr positivity by IHC predicted a survival benefit for erlotinib compared to placebo controls, whereas patients whose tumors were EGFr negative had no advantage.^34,35 Testing by IHC is simpler and easier than mutation analysis.

Likewise FISH testing in both the ISEL (Iressa Survival Evaluation in Lung Cancer) and BR21 trials delineated those who benefitted from either gefitinib or erlotinib compared to placebo.^36,37,38 In a separate, retrospective series, patients who were positive for both FISH and IHC had far better response rates and survival compared to those who were double negative, while those who were positive for one or the other had an intermediate outcome.³⁹ But these observations may only be operative in the setting of placebo-controlled trials. In the recently published INTEREST trial comparing gefitinib to docetaxel in the second-line setting, neither agent showed a clear-cut survival advantage over the other, and FISH positivity failed to differentiate outcome between the two arms of the study.⁴⁰

Finally, proteomics may be predictive.^41,42 In ECOG 3503, un-selected patients with advanced NSCLC were treated with erlotinib upfront. Ninety-six patients were ultimately analyzed for matrix-assisted laser desorption/ionisation time-of-flight.⁴⁰ Those with good risk profiles had a PFS of 3.5 months compared to 1.9 months for those with poor risk profiles (P = .0052); MS times were 11.6 and 3.9 months, respectively (P = .0007). This observation warrants follow-up. The Southwest Oncology Group in a prospective, randomized phase II trial intends to randomly assign PS 2 patients with advanced, treatment-naïve NSCLC and favorable proteomic profiles to erlotinib alone or to combination erlotinib and chemotherapy. A separate Italian trial will randomly assign patients to chemotherapy alone or combination chemotherapy and erlotinib.

LAZARUS REVISITED

In the treatment of patients with advanced NSCLC, we are on the threshold of customized or individualized medicine. Molecular markers will ultimately identify patients more or less likely to benefit from specific therapies, and should become as important as, if not more important than, disease stage and PS in selecting treatment. Our current empiric therapeutic mentality, one hopes, will ultimately fall by the wayside.

In the new testament of the Bible, Jesus raised Lazarus of Bethany from the dead. In modern medical parlance, the Lazarus phenomenon refers to an event in which a person spontaneously returns to life after resuscitation has been given up. Therapeutic realists have no delusion that miracles of this sort will become routine in oncologic practice. But the judicious application of molecular markers, as practiced by Inoue and colleagues, should go far in combating the gospel of therapeutic nihilism rampant in the management of poor PS patients with advanced NSCLC.

AUTHOR'S DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

Although all authors completed the disclosure declaration, the following author(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a "U" are those for which no compensation was received; those relationships marked with a "C" were compensated. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.

Employment or Leadership Position: None Consultant or Advisory Role: Corey J. Langer, Astra Zeneca (C), OSI (C), Genentech (C) Stock Ownership: None Honoraria: None Research Funding: Corey J. Langer, OSI, Genentech Expert Testimony: None Other Remuneration: None

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