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FOCUS ON INITIAL AND MAINTENANCE THERAPY FOR NSCLC
For years, the standard initial therapy for NSCLC was a two-drug combination of carboplatin plus paclitaxel, especially in the USA. In Europe other chemotherapy doublets are commonly used including regimens containing vinorelbine, gemcitabine, docetaxel and pemetrexed, often with cisplatin rather than carboplatin. The regimens used in Japan and other Asian countries are similar to those used in Europe. Now with the emergence of definitive data on the role of the EGFR mutation-positive patients, and newer clinical applications of combinations of bevacizumab and other systemic therapies, the paradigm for initial therapy and maintenance therapy of NSCLC has changed.
PERSONALIZING INITIAL AND MAINTENANCE ANTI-EGFR-BASED NSCLC THERAPY
Erlotinib-based initial therapy
Reported at the 2007 ASCO meeting was data from a Southwestern Oncology Group (SWOG) trial in which erlotinib was used as a single-agent in first-line therapy for NSCLC. The trial was named S0341. The efficacy results were comparable to sequential vinorelbine and docetaxel and lead to further studies using EGFR biomarker analysis to improve outcomes.
Reported at the 2008 annual ASCO meeting was data from a randomized phase II trial using sequential erlotinib and either gemcitabine, ciplatin or carboplatin. This was referred to as the FAST-ACT trial. The rationale was from preclinical data that suggested potential antagonism due to TKI-induced G1 arrest reducing cell cycle phase-dependent activity of chemotherapy, whereas sequential administration of EGFR-TKI following chemotherapy may improve efficacy. The results of this phase II trial showed a statistically significant improvement in Progression-Free Survival (PFS) with the erlotinib regimen.
During the past several months important data has emerged for the treatment of EGFR mutation-positive patients with erlotinib. On August 20, 2009 in an online publication of in the New England Journal of Medicine Dr. Rosell reported data from his trial recommending that erlotinib be used as first-line therapy for EGFR mutation-positive patients. Similarly, on August 19, 2009 in the same online journal Dr. Mok from Hong Kong, updated the IPASS data that he reported at the 2009 ASCO meeting showing that these NSCLC patients are preferentially more suited to an anti-EGFR therapy such as an oral tyrosine kinase inhibitor like gefitinib.
Erlotinib-based maintenance therapy
The KOLs reminded us of yet additional and important options for treating NSCLC with erlotininb, making the treatment landscape for these NSCLC patients even more challenging. They mentioned that PFS and OS data exists to support erlotinib's use as a single agent for maintenance therapy, and PFS data for the combination of bevacizumab plus erlotinib as maintenance therapy.
At the 2009 ASCO meeting the results of the SATURN trial were reported. SATURN was a double-blind, randomized, phase III study of maintenance erlotinib versus placebo following nonprogression with first-line platinum-based chemotherapy in patients with advanced NSCLC. At ASCO 2009 it was announced that the SATURN study met its primary endpoint, PFS, and its co-primary endpoints with high statistical significance. The conclusion at ASCO 2009 was that erlotinib in the first-line / maintenance setting is well tolerated, and significantly improves disease control and delays progression versus placebo across patient subgroups.
More importantly, at the 13th World Congress on Lung Cancer in August 2009 in San Francisco, final data were announced for SATURN showing that erlotinib met its important secondary endpoint in the SATURN trial, overall survival (OS). The trial showed that patients receiving erlotinib had a 23% improvement in OS versus placebo. This included all patients (EGFR "wild type" and EGFR mutation-positive). Patients with the EGFR mutation showed a 30% improvement in OS.
At the 2009 ASCO meeting, the preliminary results of the ATLAS trial were also reported. ATLAS is randomized, double-blind, placebo-controlled, phase IIIb trial comparing bevacizumab therapy with or without erlotinib after completion of chemotherapy with bevacizumab for first-line treatment of locally advanced, recurrent, or metastatic NSCLC. The rationale for the ATLAS trial is the data from the Be Ta trial presented at ASCO in 2008 that showed that the combination of erlotinib plus bevacizumab was superior to erlotinib alone with an improved PFS. The primary investigator for ATLAS, Dr. Vincent Miller, at ASCO 2009 revealed that the addition of bevacizumab to erlotinib after first-line chemotherapy with a platinum-containing doublet with bevacizumab significantly improved PFS, its primary study endpoint. PFS was 4.8 months for the combination of erlotinib and bevacizumab versus 3.7 months for the bevacizumab plus placebo arm. The study was stopped by the Data Safety Monitoring Committee because it met its primary endpoint. In an interview with Dr. Miller in September 2009, he told us that he believes that before ASCO 2010, the final results revealing the answer to the question about OS with ATLAS should be available.
Cetuximab-based initial therapy
At the 2008 ASCO meeting, data was presented from a randomized, multicenter phase III trial of 1,125 patients that employed than anti-EGFR monoclonal antibody, cetuximab, in the first-line setting for treating NSCLC patients. This is known as the FLEX trial and it assessed the efficacy and safety of the EGFR-targeted monoclonal antibody cetuximab in combination with cisplatin plus vinorelbine (CV) compared with CV alone in advanced NSCLC. The primary endpoint was overall survival (OS) and it was achieved with the cetuximab-containing arm. This is the first study to demonstrate a survival benefit of an EGFR-targeted agent in combination with platinum-based chemotherapy in advanced first-line NSCLC irrespective of histology and confirms the clinical relevance of cetuximab in NSCLC. 34% of the NSCLC patients were squalors cell and 47% were the adenocarcinoma subtype. There was a remarkable difference between the outcomes in Asians and Caucasian patients that among other factors lead to the IPASS and SATURN trials with erlotinib and gefitinib.
Cetuximab-maintenance therapy
There is some data to support the use of cetuximab as maintenance therapy for NSCLC. Dr. Edward Kim from M.D. Anderson in 2003 first reported data from a phase II trial using cetuximab plus docetaxel that demonstrated some activity. One of the arms in the FLEX trial contained cetuximab for 6 cycles. And although this is not really maintenance therapy, it paved the way for future maintenance trials.
Dr. Herbst also reminded us of the SWOG trial 0536 that allowed maintenance therapy with either bevacizumab or cetuximab for one year. He also told us of a similar trial SWOG 0342. Today, there is no definitive data supporting maintenance cetuximab. However, in early 2009 a phase III trial, the NEXT trial, was initiated in Germany to evaluate the role of cetuximab as maintenance therapy for NSCLC following platinum-based chemotherapy in the first-line setting.
Biomarkers for EGFR-based therapies
Personalizing the treatment of NSCLC has become essential. This was told to us by all of the KOLs that we interviewed. The positive predictive biomarkers for EGFR inhibitor therapy that have been explored include EGFR protein expression assayed by immunohistochemistry (IHC), EGFR copy number measured by chromogenic or fluorescence in situ hybridization (FISH), and EGFR mutations. EGFR protein expression is the least specific marker for detecting patients who are likely to respond to therapy, with the majority of patients with adenocarcinoma NSCLC expressing EGFR to some degree while only 10% of patients respond to erlotinib or gefitinib. Moreover, EGFR IHC expression shows little or no relationship to EGFR mutation status.
EGFR mutations are currently the most specific predictor of erlotinib or gefitinib response in patients with NSCLC, with approximately 80% of patients with an activating mutation in EGFR responding to erlotinib or gefitinib. However, there have been patients who responded to these therapies with negative results for all EGFR-related predictive biomarkers.
Dr. Thomas Lynch and Raphael Rosell are two of the world's experts on biomarkers for anti-EGFR therapies. We interviewed both of them in August 2009 in San Francisco for their perspectives for this Needs Assessment and practice gap analysis. The critical message is that the use of an oral TKI such as erlotinib can shrink NSCLC tumors in 70% of patients with EGFR mutations. Testing is essential.
Dr. Lynch told us that IHC testing for EGFR could easily and reliably be done on 10 unstained slides from a core biopsy. He mentioned that in the future, analysis of circulating tumor cells might be a simpler, less invasive method. But for now IHC is the standard testing method.
Regarding EGFR as a biomarker for outcomes Drs. Lynch and Rosell mentioned that KRAS mutants and wild types are not different for biomarker use. That information was further corroborated by the following. In a retrospective analysis of a phase III trial using a cetuximab-based regimen as initial therapy for NSCLC (the BMS 099 trial) reported at the 2009 ASCO meeting there was no significant correlation between patient response to cetuximab and any molecular marker evaluated to date (K-RAS mut, EGFR mut, EGFR IHC, EGFR FISH). So, exploratory analyses are ongoing. Additional predictive-marker studies are needed to optimize cetuximab therapeutic use in NSCLC. This was also supported with data reported at the 2009 ASCO annual meeting regarding a biomarker analysis that was performed on the SATURN trial. This biomarker data suggest that patients derived a PFS benefit with erlotinib irrespective of EGFR FISH or EGFR intron 1 CA-repeat status. The magnitude of benefit with erlotinib was similar in both KRAS-mutant and KRAS wild-type patients.
Dr. Roy Herbst provided us in August 2009 with a perspective of additional biomarker analysis. He told us about the Be Ta trial first reported in 2008, which used a combination of erlotinib plus bevacizumab. Patients with tumors that expressed EGFR mutations had better progression-free and overall survival than patients with nonmutated EGFR genes. An analysis of the role biomarkers may play in treatment indicated that no matter which arm of the Be Ta study a patient was in, having a mutated EGFR gene gave that person a survival advantage.
Also reported at the 2009 ASCO meeting was data from a retrospective analysis of the archived tissue samples used in the FLEX trial. The conclusion was that clinical data from the FLEX study do not support the hypothesis that KRAS mutation status is predictive for cetuximab efficacy when combined with 1st- line chemotherapy in advanced NSCLC, whereas early acne-like rash of any grade appears to be associated with better outcome in patients treated with platinum-based chemotherapy plus cetuximab in this setting.
PERSONALIZING INITIAL AND MAINTENANCE NSCLC THERAPY WITH ANTI-ANGIOGENESIS-CONTAINING THERAPIES
Bevacizumab-based initial therapy
With the results of a landmark trial published in 2006, ECOG 4599, the addition of bevacizumab to the chemotherapy doublet of carboplatin plus paclitaxel changed the way many clinicians treat NSCLC with initial therapy. Again, the KOLs we interviewed reminded us of the obvious--that the healthcare reimbursement system and economics in Europe and many developing countries have to date been impediments to the widespread adoption of bevacizumab in Europe and other countries ex-USA.
At ASCO 2008, initial data was presented from the European AVAiL trial, a three-arm study that compared the chemotherapy doublet cisplatin plus gemcitabine, with gemcitabine plus cisplatin plus two different doses of bevacizumab, 7.5mg/kg and 15mg/kg. Although AVAiL met its primary endpoint, PFS, it did not reach its endpoint of OS. Dr. Fred Hirsch presented additional results from AVAiL at the 2009 ASCO meeting showing that the addition of bevacizumab to platinum-based chemotherapy was associated with a manageable safety profile, thus supporting its use from a toxicity perspective.
Despite not achieving OS with AVAiL, many community-based oncologists in the USA are using the three-drug regimen of carboplatin plus paclitaxel plus bevacizumab, primarily for nonsquamous NSCLC patients. And it should be noted that both the new ECOG 5508 trial and the PointBreak trial (discussed in the following paragraphs) each have the three-drug regimen of carboplatin plus paclitaxel plus bevacizumab in their study. So the precise role of bevacizumab with carboplatin plus paclitaxel remains a key question in practice for treating NSCLC and is, thus, a practice gap.
Bevacizumab-based maintenance therapy
ECOG 4599 was also the first trial that employed maintenance therapy for NSCLC. In ECOG 4599 bevacizumab was continued as a maintenance therapy after four to six cycles of carboplatin plus paclitaxel chemotherapy, until disease progression.
Pemetrexed plus bevacizumab-based maintenance therapy
Maintenance data with pemetrexed plus bevacizumab was revealed at the annual ASCO meeting in 2008. Dr. Patel reported the results of a study in which all patients received carboplatin plus pemetrexed with bevacizumab as initial therapy for six cycles. Patients without progression continued on pemetrexed and bevacizumab for maintenance therapy every three weeks. This was a single arm study. The PFS was 9.2 months, and the OS was 13.5 months. Maintenance therapy of pemetrexed and bevacizumab was very well tolerated. The results of the Patel study are similar to those reported by Dr. Ciuleanu et al in 2008 described in the following paragraphs.
In July 2009 Dr. Patel published the results of a phase II study of pemetrexed plus carboplatin plus bevacizumab with maintenance pemetrexed and bevacizumab as part of first-line therapy for nonsquamous NSCLC. This regimen, involving a maintenance component, was associated with acceptable toxicity and relatively long survival in patients with advanced nonsquamous NSCLC. Dr. Patel stated that these results justified a new phase III trial. Thus, the following trial was planned.
With the data showing both the safety of combining pemetrexed with carboplatin, and showing the efficacy of pemetrexed in the maintenance setting, a company-sponsored trial, the PointBreak study, will utilize the 2009 data from ASCO data published in July 2009 by Dr. Patel who is the Primary Investigator of the PointBreak study. PointBreak may provide an improvement and an alternative to the current chemotherapy backbone of carboplatin plus paclitaxel. PointBreak is a phase III study of induction therapy of the three-drug regimen: pemetrexed plus carboplatin plus bevacizumab, then followed by pemetrexed plus bevacizumab as maintenance. This is compared with a second arm, induction therapy of paclitaxel plus carboplatin plus bevacizumab followed by bevacizumab as maintenance. Patients are either stage IIIB or IV. Treatment consists of up to four cycles of induction therapy followed by maintenance therapy until disease progression or treatment discontinuation in approximately 900 patients (450 per treatment arm). The efficacy objectives of this study are to compare the OS, PFS, response rates, disease control rates, and time to progressive disease between the two treatment arms. Safety, quality of life, pharmacokinetics, and translational research will also be investigated. If the primary objective, OS, is achieved, this study should provide a new treatment option for patients with nonsquamous NSCLC: pemetrexed plus carboplatin plus bevacizumab followed by maintenance therapy with pemetrexed and bevacizumab.
Pemetrexed-based maintenance therapy Dr. Ciuleanu, at the 2008 annual ASCO meeting reported the benefit of using maintenance therapy with pemetrexed following first-line chemotherapy of carboplatin plus paclitaxel. In a phase III trial, patients with stage IIIB/IV received initial chemotherapy, and then were randomly assigned to maintenance therapy with pemetrexed or placebo. This study demonstrated a significant improvement in progression free survival (PFS) for the patients who received maintenance pemetrexed therapy, with a PFS of 4 months, versus 2 months for placebo. In the subset analysis, patients with nonsquamous NSCLC histology benefited, while squamous cancers did not. The superior response to pemetrexed in nonsquamous NSCLC has been observed in two previous clinical trials leading to the drug's indications for second and first-line therapy for nonsquamous NSCLC patients.
At the 2009 annual ASCO meeting, Dr. Belani presented the final results of the trial initially presented in 2008 by Dr. Ciuleanu. The final reported data was on 663 patients receiving pemetrexed and showed that it had both a statistically significant PFS and OS versus placebo. And these improvements were observed primarily in the nonsquamous patients. Overall survival for all patients was 13.4 versus 10.6 months (pemetrexed versus placebo). But in the nonsquamous NSCLC patients the results were better, 15.5 versus 10.6 months. The KOLs' conclusions were that pemetrexed was superior to placebo as maintenance therapy and that this trial further validated the determination of personalized therapy for NSCLC by using histology. Three quarters of the patients in this trial were nonsquamous NSCLC. This trial led to an FDA approval of pemetrexed for maintenance therapy for nonsquamous NSCLC in mid-2009. Thus, a practice gap exists for this important information.
Bevacizumab plus erlotinib or plus pemetrexed?
In September 2009, in an interview with Dr. Joan Schiller, she informed us of the new ECOG study, ECOG 5508, with a different schema than PointBreak. ECOG 5508 compares three different maintenance arms: bevacizumab, pemetrexed and the combination of pemetrexed plus bevacizumab. These three maintenance arms follow initial chemotherapy of carboplatin plus paclitaxel plus bevacizumab for four cycles. Again, this trial includes only nonsquamous NSCLC patients. The KOLs reminded us again, that with all of the data and the increasing number of systemic therapy options for treating nonsquamous NSCLC, there is a major practice gap that exists with the community-based, private practice oncologists.
Histology as a biomarker for nonsquamous NSCLC
The clinical applications of predictive and prognostic biomarkers, including histology are becoming critically important for the selection of and usage of systemic therapies for all types of NSCLC. Most have not yet been validated with prospective clinical trials. But histology has been demonstrated in prospective trials to be an invaluable tool for helping clinicians personalize therapies for nonsquamous NSCLC subtypes. It is quite clear that nonsquamous NSCLC patients respond better to pemetrexed than do other subtypes. Some of the KOL faculty during the OLC's Second Annual Symposium on Personalized Therapies for Lung Cancer and Head and Neck Cancer, in Philadelphia, indicated that they would use such tests despite the fact that some are not prospectively validated but are only CLIA approved for commercial sale and use in the US. The need exists to understand how these assays can today help clinicians personalize their therapies for nonsquamous NSCLC.
At the August 2009 13th World Congress on Lung Cancer in San Francisco, Dr. Scagliotti reported that the results from several prospective trials and from retrospective subset analyses clearly indicate that in nonsquamous NSCLC versus other NSCLC subtypes there is superior activity with pemetrexed alone or in combination with platinum agents. Dr. Scagliotti also presented preclinical and clinical data suggesting that low levels of thymidylate synthase expression may be a biomarker for chemosensitivity to pemetrexed.
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