Lung Cancer: Poster Discussion Session and Oral Abstracts, Monday June 1st

Post by M. Catherine Pietanza, MD:

Once again, a common theme in the treatment of NSCLC was that molecular characterization is necessary and will assist in directing the appropriate therapies toward our patients.

Multiple presentations showed the ability of using molecular markers to guide patient selection for trials, of which I will provide a few examples. The North-East Japan Gefitinib Study Group presented phase III data where 198 patients with newly diagnosed, advanced NSCLC and EGFR activating mutations were randomized to receive either gefitinib or carboplatin/paclitaxel (Abstract #8016). The results of this trial are impressive and show that the response rates and median progression free survival for patients randomized to gefitinib compared to those receiving chemotherapy were 75% and 10.6 months versus 29% and 5.5 months, respectively. This study validates the use of EGFR tyrosine kinase inhibitors in the first line setting for patients with activating mutations. Several other studies based patient eligibility upon the presence of activating EGFR mutations (Abstracts #8013, #8023, #8026). In a phase II study using salirasib, which inhibits RAS binding to plasma membrane and blocks RAS-dependent cell growth, Johnson et al. demonstrated that K-RAS selective trials are feasible (Abstract #8012). These data underscore the importance of genotyping NSCLC, as has become a standard at our institution.

Two abstracts showed that biopsying patients upon progression of disease was safe and feasible. The BATTLE study presented by Kim et al. at MD Anderson Cancer Center demonstrated that rebiopsy allowed for the identification of biomarkers prospectively, the results of which directed patient treatment in various available protocols (Abstract #8024). Similarly, Dr. Arcila and colleagues at Memorial Sloan-Kettering Cancer Center showed that patients can be rebiopsied when they no longer respond to EGFR tyrosine kinase inhibitors to determine the patterns of resistance and guide decision making for further targeted therapies (Abstract #8025).

A few important points were garnered during the oral presentations focusing on local-regional and adjuvant treatment for NSLC. Updated survival analysis of JBR.10, the randomized phase III study comparing cisplatin/vinorelbine to observation in patients with resected stage IB and II was presented (Abstract #7501). After a median follow-up of greater than nine years, survival analysis continues to show a benefit for adjuvant chemotherapy (HR 0.78 with p = 0.04), which is primarily in patients with stage II disease. Adjuvant chemotherapy for patients with stage IB remains controversial, although there is a trend toward improved outcomes for those with large tumors. Importantly, in early stage disease, biomarkers also may be able to predict benefit from adjuvant chemotherapy, as demonstrated in the study presented by Dr. Fouret (Abstract #CRA7502). Here, tissue samples of patients that had participated in the IALT trial were studied in a retrospective manner and MSH2 was identified as a predictive marker. Further studies are warranted to prospectively analyze biomarkers, which are underway.

A phase II study comparing pemetrexed, carboplatin, and concurrent thoracic radiation with or without cetuximab (CALGB 30407) showed that this regimen is safe and effective, with both arms meeting a predefined threshold of median survival of 20.9 months (Abstract #7505). However, the addition of cetuximab did not benefit outcomes. Further, there was a trend toward better outcomes observed with non-squamous NSCLC. The results of this work are being used to launch two large phase III studies, one of which will contain a pemetrexed arm in non-squamous NSCLC and another will address the use of cetuximab. The RTOG 0214 study attempted to evaluate prophylactic cranial irradiation (PCI) in patients that had completed treatment for locally advanced disease (Abstract # 7506). The study did not meet its target accrual and closed early, thus was not able to show benefits in outcomes. It demonstrated that PCI decreased the incidence of CNS metastases in this group of patients. Quality of life data will be presented later in the year.

In small cell lung cancer, treatment options continue to be limited. Several abstracts showed that the standard of care for first line treatment of extensive stage SCLC remains etoposide/platinum in the US and Europe, whereas in Japan it is irinotecan/platinum (Abstracts #8027 and #8029). In the second-line setting, amrubicin was compared to topotecan in a randomized phase II trial for patients with relapsed sensitive SCLC and found to have significantly improved response rate and a trend toward improved survival (Abstract #8028). Similarly, amrubicin shows response in those patients with refractory disease (Abstract #8103).

This marks the end of the lung cancer presentations at ASCO 2009. I hope you found these summaries helpful.

Lung Cancer: Oral Abstract Session in Metastatic Disease, Sunday May 31st

Post by M. Catherine Pietanza, MD:

The oral presentations in metastatic non-small cell lung cancer focused on maintenance chemotherapy, new targets for the disease, and molecular markers.

Much awaited results from three individual trials evaluating the use of maintenance therapy were presented. Current treatment guidelines recommend waiting until disease progression to administer second- and third-line regimens after 4-6 cycles of first-line platinum-based doublet chemotherapy. Each of the trials presented discussed initiating therapy immediately after first-line platinum-based chemotherapy in patients with no evidence of disease progression.

Dr. Chandra Belani discussed the phase III study in which 660 patients were randomized in a 2:1 fashion to receive pemetrexed or placebo with best supportive care (Abstract # CRA8000). The primary endpoint of progression-free survival was met, with a median of 4.3 months for the patients receiving pemetrexed and 2.6 months for those receiving placebo. Overall survival, a secondary end-point, was 13.4 and 10.6 months for pemetrexed and placebo, respectively. The magnitude of benefit was seen primarily in patients with non-squamous histologies. Upon progression of disease, post-study treatment was administered to the majority of patients. Interestingly, only 19% of patients in the placebo arm went on to receive pemetrexed upon progression.

SATURN, the randomized phase III study of maintenance erlotinib versus placebo, was presented by Dr. Federico Cappuzzo (Abstract #8001). 889 patients were randomized to erlotinib or placebo. Progression free survival, the primary endpoint, was significantly prolonged with erlotinib (median 12.3 weeks) versus placebo (median 11.1 weeks). Clinical benefit was seen across all subgroups of patients, irrespective of histology, race or smoking status. The majority of patients received post-study treatment, yet only 16 % of patients in the placebo arm received further tyrosine kinase inhibitors. Overall survival data are not mature.

Finally, Dr. Vincent Miller presented data from the ATLAS trial, the randomized, placebo-controlled phase IIIb study comparing bevacizumab therapy with or without erlotinib after completion of platinum-based chemotherapy with bevacizumab (Abstract #LBA8002). 768 patients were randomized to either group in a 1:1 fashion. The primary endpoint of progression-free survival was met, with a median of 4.76 months for bevacizumab and erlotinib versus 3.75 months for bevacizumab and placebo; this improvement was demonstrated across multiple subgroups. Post-study treatment was administered to approximately half of the patients. Overall survival data are not yet mature.

These results are compelling and show a benefit in maintenance treatment. However, we must choose these patients carefully, a point made by the discussant, Dr. Nasser Hanna. Specifically, patients deriving a benefit from treatment and those with cancer-related symptoms may be considered for such therapy. We must remember that though well tolerated, maintenance chemotherapy is not without associated toxicities. For those patients that we choose not to continue maintenance therapy, they must have frequent, close follow-up as we do not want to lose the opportunity to treat them.

Biomarker analysis from the FLEX (phase III study comparing cetuximab with or without cisplatin/vinorelbine in NSCLC) and IPASS (phase III randomized study of gefitinib versus carboplatin/paclitaxel in selected patients) studies were presented. In the FLEX study, KRAS mutation testing was performed on archived tumor samples from treated patients (Abstract # 8007). Here, KRAS mutation status was not found to be predictive for cetuximab efficacy when added to chemotherapy. A rash of any grade was found to be associated with improved outcomes in patients treated with cetuximab.

Tissue was evaluated for EGFR mutation status, EGFR copy number by FISH, and EGFR protein expression by immunohistochemistry in the IPASS study (Abstract #8006). The authors found that patients with EGFR mutation status was significantly related to outcomes in patients treated with gefitinib compared to chemotherapy. Those patients with mutations treated with gefitinib compared to carboplatin/paclitaxel had significantly higher overall response rates and longer progression free survival. However, those patients that lacked mutations had poorer outcomes when treated with gefitinib compared to chemotherapy. EGFR immunohistochemistry status did not correlate with outcomes. Therefore, sensitizing mutations supersede EGFR copy number and immunohistochemistry as predictors for response and outcomes to gefitinib. These data strongly support the use of mutation testing in patients being considered for treatment with tyrosine kinase inhibitors.

Lung Cancer: Poster Discussion Session Saturday, May 30th

Post by M. Catherine Pietanza, MD:

Welcome to the 45th Annual Meeting of the American Society of Clinical Oncology. I will be discussing some of the highlights in lung cancer presented during the conference over the next few days.

The non-small cell lung cancer (NSCLC) abstracts were presented at a poster discussion session that concentrated upon early stage disease and adjuvant therapy.

To start, two abstracts underscored the importance of adequate surgical resections, both of which were retrospective studies. Allen et al. (Abstract # 7512) evaluated good quality oncologic resection (GQR), which according to the NCCN includes lymph node sampling from stations 10-14 and greater than 2 mediastinal stations. They observed that three year survival was 72% in those with GQR versus 63% in those without GQR. However, they noted that the majority of surgical resections did not achieve GQR standards. Osarogiagbon and colleagues (Abstract #7513) analyzed the survival of patients that had undergone resections with node negative disease and at least one lymph node examined (pN0) compared to those with no lymph nodes examined (pNx). Eleven percent of patients were pNx and 68% of patients were pN0, although the majority of these had less than 10 lymph nodes sampled. The three year survival estimates for T2NxM0 and T2N0M0 were 25% and 65%, respectively. These studies emphasize the significance of the quality of the resections to correctly stage disease and treat our patients.

Molecular characterization of lung cancer is feasible, as shown by multiple abstracts presented today (Abstracts #7520 through #7526). This will allow for “personalized cancer care”, the theme of the 2009 ASCO annual meeting.

Dr. Scagliotti and his colleagues (Abstract #7521) demonstrated the differential expression of thymidylate synthase according to histologic subtypes (adenocarcinoma, squamous cell carcinoma, large cell carcinoma, large cell neuroendocrine carcinoma, and small cell lung cancer); which was lowest in adenocarcinoma and highest in small cell lung cancer. This suggests that thymidylate synthase expression may be predictive of the response to pemetrexed, a thymidylate synthase inhibiting agent.

As part of the phase III IFCT-0002 study conducted in France assessing neoadjuvant and peri-operative chemotherapy, tissue expression of beta-tubulin III was evaluated (Zalcman et al., Abstract # 7526). These authors found that beta-tubulin III expression was associated with poorer progression free- and overall-survival in patients with early stage disease receiving neoadjuvant chemotherapy.

Janjigian et al. conducted a retrospective review of patients with resected stage I – III lung adenocarcinoma harboring EGFR activating mutations in exon 19 or 21 treated with EGFR tyrosine kinase inhibitors (gefitinib or erlotinib) and evaluated outcomes. Fifty-three patients received either erlotinib or gefitinib post-operatively (total number of patients 167). Individuals who received adjuvant gefitinib or erlotinib had a better disease free- and overall-survival than those who did not receive a tyrosine kinase inhibitor.

Although not presented during the lung cancer poster discussion, a final abstract is worth mentioning as it also shows the feasibility of molecular characterization in non-small cell lung cancer and the possibility of targeted therapy. Approximately 4-5% of lung adenocarcinomas harbor the EML4-ALK fusion gene, which encodes an activated tyrosine kinase. Dr. Kwak presented data using PF-02341066, a selective, ATP-competitive, oral small molecule inhibitor of the c-Met/HGFR and ALK receptor tyrosine kinases (Abstract # 3209). In a cohort of NSCLC patients harboring the EML4-ALK fusion gene with advanced disease, PF-02341066 was found to have an overall response rate of 53% and disease control rate 79% at eight weeks in 19 evaluable patients.