Lung Cancer Update, Issue 4

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Gregory J Riely, MD, PhD

Tracks 1-21

Track 1	Clinical and molecular predictors of response to EGFR tyrosine kinase inhibitors (TKIs)
Track 2	Single-agent activity of EGFR monoclonal antibodies in NSCLC
Track 3	EGFR protein expression, gene amplification and mutation status as predictors of response to EGFR TKIs
Track 4	Barriers to routine performance of EGFR mutation testing
Track 5	Adjuvant clinical trials in lung cancer for patients with tumors containing EGFR mutations
Track 6	Decisional analysis in offering adjuvant erlotinib off protocol to patients with EGFR mutations
Track 7	EGFR TKI-associated interstitial lung disease
Track 8	Use of first-line erlotinib with or without chemotherapy in select patients with advanced NSCLC
Track 9	FLEX: Cetuximab with cisplatin/vinorelbine (CV) versus CV alone in the first-line treatment of advanced NSCLC
Track 10	K-ras mutation as a predictor of primary resistance to EGFR TKIs and monoclonal antibodies in NSCLC
Track 11	Utilization of K-ras and EGFR mutation status in clinical decision-making for NSCLC
Track 12	Tradeoffs with cetuximab/chemotherapy as first-line therapy for advanced squamous cell carcinoma of the lung

Track 13	Risks and benefits of carboplatin/paclitaxel and bevacizumab for advanced NSCLC
Track 14	Continuation of EGFR TKIs after disease progression
Track 15	Increased EGFR gene copy number via FISH predicts outcomes for patients with NSCLC treated with cetuximab/chemotherapy: Clinical implications of SWOG-S0342
Track 16	Prediction of response to erlotinib in patients with bronchoalveolar carcinoma (BAC) or adenocarcinoma with BAC features
Track 17	Phase I/II trial of weekly nanoparticle albumin-bound (nab) paclitaxel as initial chemotherapy for Stage IV NSCLC
Track 18	Maintenance pemetrexed for patients with Stage IIIB/IV NSCLC who had not experienced disease progression on platinum-based induction chemotherapy
Track 19	Nonsquamous cell histology and benefit from first-line cisplatin and pemetrexed in advanced NSCLC
Track 20	Carboplatin/pemetrexed and bevacizumab with maintenance pemetrexed and bevacizumab as first-line therapy for advanced nonsquamous NSCLC
Track 21	Investigational agents with dual targeting of EGFR and VEGF in NSCLC

Select Excerpts from the Interview

Track 3, 5

DR LOVE: Can you discuss the assays for molecular markers that have been studied for predicting response to the EGFR TKIs?

DR RIELY: A number of retrospective evaluations have been conducted of tumor sets from large randomized trials evaluating EGFR overexpression with immunohistochemistry (IHC) and FISH in addition to evaluating EGFR mutations. It’s complicated, but I would break it down to an issue of sensitivity and specificity. Patients with EGFR IHC-positive tumors represent the majority of lung cancer patients, and these patients may or may not respond to EGFR TKIs. IHC does not serve as much of an enrichment for patients likely to respond to erlotinib.

Fewer patients have true FISH-positive tumors. Among unselected patients, the overall response rate with erlotinib is approximately nine percent. If you identify those patients with FISH-positive tumors, the response rate jumps significantly and is closer to 40 percent. Approximately 10 percent of patients with lung cancer have EGFR mutations, but the response rate for those tumors is closer to 80 percent (van Zandwijk 2007).

The EGFR mutation represents the most specific predictor of response to EGFR TKIs, whereas EGFR overexpression as determined by IHC and FISH describes a larger number of patients, but those patients are less likely to respond to erlotinib (Jackman 2008; Zhu 2008).

Tracks 6, 8

DR LOVE: What is your approach to treatment for a patient with an EGFR mutation in the adjuvant setting? Do you offer erlotinib?

DR RIELY: It is difficult to argue against the idea of using erlotinib — with a response rate of more than 80 percent — for a patient with an EGFR mutation. However, it’s unclear whether the EGFR mutation is a predictive factor or a prognostic factor. Retrospective analyses of patients with EGFR mutations have shown that they fare relatively well after resection in comparison to those with EGFR wild-type tumors, and these patients may go on to fare better overall, whether we administer erlotinib or not.

At the same time, lung cancer is a difficult diagnosis. For a patient with early-stage resected lung cancer who has a known EGFR mutation, I explain that no data exist to demonstrate improvements in overall survival with erlotinib, but my scientific estimation is that it will.

DR LOVE: For patients with metastatic NSCLC who have the EGFR mutation, do you recommend erlotinib up front?

DR RIELY: You can make a perfectly reasonable argument to start patients with known EGFR mutations or with clinical characteristics that are likely to be associated with mutations — such as never smokers with adenocarcinomas — on erlotinib monotherapy, which is what I generally do off protocol.

Track 9

DR LOVE: Can you summarize the FLEX trial results that were presented at ASCO (2.1)?

DR RIELY: In the FLEX study, patients were randomly assigned to receive either cisplatin/vinorelbine alone or cisplatin/vinorelbine with cetuximab (Pirker 2008). Patients received cetuximab on a weekly basis, and after six cycles of chemotherapy, those patients who were on cetuximab continued it as maintenance therapy.

Approximately a one-month improvement in overall survival was observed, without a marked difference in progression-free survival, for patients treated with cetuximab. Subset analysis revealed that cetuximab was equally efficacious in squamous cell tumors and adenocarcinomas. As such, chemotherapy with cetuximab would be a reasonable choice for patients with squamous cell tumors, for which we are unable to use bevacizumab safely.

2.1

Tracks 12-13

DR LOVE: Do you think cetuximab has a positive risk-benefit ratio for patients with advanced squamous cell NSCLC?

DR RIELY: It’s reasonable to consider cetuximab for patients with squamous cell tumors. The side effects of cetuximab are real, including the rash and the side effect that is rarely talked about, which is weekly therapy. Patients must come to the doctor’s office once a week for the first six cycles of therapy, which is a burden for a patient with Stage IV NSCLC.

DR LOVE: How do you approach patients with adenocarcinomas who meet the entry criteria for ECOG-E4599, which evaluated carboplatin/paclitaxel and bevacizumab?

DR RIELY: Chemotherapy with cetuximab is an option, but carboplatin/paclitaxel and bevacizumab led to a two-month improvement in overall survival, compared to somewhat less improvement in overall survival in the FLEX trial. Therefore, it’s reasonable to consider bevacizumab as probably superior, acknowledging the caveats about cross-trial comparisons. Additionally, we have much greater experience administering bevacizumab for a large number of patients.

Track 14

DR LOVE: How do you treat the patient with an EGFR mutation who responds to erlotinib and then experiences disease progression?

DR RIELY: This is an important question, to which we don’t have an answer. The direct analogy is a patient with HER2-positive breast cancer who responds to trastuzumab and then develops progressive disease. The standard approach to those patients without evidence from a randomized trial is to continue trastuzumab and add chemotherapy.

We investigated this situation with a relatively small study, in which we took 10 patients with what we defined as acquired resistance to erlotinib or gefitinib (Riely 2007). Those patients had all been treated with erlotinib or gefitinib for more than six months and all had responded to therapy. If we couldn’t document a response to therapy, we verified that the tumor had an EGFR mutation.

So we took this relatively select group of patients and performed scans on them. We discontinued therapy at disease progression and rescanned them. As you would expect, most of the tumors grew. FDG avidity also rose on the PET scan because disease was progressing in all cases beforehand, so it’s reasonable to presume that it would continue to progress off treatment. We restarted gefitinib or erlotinib for another three weeks and then reassessed. Somewhat surprisingly, all of the tumors stabilized in their growth rate and FDG uptake on PET scan. These data suggest that these patients are continuing to benefit from erlotinib therapy, so our standard treatment is to continue erlotinib and add chemotherapy.

Track 17

DR LOVE: Can you discuss the study you were involved with evaluating nanoparticle albumin-bound (nab) paclitaxel in patients with previously untreated NSCLC (Rizvi 2008)?

DR RIELY: This was a Phase I/II trial. After initially identifying the maximum tolerated dose (MTD), we treated patients with the MTD of nab paclitaxel on a weekly administration schedule. The response rate with single-agent nab paclitaxel was 30 percent, and the overall survival was acceptable for up-front treatment in NSCLC (Rizvi 2008; [2.2]).

Nab paclitaxel is clearly an effective drug, and compared to conventional taxanes, its benefits are apparent, such as the absence of hypersensitivity reactions in patients who are receiving the taxane without steroid premedication.

2.2

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Neil Love, MD

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Gregory J Riely, MD, PhD
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Alan B Sandler, MD
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David S Ettinger, MD
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