HER1/EGFR-Tyrosine Kinase Inhibitors: Clinical Experience

Slide 1. HER1/EGFR-Tyrosine Kinase Inhibitors: Clinical Experience

We will now switch gears and put on our clinical hats and see if everything that made very clear sense in the preclinical models translates into activity clinically.

Slide 2. Outline

The outline for my talk is to look at phase I trials, both as single agents and then in combination with chemotherapy with erlotinib; to look at the phase II trials that have been completed in non-small cell lung cancer in general, as well as in bronchioloalveolar carcinoma (BAC); specifically, to look at one such study combining erlotinib with another targeted therapy, bevacizumab; and to discuss briefly the ongoing phase III trials and the rationale behind them.

Slide 3. Erlotinib (Tarceva) Phase I Monotherapy Studies

Looking at the phase I monotherapy studies, there have been 4 phase I studies that have been conducted, and 2 such studies were conducted in healthy volunteers. Two studies have been performed in patients with treatment-refractory cancers; the typical phase I studies you see in oncology -- on a weekly dosing basis, as well as on a daily dosing basis. Erlotinib is administered orally in all such studies.

Slide 4. Erlotinib Phase I Monotherapy Studies: Antitumor Activity and Tolerability

In terms of antitumor activity -- which is not the major purpose of a phase I study -- there was some evidence of activity in terms of numbers of patients with prolonged stable disease, although no responses were seen in this setting. In terms of tolerability -- which is the principle role of a phase I study (looking at tolerability in establishing the dose for subsequent study) -- acneiform rash and some mild diarrhea had been seen at the 200-mg dose, and it was felt to be the dose-limiting toxicity. In the weekly dosing study, the maximum tolerated dose (MTD) was not reached, but on the daily schedule, 150 mg/day was selected for the phase II studies, and that has been the basis of all such studies beyond. There have been comparable data from studies in Japanese patients vs Caucasian studies.

Slide 5. Erlotinib Phase I Monotherapy Studies: Pharmacokinetics (Daily Dosing Schedule)

This illustrates the erlotinib phase I monotherapy studies and the pharmacokinetics. You do have dose proportionality between the maximum concentration (C_max) and the area under the curve (AUC); and repeated daily dosing does not result in drug accumulation, allowing for the daily dosing. There is high plasma exposure at 150 mg/day; the dose that is near the dose-limiting toxicity is 2000 mcM, which is beyond the 1000 mcM mentioned earlier as necessary for both epidermal growth factor receptor (EGFR) inhibition and downstream effects. In comparison, another tyrosine kinase inhibitor, Iressa (gefitinib), also has high dose levels; the dose that is highest to the dose-limiting toxicity is 700 mg/day, but the currently accepted dose is around 250 mg, a slightly lower dose. Perhaps this may translate into differences between the 2 compounds.

Slide 6. Erlotinib Phase I Combination Studies: Rationale

A rationale for phase I combination studies: basically, you would like to look at different mechanisms of action, in hopes of improving efficacy by minimizing resistance. There are preclinical data that seem to be encouraging, in that there is at least additivity, if not synergy, between erlotinib and the various chemotherapy agents. There have been clinical trials that have been completed, as well as ongoing trials, looking at erlotinib with chemotherapy agents.

Slide 7. Erlotinib Phase Ib Combination Trials

These are the phase Ib combination trials looking at erlotinib with chemotherapy; they have been performed with docetaxel, with paclitaxel and carboplatin, and with gemcitabine and cisplatin. What has been shown is there are no significant pharmacokinetic interactions between chemotherapy and erlotinib. There is some preliminary antitumor activity, and a number of studies remain ongoing.

Slide 8. Erlotinib Phase II Trial in NSCLC: Objectives

Let's look at a specific phase II study, looking at erlotinib in previously treated non-small cell lung cancer. The primary objective was tumor response, and there were the usual secondary objectives of safety, tolerability, and survival.

Slide 9. Erlotinib Phase II Trial in NSCLC: Study Design

The design of the single-agent, open-label study: Patients had to have non-small cell lung cancer and, of importance, all the patients were considered EGFR positive to some degree. Performance status (PS) included PS2 patients, and the dose was 150 mg daily.

Slide 10. Erlotinib Phase II Trial in NSCLC: Patient Characteristics

These are some of the details of the patient characteristics: 57 patients were entered into the study. Interestingly, there is a predominance of females in this particular study; the median age is 62 years. The majority of patients had good performance status. Although all of the patients have recurrent non-small cell lung cancer, the vast majority had evidence of metastatic disease. All patients had to be EGFR positive, with the majority (over half) having a strong expression, and nearly 90% having what we considered weak-to-strong expression.

Slide 11. Erlotinib Phase II Trial in NSCLC: Antitumor Activity

Antitumor activity is shown here: 2 complete responses -- remember that this class of agents was initially felt to be cytostatic. We have 2 complete responses and 5 patients with partial responses, for an overall traditional response rate of 12.3%, and nearly 40% of patients had stable disease. The durations are shown, and those patients who did respond did seem to have a durable response.

Slide 12. Erlotinib Phase II Trial in NSCLC: Overall Survival

This is the survival curve. The median survival, 8.4 months, with 40% of patients alive at 1 year. This certainly compares favorably to previous work in second-line therapy.

Slide 13. Erlotinib Phase II Trial in NSCLC: Toxicity

Toxicity is shown here; the treatment was well tolerated. This class of agent does not have the typical toxicity of chemotherapy. Most of the adverse events were acneiform rash and diarrhea. There were 5 patients who had to withdraw because of toxicity, although there were no grade 4 events in this study, and a smattering of patients who had some grade 3 dermatologic toxicities, and 1 patient with grade 3 diarrhea.

Slide 14. Comparison of Phase II Studies in Advanced NSCLC

This is a comparison of the erlotinib data that I just showed, comparing it with 2 studies involving gefitinib in single-agent phase II studies. Two columns depict results of a randomized phase III study. Looking at supportive care, what we could expect in this previously treated patient population, is a survival of 4.6 months, and 1-year survival was 11%. This is in Shepherd's study at the National Cancer Institute (NCI) of Canada, comparing docetaxel with supportive care. In that study, docetaxel, a more traditional chemotherapy, had a 7.5-month median survival and a 7% response rate. Compare that with erlotinib with a 12% response rate, 8.4 months overall survival, and 40% 1-year survival. The erlotinib data were a phase II study. It is often not totally fair to compare these data with results from phase III; but it certainly gives you pause to think that there is some activity with erlotinib, which compares quite favorably with the results of gefitinib as well.

Slide 15. Ongoing Trials With Erlotinib

Other ongoing studies I will discuss include some randomized placebo-controlled trials in the first-line setting with chemotherapy -- the TRIBUTE and the TALENT trials -- and another phase III monotherapy study that is placebo-controlled in refractory non-small cell lung cancer, also led by Shepherd of the NCI of Canada. Earlier phase studies include a single agent in BAC, erlotinib and bevacizumab, and other studies that I will not be discussing.

Slide 16. Erlotinib Phase II Trial in Bronchioloalveolar Cell Carcinoma (BAC): Objectives

Here are the BAC data that have been very intriguing. This was presented by Miller at the 2003 American Society of Clinical Oncology (ASCO) and will be updated soon.

The principle objective again is tumor response, with the other usual secondary objectives.

Slide 17. Erlotinib Phase II Trial in BAC: Study Design

Study design is shown here. Patients had BAC, but the uniqueness of this study was not to involve patients just with BAC. As previous papers have suggested that patients with any component of BAC appear to behave similarly to those patients with pure BAC, this study design included those with pure BAC, those with focal invasion, and even those with adenocarcinoma with BAC features. It allowed patients down to a Karnofsky performance status (KPS) of 60%; and because of the nature of BAC, it allowed patients with no prior therapy or 1 prior chemotherapy. The usual dose for erlotinib was used. The plan was that if there was at least 1 response seen on the initial cohort of patients, they were to proceed to upwards of 100 patients.

Slide 18. Erlotinib Phase II Trial in BAC: Disease Characteristics

Here are the results, in terms of the disease characteristics. Initially 98 patients' tissue was submitted for a central review at Memorial Sloan Kettering. Of those -- all of whom were thought to have some form of BAC going into the study -- 28%, or 27 patients, on second review, did not have any evidence of BAC. The remaining patients -- and these percentages are a reflection of the initial 98 -- have adenocarcinoma with BAC features, BAC with focal invasion, and pure BAC (representing only about 17% of the total initial cohort), leaving 71 patients for treatment, and 55 patients ultimately officially entered on study after signing consent.

Slide 19. Erlotinib Phase II Trial in BAC: Evaluable Patient Characteristics

Fifty patients were evaluable and, not surprising with BAC, the predominance was females. The median age was around 66 years, the majority of patients with very good performance status, and about 26% of patients were never smokers. The majority of patients had no prior chemotherapy.

Slide 20. Erlotinib Phase II Trial in BAC: Antitumor Activity

Here is the antitumor activity; response rate of 26%. This compares quite favorably with previous studies in terms of non-small cell lung cancer in general, with response rates of 10%. Another signal that BAC is an interesting cohort of patients. The median duration of response has not yet been reached.

Slide 21. Case History of Response to Erlotinib

Here is a typical response; this is the typical CT scan appearance of bilateral evidence of BAC and of the response after treatment. Also, note the duration of this; this is nearly a year from July 2002 to May 2003.

Slide 22. Erlotinib Phase II Trial in BAC: Toxicity

The treatment was well tolerated, with the usual toxicity pattern of skin rash and diarrhea that was not terribly significant. Only 1 patient discontinued due to toxicity, and there were no treatment-related deaths.

Slide 23. Phase II Trials in BAC: Can Smoking History Predict for Response?

A question that has been raised is can smoking history predict for response? Data from this particular study show that patients with a "never" history of smoking -- this included patients who had smoked up to 100 cigarettes total in their lifetime -- had a response rate of 46%. Other current or former smokers had a response rate of 19%, and despite the small numbers of this study, that almost reached statistical significance, certainly sending a strong signal that tobacco use may play some role in developing resistance.

Another paper was presented on 140 patients who have been previously treated with gefitinib and, looking at predictors of response, suggested again that BAC features and a nonsmoking history may well be predictive of response in this group of patients. There are further studies that are ongoing in an attempt to further elucidate this.

Slide 24. Erlotinib Plus Bevacizumab Phase I/II Trial in NSCLC: Rationale

Here is a study that is ongoing, at MD Anderson Cancer Center with Dr. Roy Herbst and with myself at Vanderbilt, looking at erlotinib and bevacizumab, the antibody to vascular endothelial growth factor (VEGF) in previously treated non-small cell lung cancer. The rationale is that there should be at least an additive effect -- looking at 2 different mechanisms of action in this group -- and that combining targeted therapies may be easier than chemotherapy because they generally have milder toxicity profiles. The biologic heterogeneity of these tumors would suggest that more than a single-pronged attack may be important.

Slide 25. Erlotinib Plus Bevacizumab Phase I/II Trial in NSCLC: Objectives

The objectives: this was a phase I and phase II study, and so the objective for phase I was to establish the dose to take forward into phase II; and for the phase II trial, to look at response rate, toxicity profiles, and survival.

Slide 26. Erlotinib Plus Bevacizumab in NSCLC: Phase I Trial Schema

This is the schema: essentially patients who had previously treated non-small cell lung cancer. Squamous cell patients were not eligible for this study because of previous data involving bevacizumab that showed a potential tendency for hemoptysis in squamous cell patients. They had to have had at least 1 prior chemotherapy regimen; there was no limit on the numbers of prior chemotherapy. In terms of treatment, each drug was given on day 1; erlotinib was continued once daily without interruption and the bevacizumab was given on an every 3-week basis. There are 3 cohort levels, with the goal of attempting to reach full doses for both erlotinib and bevacizumab in a standard 3 plus 3 design. The phase I study did achieve that with 3 cohorts of 3 patients each, and an additional number of patients have been put on. There are 19 evaluable patients at this time.

Slide 27. Erlotinib Plus Bevacizumab in NSCLC: Phase II Trial Schema

We are well into the phase II portion of this study, and this will be updated. The concept was, if at least 1 response was seen in this previously treated population, we would proceed, and that has happened.

Slide 28. Erlotinib Plus Bevacizumab in NSCLC: Patient Characteristics (Phase I)

These are the phase I data: 12 patients on study, 3 at level 1, 3 at level 2, and 6 at level 3; 2:1 male-to-female population; a younger patient population, with median age of 55 years; the majority has metastatic disease; and all patients received prior chemotherapy, the majority having 2 or more.

Slide 29. Erlotinib Plus Bevacizumab in NSCLC: Toxicity (Phase I)

Here is the toxicity; there is no grade 3 or grade 4 toxicity in the phase I setting; rash, diarrhea, and some mild nausea were seen. No problems with proteinuria or bleeding with this combination in this phase I group.

Slide 30. Erlotinib Plus Bevacizumab in NSCLC: Antitumor Activity (Phase I)

Three responders out of the first 12 patients were noted; also an additional 5 patients with stable disease, and so, 8 out of 12 patients with some disease control.

Slide 31. Example of Response to Erlotinib Plus Bevacizumab (Phase I)

This illustrates a response, a patient with pleural-based disease who had responded nicely to therapy.

Slide 32. Erlotinib Plus Bevacizumab in NSCLC: Summary

In summary, for the combination of erlotinib and bevacizumab, the phase I is complete with the MTD at 15 mg/kg intravenously (IV) for bevacizumab every 21 days, and continuous daily dosing with erlotinib at 150 mg/day. No unexpected toxicities, simply the rash and diarrhea. There is also a preliminary evaluation of pharmacokinetics, no interaction between these 2 agents. Antitumor activity has been seen and the phase II study is ongoing.

Slide 33. Phase III Trials in NSCLC: Rationale for Combination Trials

What about combination trials? It appears preclinically to have some additivity, if not synergy, with chemotherapy. Erlotinib has its own antitumor activity noted as well, and there does not appear to be any reason, in terms of toxicity, not to combine these 2 groups. There have been 2 phase III trials of chemotherapy and erlotinib.

Slide 34. TALENT and TRIBUTE: Study Design

The schema is shown here: the TALENT and TRIBUTE studies, with chemotherapy given for a total of 6 cycles of therapy, along with concurrent and subsequent oral erlotinib, until evidence of progressive disease. Chemotherapy was with either Taxol (paclitaxel) and carboplatin, or with cisplatin and gemcitabine. Those studies were designed to show a 25% improvement in survival, and we hope to see that at some point in the next weeks to months.

Slide 35. BR.21: Erlotinib Phase III Study in Advanced, Refractory NSCLC

Another phase III study that is shown here is the BR.21, a Canadian study, that looks at patients with 1 or 2 prior therapies, erlotinib vs placebo. A large study of over 700 patients; the accrual is completed, and survival is the overall endpoint, looking for power to a 33% survival benefit.

Slide 36. Conclusions

In conclusion, erlotinib is an active and well-tolerated agent in previously treated non-small cell lung cancer. It appears very interesting in BAC. It is being administered in combination with chemotherapy, as well as with at least 1 other targeted agent, bevacizumab. Future studies will be looking to identify markers that are predictive of response, looking at combination with other biologic agents, and also hoping to develop additional dosing strategies.