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Lung Cancer Update 2007 (1)

DR CHANDRA P BELANI: Adjuvant therapy has become the standard for patients with resected non-small cell lung cancer. After 2005, it was the standard for patients with Stage IB to IIIA disease. Recently we have developed a brewing controversy regarding whether we should administer adjuvant therapy to patients with Stage IB disease.

One issue in the controversy is whether or not it was carboplatin that caused the failure of the carboplatin and paclitaxel regimen for patients with Stage IB disease in CALGB-9633. At long-term follow-up, the data failed to show an improvement in overall survival because the hazard ratio fell from 0.62 to 0.80 and the p-value was no longer significant. As a word of caution: This was a small trial, and it is still not completed. In general, considering the results of the other clinical trials, the JBR.10 study, the IALT study and the ANITA trial, adjuvant chemotherapy did play a role in Stage IB disease, but in those trials the chemotherapy was cisplatin based.

The CALGB-9633 trial has shown in a subset analysis that among patients who have tumors greater than four centimeters, a benefit still exists. But again, we may be reading too much into these subset analyses, which were not clear endpoints of these clinical studies.

In the clinical setting, for Stage IB disease, I offer chemotherapy to patients, informing them that in a small subset it has shown a benefit and in another subset it has not shown a benefit. I let the patient decide whether he or she wants to receive adjuvant chemotherapy. If the tumor is greater than four centimeters in size, then I usually suggest that the patient receive it.

Lung Cancer Update 2007 (4)

DR MARTIN J EDELMAN: I believe the weight of data supports a cisplatin-based adjuvant regimen. If one wants to be completely data driven, cisplatin/vinorelbine is probably the most validated regimen out there, but it’s difficult to administer. In Stage IV disease, cisplatin/docetaxel is at least as good — possibly even superior — and probably better tolerated than cisplatin/vinorelbine, so I consider that a reasonable regimen.

If somebody told me that he or she intended to administer cisplatin/vinorelbine, I would not argue about it.

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The combination of cisplatin/gemcitabine is also a reasonable approach. I believe the crucial drug in this regimen is the platinum agent.

However, despite all the arguments, I believe carboplatin/paclitaxel is also reasonable. It has been pointed out that to conduct an adequately powered study of patients with Stage IB disease, you’d have to enroll about 2,000 patients.

So the CALGB carboplatin/paclitaxel study that showed an improvement in progression-free survival in Stage IB disease was probably underpowered.

If you consider the subgroup of patients with tumors measuring four centimeters, you see that those patients clearly fared better. I don’t believe carboplatin/paclitaxel is inactive in this setting — occasionally we do use that combination.

Why? We use it because some patients simply cannot tolerate cisplatin-based therapy. It is not unusual for us to start with a cisplatin-based therapy and then switch the patient after one or two cycles because he or she cannot tolerate it. So for their final couple of cycles, these patients are treated with a carboplatin-based therapy.

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Interview, July 2007

DR NASSER H HANNA: I use cisplatin-based adjuvant therapy, unless the patient has a contraindication for cisplatin. If a patient has modest renal insufficiency, I’ll administer carboplatin. I believe the general practice in the oncology community is to use carboplatin-based therapy. However, I think little difference in outcome is likely to appear.

We had a clue about that from ASCO 2007, when Milleron presented an early analysis of a neoadjuvant trial. He indicated that a regimen of carboplatin/paclitaxel resulted in the same degree of success as cisplatin/gemcitabine — in terms of complete resection rate, response rate and percent necrosis — suggesting that a carboplatin-based neoadjuvant regimen may be as good as cisplatin. We don’t have any survival data on that study yet.

I generally combine docetaxel with cisplatin. The majority of data we have from the adjuvant setting is with cisplatin/vinorelbine. But multiple trials have been conducted comparing cisplatin/docetaxel to cisplatin/vinorelbine or single-agent docetaxel to single-agent vinorelbine, in which docetaxel is a more active and effective agent.

Lung Cancer Update 2007 (3)

DR MARK A SOCINSKI: We are currently conducting a Phase II study evaluating docetaxel and carboplatin in the adjuvant setting.

We previously conducted a feasibility study of that combination, and our endpoint was to determine whether we could deliver four cycles of therapy within 12 weeks to more than 80 percent of the patients.

The study included 72 patients and showed that 80 percent of them were able to receive four cycles. We allowed patients to receive growth factor support, and approximately one third of the patients received growth factors at some point during the four cycles.

No treatment-related deaths occurred. Our conclusion was that this is a feasible regimen for the patient whom you consider not to be a good candidate for a cisplatin-based approach. The Phase II safety data suggest that you can use that regimen. The data in our trial were similar to what the CALGB showed with carboplatin and paclitaxel.

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Lung Cancer Update Think Tank 2007

DR THOMAS J LYNCH: My use of neoadjuvant therapy has declined over the years.

I had a lot more enthusiasm for it before we had evidence that adjuvant therapy had benefit. The only patients for whom I tend to think of neoadjuvant therapy now are those with bulky N2 disease, for whom we will administer neoadjuvant chemotherapy up front and proceed to surgery.

Adjuvant therapy has completely changed the dimension of neoadjuvant therapy. I don’t see a great advantage to neoadjuvant therapy over adjuvant therapy for Stage I and Stage II disease. Even for patients with resectable Stage IIIA disease, neoadjuvant therapy is questionable at that point.

Lung Cancer Update Think Tank 2007

DR HANNA: I can think of a couple of patients for whom we have used preoperative therapy recently.

Some patients have lost weight, and you become nervous about moving them to surgery up front, but you believe the disease is still curable radiographically — bulky N2 disease — and ultimately, you know they will require both surgery and chemotherapy. So you administer a few courses of chemotherapy and allow the disease to declare itself.

Lung Cancer Update 2006 (4)

DR VINCENT A MILLER: We now have several markers that can predict benefit from EGFR TKIs in the metastatic setting, which can be determined in any patient — such as smoking history, ethnicity and pathology — and some in the molecular arena.

In the arena of clinical variables, factors include never smoking, adenocarcinomas and Asian ethnicity. I believe a history of never smoking is the most powerful predictor of benefit.

ASCO 2006 was important in terms of reporting some prospective trials of EGFR tyrosine kinase inhibitors in patients known to have EGFR mutations. The lowest response rate in prospectively identified patients with mutations was about 65 percent, and it went up to about 85 or 90 percent. So a patient has about a 75 or 80 percent chance of having a response if he or she has an EGFR mutation. That is pretty good compared to what we had two or three years ago and even compared to what we have in other commonly studied diseases that are driven by diagnostic testing.

In our trial for patients with bronchoalveolar cancer — presented at ASCO 2006 — we had some patients with an EGFR mutation and a high EGFR copy number. Their response rate was 90 percent and their median survival was about three years with erlotinib.

The response rate for patients without an EGFR mutation and with an EGFR copy number lower than four was four percent, and their median survival was only 15 months. Those are pretty powerful predictors for a difference in clinical outcome.

Lung Cancer Update Think Tank 2006

DR HARVEY I PASS: For the patient who is a never smoker or has an EGFR mutation, I have to say that I can’t, off trial, dissuade him or her from adjuvant erlotinib because it makes sense to me.

Obviously, the trial must be performed to answer the clinical question: If we compare erlotinib with the best adjuvant chemotherapy regimens, is that the way to go? I believe we’re talking about a selected population. In that situation, I can’t go against the patient who has read all the data and wants to go that route.

DR LYNCH: I’ve softened on this issue. I believe for patients who have mutation-positive disease, you need to have a detailed discussion with them. They’re not going to be able to wait for the Phase III trials to be conducted, and obviously, I endorse the concept of Phase III trials.

However, for that patient with mutation-positive disease, I have a long discussion with them, and I don’t believe it’s crazy to consider adding erlotinib after chemotherapy.

Lung Cancer Update 2007 (3)

DR BRUCE E JOHNSON: The adjuvant setting is more complicated, and it will be a long time before we know how to use assays for EGFR and incorporate them into the therapeutic algorithm. The trial currently being planned will evaluate patients with the epidermal growth factor present either by immunohistochemistry receptor or by fluorescence in situ hybridization.

After surgical resection, those patients who are believed to benefit from chemotherapy will receive adjuvant therapy. If the tumor is EGFR-positive by immunohistochemistry or fluorescence in situ hybridization, those patients will be randomly assigned to receive erlotinib versus placebo (Figure 9).

That trial will take several years to accrue the patients, and because it’s in patients with relatively early-stage disease, we will have to wait for three to five years from the time the last person is enrolled to see the survival information. So we don’t know that just yet.

The other part that’s embedded within that trial is that those patients will also be studied for other determinants of benefit, including the mutations of the epidermal growth factor receptor.

The amount of tumor tissue available for these adjuvant studies is obviously much greater than in studies of patients with advanced disease, with whom we’re typically working with needle aspirations or bronchoscopic biopsies.

Lung Cancer Update 2007 (3)

DR SOCINSKI: In the absence of data and in the wake of SWOG-S0023, in which the use of an EGFR TKI after chemoradiation therapy showed a decreased survival rate, I have been conservative in my approach. I administer adjuvant chemotherapy — I have not yet administered adjuvant erlotinib or gefitinib.

There is an outstanding prematurely stopped trial by the NCI of Canada, in which adjuvant gefitinib was studied in unselected patients. It was closed before it met its accrual goal, and we don’t have any information yet.

We currently have an adjuvant trial, RADIANT (Figure 9), which selects patients with EGFR-positive disease by immunohistochemistry or FISH analysis, in which you can administer chemotherapy or not. Then they’re randomly assigned to a placebo or erlotinib. Until we see data from that trial, I have not used it as a recommended treatment in the adjuvant setting.

Lung Cancer Update 2007 (2)

DR COREY J LANGER: In the ECOG-E4599 first-line advanced NSCLC study, the addition of bevacizumab to paclitaxel/carboplatin demonstrated a two-month improvement in median overall survival and about a six to eight percent improvement in one- and two-year survival. It also showed more toxicity, particularly pulmonary hemorrhage.

In the bevacizumab/paclitaxel/carboplatin arm, 15 treatment-related deaths occurred out of 305 patients. Not all were related to hemorrhage — some were from neutropenic fever or other causes.

In the control group, two treatment-related deaths occurred out of 344 patients. So, although we excluded patients with squamous histology, brain metastases, ongoing thromboembolic phenomena, anticoagulation use or antecedent hemoptysis, we still saw a heightened treatment-related death rate.

I believe many of those concerns are going to fall by the wayside in the adjuvant trial. The tumors have been resected. By definition, these patients have no residual tumor in the chest. Ideally, they should not have pulmonary hemorrhage.

Lung Cancer Update 2006 (3)

DR EDWARD S KIM: Bevacizumab works well in the metastatic setting, so there is a rationale to move our best metastatic regimen to adjuvant therapy.

With bevacizumab, you need to consider the problems that could occur in a postoperative setting. We have to derive that from the colon trials. We’re not sure if there will be any wound dehiscence in lung cancer patients who have had surgery.

Lung Cancer Update 2007 (3)

DR HEATHER A WAKELEE: We activated the ECOG-E1505 (Figure 12) study recently and are more comfortable than ever with our choice of regimens that investigators can select: cisplatin/gemcitabine, cisplatin/vinorelbine and cisplatin/docetaxel, all with and without bevacizumab.

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At this point, we’re still sticking with the 15-mg/kg dose of bevacizumab because that’s the dose for which we have known survival benefit in the metastatic setting. The bevacizumab is administered at the 15-mg/kg dosing every three weeks starting with the first cycle of chemotherapy and then continuing for one year.

We are limiting patients with Stage IB disease to those whose tumors are four centimeters or larger. We know from subset analyses of the larger adjuvant trials that patients with Stage IB disease don’t seem to benefit overall. The CALGB IB trial was statistically negative overall, but those whose tumors were four centimeters or larger did show a survival benefit. That’s why we came up with the 4-cm cutoff.

At this point we’re not limiting to any specific non-small cell histology. We’re also not excluding patients receiving anticoagulation.

Based on the safety data that have emerged in colorectal cancer — and now hints that have emerged in the AVAiL study — patients who have had any sort of stroke or transient ischemic attack are excluded. Patients who have had any other arterial thrombotic events within six months — such as myocardial infarction — are also excluded.

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