Case Studies

Case Study 1

Dr. Hanna: I would recommend Option 3, following the ECOG 4599 protocol. Assuming he has had no radiographic progression, I would then treat him with maintenance bevacizumab. I usually stop after 4 initial cycles of chemotherapy. The rare exception would be the patient who has significant cancer symptoms at baseline. If he has a significant radiographic response after 2 cycles and a further significant response following 2 more cycles, with very good tolerance to therapy in both, I would tend to give 2 additional cycles for a total of 6.

"I would recommend ... following the ECOG 4599 protocol. Assuming he has had no radiographic progression, I would then treat him with maintenance bevacizumab."

Dr. Fidias: Most patients do not get an additional radiographic response beyond 4 cycles. Since the toxicity is cumulative, most will stop at 4 cycles, though I go to 6 cycles in about 20% of patients.

Dr. Lynch: Dr. Hanna, do you think that in this circumstance you could support Option 1: carboplatin/paclitaxel x 4 cycles?

Dr. Hanna: Based on the safety profile, convenience, and efficacy, I would prefer Option 2: platinum/ pemetrexed x 4 cycles. I do not think all patients need bevacizumab. I do talk to them about it, and inform them that the risk of complications is low but real. Most of my patients do end up receiving it.

"Based on the safety profile, convenience, and efficacy, I would prefer ... platinum/pemetrexed x 4 cycles. I do not think all patients need bevacizumab."

Dr. Lynch: If this patient was 78 years of age rather than 48, how would you have answered this question?

Dr. Fidias: For older patients it is primarily an issue of performance status. We know from the ECOG analysis that with bevacizumab there is a higher rate of significant complications for older individuals, including grade 5 toxicities. However, these data were based on a subgroup analysis, so the ECOG results alone are not sufficient to suggest that bevacizumab should not be used in this population. For our elderly patients we do use bevacizumab. If a patient has significant vascular disease, such as uncontrolled hypertension, you may want to consider other options. For a relatively healthy elderly patient with minimal comorbidities, I would treat using Option 3, the ECOG 4599 regimen.

Case 1A

Dr. Hanna: These are small brain metastases, probably well controlled. I would discuss with him the potential of bleeding and what that could mean. Subsequent to E4599, studies have demonstrated acceptable safety in this population. I think this patient can still be treated with Option 3: carboplatin/paclitaxel/bevacizumab x 4 cycles, followed by maintenance bevacizumab.

Dr. Lynch: Dr. Jalal, why do you think none of us has chosen Option 5: pemetrexed and bevacizumab maintenance, in any of these scenarios? It seems that could provide the best adenocarcinoma therapy: use of bevacizumab and incorporation of maintenance therapy.

Dr. Jalal: I do not think the data are mature enough. Patients do benefit from treatment breaks, and if they stay on pemetrexed and bevacizumab maintenance they will end up having some toxicity. I do not think that the data are compelling enough to continue pemetrexed and bevacizumab after being treated with a combination regimen using both agents.

Case 1B

Dr. Hanna: In this case, the patient has an adenocarcinoma but is contraindicated for bevacizumab because of the bleeding. I would choose Option 4: platinum plus pemetrexed, generally for 4 cycles, and I would closely observe him with a treatment break.

Dr. Fidias: I would do the same. I think the standard at this point, based on the Scagliotti data, would be to treat him with a pemetrexed/platinum combination. In the United States we may prefer a carboplatin/pemetrexed regimen rather than cisplatin/pemetrexed, but both are for patients with good performance status. In light of the absence of an overall survival benefit, I would not proceed with early second-line treatment. Since the Belani study did not include patients who received upfront pemetrexed, it is unclear whether maintenance pemetrexed in that setting would be beneficial.

Dr. Sandler: I agree as well. I would use Option 4, and would try to use cisplatin if possible. Given the data and ease of use of that regimen in our mesothelioma patients, I would try to reserve carboplatin for elderly patients and those with lesser performance status. Since the Belani study did not include patients who received upfront pemetrexed, it is unclear whether maintenance pemetrexed in that setting would be beneficial.

"I think the standard at this point, based on the Scagliotti data, would be to treat him with a pemetrexed/ platinum combination."

Case Study 2

Dr. Fidias: This is the typical case of a bevacizumab-ineligible patient, due to the squamous cell histology. Based on the study by Scagliotti et al, either a platinum/taxane or platinum/gemcitabine regimen could be used. I tend to use more carboplatin/ paclitaxel than carboplatin/gemcitabine, although I assume both work equally well. If the patient wanted monoclonal antibody therapy, you could discuss cetuximab, but this has not been my practice since it is not yet approved and is expensive. Cetuximab has its own toxicity profile, and the results from the FLEX trial are less impressive than the ECOG 4599 data.

Dr. Lynch: Dr. Fidias, your study showed a benefit in progression-free survival with early second-line docetaxel, with a trend towards an overall survival benefit. Do you not believe your own data?

Dr. Fidias: I believe that you can improve progression-free survival by continuing chemotherapy, but there is probably little impact on overall survival. The main change in practice for me was to follow patients very closely, and to have a lower threshold than I previously used to reinitiate chemotherapy. It is interesting to note that the hazard rate for progression-free survival and overall survival for the docetaxel and pemetrexed maintenance studies were almost identical for the patient population as a whole, although only statistically significant for overall survival in the pemetrexed study. This may be due to the smaller size of our study.

Dr. Jalal: I would use either carboplatin/paclitaxel or carboplatin/gemcitabine.

Dr. Hanna: I would choose Option 1 or 2 as well. One of the take-home messages from Dr. Fidias' study was based on the outcome of patients who were randomized to the delayed docetaxel arm and received docetaxel therapy. If those patients did poorly, you would have missed an opportunity. However, those patients did just as well. So we want to make sure we do not miss the opportunity to give them second-line therapy, and I have a very low threshold.

Dr. Lynch: I have not seen much enthusiasm in this group for the use of earlier erlotinib, the so-called SATURN approach. When erlotinib first became available, community oncologists were frequently using that as a sort of a default way of treating. They would give patients upfront chemotherapy (e.g., a carboplatin-based doublet), then after 4 cycles administer single-agent erlotinib. We now have a randomized trial that is reported as being positive, at least in press release form. Why do you think no one here has enthusiastic support for the SATURN-type approach?

Dr. Sandler: There never was any data to support this, and we still need to see the full study report. The question of early versus late therefore remains.

Dr. Hanna: One of the differences between cetuximab and erlotinib is that an erlotinib-associated skin rash, when it is severe, flares in the first few weeks, then typically plateaus and improves, sometimes with periods of flares but not worse than the original rash. In my experience a cetuximab-associated rash, however, tends to flare early and, when severe, sometimes remains persistently severe throughout treatment. In this case, would you give these patients maintenance cetuximab? If the patient is having a grade 2 rash, would that persuade you to stop therapy, or would it have no impact?

Dr. Lynch: If a patient is having a miserable time with a rash, I have no trouble stopping maintenance cetuximab in that setting. If the patient is not having too much trouble, I think that is fine.

"This is the typical case of a bevacizumab-ineligible patient, due to the squamous cell histology. Based on the study by Scagliotti et al, either a platinum/taxane or platinum/ gemcitabine regimen could be used. 12

Case Study 3

Dr. Jalal: I would choose Option 1. I think she has the phenotype and genotype (EGFR-positive) that would respond to erlotinib. I would, however, monitor her very closely, especially to see if she has liver lesions, to ensure she is responding to monotherapy.

Dr. Sandler: The choice I would probably use actually is not here, which is the ECOG 4599 regimen. When she progresses, I would use erlotinib as second-line therapy. This is also a case where I have used Option 4, adding erlotinib to the maintenance phase of the 4599 regimen.

The results from the IPASS trial comparing a single-agent EGFR TKI (gefitinib) to chemotherapy in an Asian population showed a vastly superior progression-free survival, though overall survival for both groups was similar. This patient is ultimately going to get chemotherapy and an EGFR TKI. And the results with the EGFR TKI in the second-line setting were fairly impressive as well.

The physician needs to discuss what the patient would like to consider. Would she prefer no chemotherapy at all, and just EGFR TKI monotherapy? I would be comfortable with EGFR TKI monotherapy, although I would lean towards adding bevacizumab if she wanted a non-chemotherapy approach.

"This patient has to have erlotinib at some point, and her likelihood of responding is very high."

Dr. Hanna: I would agree with Dr. Sandler — all of these options are reasonable. This patient has to have erlotinib at some point, and her likelihood of responding is very high. We should recognize that there may be biologic differences between North American and Asian populations, which may not make the IPASS results entirely reproducible in North America. If this patient were to ask me what I would recommend, I would probably recommend erlotinib.

Dr. Fidias: This is one situation where I would definitely start with EGFR TKI monotherapy, using either erlotinib or gefitinib, based on the IPASS data. We do not know if that translates to the Western population, although we know that patients with an EGFR mutation will have a response rate of about 70% to the EGFR TKI monotherapy, which is more than double that achieved with chemotherapy. This also results in a better progression-free survival. So the real question is whether you add bevacizumab, which has interesting phase II data but no phase III results at this point. There are also occasional patients with an EGFR mutation who will never receive chemotherapy, and I find no reason why you would not start with erlotinib monotherapy here.

Dr. Lynch: We do have a bias towards first-line erlotinib. When progression occurs, if it is relatively short, I immediately initiate chemotherapy plus bevacizumab. I have always felt this population was ideal for bevacizumab-based therapy. I think we do not know yet about the benefit of using a bevacizumab regimen as first-line therapy.

In contrast with Dr. Sandler and Dr. Hanna, I have been less concerned about geography than biology. I believe that the experience across geographical locales — in Europe, the U.S., and Asia — is fairly similar in patients with an exon 19 EGFR deletion. I do recognize that the Asian population in particular fares better, but I am less convinced that geography is something to be very concerned about.

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