Giorgio V. Scagliotti, MD, PhD; Tony Mok, MD


October 06, 2014

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Giorgio V. Scagliotti, MD, PhD: I'm Giorgio Scagliotti, professor and chair of medical oncology in the Department of Medical Oncology at the University of Turin and San Luigi Hospital in Orbassano, Italy. Welcome to this edition of Medscape Oncology Insights in non-small cell lung cancer (NSCLC).

Today we will highlight the key studies on lung cancer presented at the 2014 Congress of the European Society for Medical Oncology (ESMO). Joining me is Dr Tony Mok, professor of clinical oncology at the Chinese University of Hong Kong.

We will review lung cancer studies in two major areas. The first is how we should treat patients with epidermal growth factor receptor (EGFR)-mutant tumors that are progressing on EGFR tyrosine kinase inhibitors (TKIs). The second is the potential use of adjuvant vaccines in the field of early-stage NSCLC.

Which kind of treatment strategies should we administer to our patients at the time of disease progression on EGFR-TKI? There are different opinions and different avenues. At this meeting, two relevant studies[1,2] have been presented. One is the ASPIRATION study,[1] presented by our Korean colleagues. There is also the IMPRESS study,[2] a multinational trial that you presented. I would like to start with the ASPIRATION study, if you would review the data.

Value in Staying on TKI After Progression?

Tony Mok, MD: The ASPIRATION study[1] was designed to look into the difference in treatment beyond progression. The first progression-free survival (PFS) point is defined by the RECIST criteria. The second PFS point is defined by the physician's discretion to stop the drug. We enrolled 207 patients and 93 of them eventually continued treatment beyond progression. The first PFS is11 months; the second PFS is14.1 months, meaning that there was a gain of 3.1 months if the patient received treatment beyond progression. These are the types of data we have from the ASPIRATION study that support the treatment of TKI beyond the progression according to RECIST criteria.

Dr Scagliotti: Do you believe that these findings will lead us to a real randomized clinical study? At the end of the presentation, I felt that the suggestions that Dr Park made were for the selection of patients on the basis of best prognostic factors, meaning that you are selecting the best subgroup of patients to be treated with EGFR-TKI.

Dr Mok: This is not a standard selection process. It's what I would call a natural selection process. There were 93 patients who continued, and there are patients who did not continue for various reasons. Obviously, the patients who continue therapy will end up with the longer median PFS. This is exactly how real life is. In a sense, we are not saying that this is a so-called practice-changing situation, but rather a reflection of a real-life situation. In our clinics, we do not use the RECIST criteria as a decision point. So this is what you would describe as a prospective observational study. The patients who stay well at the RECIST criteria point of progression should not stop the TKI. For that, we documented an extra 3.1 months.

Dr Scagliotti: Which patients are these, those with recurrent disease?

Dr Mok: We looked into the clinical criteria for the patients who continued on the TKI beyond progression and the ones who did not. There are some slight differences, including higher numbers of patients with a complete response and partial response. In a sense, you are correct. It is likely that the patients who are doing better will continue with treatment.

I don't think there will be a randomized study per se. It's probably not ethical to randomize patients in such a condition. On the basis of the ASPIRATION study, we can say that if you are good at the RECIST progression point and you are responding—if you have benefit from the drug—then carry on.

IMPRESS: Use Chemo Alone After Progression

Dr Scagliotti: Let me now switch to the IMPRESS study.[2]

Dr Mok: IMPRESS, which is not too impressive.

Dr Scagliotti: Let's summarize the major findings from your study.

Dr Mok: This is a randomized phase 3 study comparing the continuation of gefitinib with standard chemotherapy with pemetrexed and cisplatin vs chemotherapy plus placebo. The primary endpoint is PFS. We randomized 265 patients, 132 in one arm and 133 in the other. We are looking into the response rate and the primary endpoint of PFS and some data on overall survival, which are premature. At this point, the response rate is not different: about 31% vs 34%. In the overall PFS, the medians are both 5.4 months—exactly the same. The hazard ratio is not significantly different either.

We conclude from this study that continuation of EGFR-TKI beyond progression in combination with chemotherapy is not the right thing to do. If you look at the ASPIRATION data, patients should probably continue the TKI as long as they can, with respect to recent progression. At the point when they really have to change, they should change just to chemotherapy and not continue with the TKI. This is an important message.

Dr Scagliotti: What is coming out from these studies is that we are trying to optimize the treatment strategy in a sequential way for these EGFR mutants.

Dr Mok: Exactly. If I had to put it in one single sentence, TKI as long as you can and then switch to chemotherapy. That would be the simplest way to describe it.

Squamous Cell and TKI: Marginal Benefit

Dr Scagliotti: Another study[3] that was presented at this meeting looked at the other side of the histologic types—squamous cell carcinoma—using EGFR-TKI. There are negative attitudes [toward this strategy] derived from a series of studies that showed that chemotherapy is better than EGFR-TKI in squamous cell carcinoma; in general, in the absence of EGFR mutation, the EGFR-TKI does not work well.

This study was looking specifically at afatinib vs erlotinib in the setting of squamous cell carcinoma. What is your opinion on this study?

Dr Mok: Basically, they used squamous cell carcinoma as a surrogate selection for EGFR mutation wild-type. Although it's not 100% correlation, this is a surrogate selection. In this study, the endpoint was PFS; for the afatinib arm vs the erlotinib arm, PFS was 2.4 vs1.9 months. Although, because this is a big study, they will say that there is some marginal statistical difference, but 0.5 months (2 weeks) is actually a very small difference.

Although it is uncommon to have an EGFR mutation in squamous cell carcinoma, they exist [in approximately 30% of NSCLC cases]. Without knowing the mutation status, and whether the two arms are equal, it's hard to say whether the small difference is because of the small difference in the incidence of EGFR mutation, rather than the difference between the two drugs. This study wouldn't inform me or in any way change my practice in the management of squamous cell carcinoma.

Dr Scagliotti: Let's say that if we see a patient with squamous cell carcinoma who is a never-smoker or a light smoker, we should consider submitting the tumorous tissue for EGFR mutation testing. If it is positive, we can consider EGFR inhibition. Otherwise, there is no clear evidence to change anything in what we are currently doing in our clinical practice.

MAGRIT: Largest Adjuvant Trial Disappoints

Dr Mok: I agree with that entirely. Let's switch topics to vaccines. There is a major study called MAGRIT,[4] which is the largest adjuvant study ever. You are an expert in the adjuvant area, so would you like to comment on this particular study?

Dr Scagliotti: The integration of systemic therapies in the field of early NSCLC has been an ongoing subject for more than 20 years. We know that with chemotherapy we can get the survival advantage of 5 years in the range of 4%-5%.[5] This is what the meta-analysis showed us. On the basis of a couple of phase 2 randomized clinical studies[6,7] (specifically, one that looked at the addition of the melanoma antigen encoding gene A3 [MAGE-A3] vaccine[6]), we had limited, positive findings indicating that immunotherapy provided improved PFS, especially in stage II disease. Those findings led to this big and probably largest randomized clinical study testing adjuvant chemotherapy plus vaccine in the setting of early-stage NSCLC. MAGE-A3 is a surface antigen that is expressed in a variety of solid tumors. In melanoma, it's expressed in almost 100% of tumor cells. In NSCLC, it's expressed only in proportion of 30%-40% of the tumor cells.

In this study, a huge number—more than 13,000—patients were screened. The number of patients who were positive for the MAGE-A3 antigen was about 4000. Among these 4000 patients, 2272 were randomized. There were two major treatment possibilities: If the physician recommended adjuvant chemotherapy, the patients received adjuvant chemotherapy and then they were randomly assigned to receive vaccination or placebo. In the other cohort, patients who did not receive adjuvant chemotherapy were straightaway randomly assigned to vaccination or placebo.

Unfortunately, the study turned out to be negative. After a median follow-up of almost 39 months, in the 52% of patients who received chemotherapy first, the disease-free survival was 60.5 months vs 57.9 months for vaccine vs placebo, respectively. The hazard ratio was slightly above that for adjuvant chemotherapy. In the patients who did not receive adjuvant chemotherapy, the disease-free survival was almost identical (58 months vs 57.9 months) and the hazard ratio was getting close to 0.

In addition to the overall negativity of the study, the investigators were also unable to identify a gene signature that could define a subgroup of patients who potentially benefited from vaccination. That was the disappointing conclusion of this big study, but we have new avenues represented by the immune checkpoints. But it's too early to say something about these.

Dr Mok: What do you think is the reason for the negative findings? Is it that the vaccine is not useful, or would it be a mixture of different stages of disease in a large study? The prognostic value of staging is still the strongest. When you have a conglomerate of different stages, and also a conglomerate of different exposures to adjuvant therapy, would these factors have an impact on the outcome?

Dr Scagliotti: We need to look at secondary analyses to see whether there was any benefit by stage of disease. I am not expecting any major differences, because even in the phase 2 study[6] they failed to identify a subgroup of patients and they overall failed. Furthermore, there is news that other vaccines in the setting of locally advanced and NSCLC, as indicated by a different study,[8] generated some positive findings when vaccination was associated with concurrent chemotherapy and radiotherapy.

Dr Mok: What would be the next big thing for adjuvant therapy?

Dr Scagliotti: We have new avenues for immune checkpoints. If we are able to see minimal toxicities in the metastatic setting, I believe that potentially we have space for a new series of clinical trials, but it is too early to think about that. We are still looking to optimize adjuvant chemotherapy. Remember: Adjuvant chemotherapy is of benefit when it increases the survival benefit by 5% at 5 years, which is exactly what we see in breast cancer.

It was a pleasure to speak with you this morning. Thank you for joining us for this edition of Medscape Oncology Insights. This is Giorgio Scagliotti, reporting from ESMO 2014.


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