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Optimising Disease Control in Advanced NSCLC

F. Grossi (Italy)

SlotAE-5 Grossi, F.

Presentation by the Dr. Francesco Grossi of the current and futures strategies to optimise disease control in NSCLC

Transcription

Good evening and thanks to Pierre Fabre for the invitation. The purpose of my talk is to discuss how to optimise the disease control in advanced non-small cell lung cancer.

Agenda

In my presentation I will discuss the role of maintenance, switch or continuation after induction chemotherapy and the metronomic chemotherapy.

Full transcription

Full transcription

Good evening and thanks to Pierre Fabre for the invitation. The purpose of my talk is to discuss how to optimise the disease control in advanced non-small cell lung cancer.

Agenda

In my presentation I will discuss the role of maintenance, switch or continuation after induction chemotherapy and the metronomic chemotherapy.

Agenda: Optimising disease control with maintenance therapy (switch or continuation)

 A new approach in advanced NSCLC.

Traditional approach to NSCLC

What about the maintenance treatment?  As we know for many years we have treated our patients with four to six cycles of chemotherapy with platinum doublets, with third generation agents for four to six cycles and the patients with at least disease stabilisation stopped the treatment, watch and wait and at progression start second-line treatment.

New approach to NSCLC    

Now we know that if we treat the patients with maintenance therapy we can prolong the progression-free survival and we can also prolong the survival of our patients.

Rationale for “continuation” or “switch” maintenance

We have two different strategies for maintenance; the switch, that means change the drug, another drug, a new drug, different to the drug used in the induction phase or continuation, so use one of the drugs used in the induction phase.

The switch maintenance is based on the hypothesis of Goldie and Coldman stating that the early use of non-cross-resistant agents might increase the probability of killing more cancer cells before resistance.

The continuation is based on the Day model that indicates that the most active regimens should be used as a consolidation treatment.

Recent “switch” maintenance trials

Now we have a lot of recent trials of switch maintenance and also of continuation maintenance.

For the switch maintenance, I summarise in this table the major trials and as you can see there is a Phase III randomised trial that compares maintenance versus observation and there is a significant difference or a trend for a difference in favour of maintenance in terms of progression-free survival and overall survival.

 “Continuation” maintenance trials

And also for continuation maintenance we have similar results in terms of progression-free survival and overall survival.

Maintenance meta-analysis

If we put together the results of this trial in a meta-analysis, as you can see we have significant difference in favour of maintenance compared to observation and very important, this difference in favour of maintenance, when we use cytotoxic agents and also when we use the EFGR TKIs.

ESMO Clinical Practice Guidelines

If we look at the ESMO clinical practice guidelines, in these guidelines maintenance chemotherapy should be offered, they recommend to offer this strategy in patients with a good Performance Status.

The decision about maintenance must take into account the histology.  We haven’t a lot of data about the squamous cell carcinoma.  Most of the results we have in other carcinomas, non-squamous carcinoma.

Very important the response to the induction phase with platinum doublets chemotherapy and also important is the remaining toxicity, after first-line chemotherapy and the patient preference.

The guidelines recommend the use of pemetrexed in switch maintenance or continuation maintenance because we have a lot of data about these agents or erlotinib, especially as switch maintenance in patients with stable disease after induction chemotherapy.

Maintenance therapies: patients’ perceptions

It is also very important the patients’ perceptions about the use of maintenance.  This is a very nice study published three years ago that demonstrates that patients accept the maintenance treatment, if they have at least three months of benefit in overall survival.

And also very importantly, the patients preferred the use of the administration of oral therapy compared to intravenous therapy.

NAVo Trial 01: trial design

Now we have important data about maintenance in a trial recently published, the NAVo Trial 01.  This is a Phase II randomised trial that compared cisplatin plus oral vinorelbine at the standard doses of cisplatin and vinorelbine for four cycles.  Patients without progression continue the treatment with oral vinorelbine as a maintenance therapy.

In the other arm we have cisplatin/pemetrexed at a standard dose for four cycles and again in patients without progression continue with maintenance with pemetrexed.

NAVo Trial 01: efficacy results (ITT population)

The primary endpoint of the trial is the disease control rate and this trial demonstrates that we have no difference between oral vinorelbine plus cisplatin. This is  compared to cisplatin and pemetrexed, in terms of response and disease control rate in the combination period but also in the combination and maintenance period.

NAVo Trial 01: OS and PFS

If we look at the overall survival and the progression-free survival curves, as you can see the curves are superimposed so no difference for oral vinorelbine compared to pemetrexed.

NAVo Trial 01: safety

What about the safety?  As expected in the combination period with cisplatin vinorelbine had more toxicity in terms of neutropenia compared to cisplatin/pemetrexed but very interesting, if you look at the maintenance period we have more neutropenia for the pemetrexed compared to the oral vinorelbine.

In this trial we have the evaluation of the blood count every week, so probably this is the reason why we found an important more neutropenia in the maintenance treatment for pemetrexed compared to oral vinorelbine.

A better clinical outcome with pemetrexed/cisplatin

It’s also interesting to consider the role of TS for the patient selection.  TS is an enzyme, thymidylate synthase that plays an important role in the mechanism of action of pemetrexed.

As you know, if we have a high expression of TS we have resistance to pemetrexed and in squamous cell carcinoma we have high expression of TS.

On the other side, if we have low expression of TS we have sensitivity to pemetrexed and so in non-squamous we have a low expression of TS.

We have a lot of retrospective analyses about the role of TS as a predictive factor for pemetrexed but now we have also a recent prospective trial.  In this trial, patients were stratified to high expression of TS and low expression of TS and in the two groups patients were randomised to cisplatin/pemetrexed or cisplatin/gemcitabine.

As you can see, patients with low expression of TS have better progression-free survival with cisplatin/pemetrexed compared to patients treated with the same regimen with high expression of TS.

So probably we can consider the expression of TS for the patient selection.  The expression of TS is not very difficult because we can evaluate this expression using the immunohistochemistry or also the real-time PCR.

How to integrate Oral Vinorelbine in this context?

If we consider the oral vinorelbine in the context of the advanced NSCLC, the results of the NAVo Trial are very important because they demonstrate that we have similar results using oral vinorelbine combined to cisplatin compared to cisplatin/pemetrexed.

Vinorelbine is not depending on the TS expression and oral vinorelbine plus platinum salt could be considered an interesting alternative to treat patients with advanced NSCLC.

Another important issue in this economic context is the cost of these agents because as you know, oral vinorelbine is cheap compared to the pemetrexed.

Squamous NSCLC: NAVo Trial 3 – trial design

Now probably in the near future we will have the results of the NAVo Trial 3.  This is a Phase II randomised trial in squamous carcinoma.  In this trial patients were randomised to cisplatin plus oral vinorelbine for four cycles followed by maintenance with oral vinorelbine in patients with at least disease stabilisation versus cisplatin/gemcitabine for four cycles followed by maintenance with gemcitabine.

Vinorelbine + carboplatin appears an appropriate choice for advanced NSCLC

The background of this study is a trial with intravenous vinorelbine combined to carboplatin and compared to gemcitabine and carboplatin.

In this trial there is a trend in favour of the combination of intravenous vinorelbine plus carboplatin in terms of median survival.

Toxicity profile for Vinorelbine +CBDCA vs gemcitabine + CBDCA

If we look at the toxicity we have less toxicity with the vinorelbine/carboplatin compared to gemcitabine/carboplatin in terms of haematological toxicity, in particular in grades three and four anaemia and thrombocytopenia.

Agenda: Optimising disease control with metronomic chemotherapy  

What about the metronomic approach?  Professor Milano has explained the mechanism of action of metronomics which is really an intriguing mechanism of action.

Efficacy of metronomic chemotherapy in lung cancer

We have few data about the metronomic chemotherapy in lung cancer.  We have all the studies with some interesting results in terms of response.

Move trial: metronomic Oral VNR in elderly NSCLC

Recently Dr Camerini and colleagues published this very interesting trial of metronomic oral vinorelbine in elderly patients.  This is a really very old population because the median age of this population is 80 years and interesting, it is also an unfit population because most of the patients have PS 2.

They use a flat dose of vinorelbine 50mg three days per week continuously.  Each cycle is three weeks of treatment with a maximum of six cycles and they had a very interesting result in terms of response but also disease control and overall survival; nine months of overall survival and five months of time to progression with a very good tolerability of this regimen with few patients with neutropenia.

Metronomic Oral Vinorelbine monotherapy in pre-treated patients with advanced NSCLC

In another trial with metronomic oral vinorelbine monotherapy in pre-treated patients, so second line of second line using again the flat dose of oral vinorelbine, we have interesting results in terms of median overall survival, 9.4 months.

Tolerability of metronomic Oral Vinorelbine monotherapy in pre-treated patients with advanced NSCLC

In this study we have good tolerability.

Feasibility of metronomic Oral Vinorelbine plus cisplatin in advanced NSCLC

And we have also data about the combination of oral vinorelbine, metronomic oral vinorelbine plus cisplatin.

In particularly, in this Phase I trial we have escalating doses from 40mg to 70mg of oral vinorelbine and for cisplatin we have doses from 70mg to 85mg/m2.

The MTD of this study is 60mg, a flat dose for the oral vinorelbine and 85mg for cisplatin.

CDDP+metronomic Oral Vinorelbine as front-line: a phase II HORG trial

In the HORG trial, which is another Greek trial, it is a Phase II trial with cisplatin at the dose of 80mg/m2 and oral vinorelbine metronomic at the flat dose of 60mg.

Again we have interesting results.  In terms of median survival we have 12 months.  We have about 30% of patients with Grade 3 and 4 neutropenia but in my opinion in the real life, if you consider the use of oral vinorelbine as in the metronomic schedule you can use the flat dose of 50mg, not 60mg like in this trial, especially if you combine with cisplatin.

Ongoing evaluation of metronomic Oral Vinorelbine as maintenance chemotherapy (ONC-MANILA study)

Now we have another trial ongoing with this strategy of metronomic oral vinorelbine in particular.  This is an Italian trial, the MANILA study.  A very interesting design because patients after induction chemotherapy with at least disease stabilisation were randomised to metronomic oral vinorelbine as a maintenance treatment at a flat dose of 50mg three times per week compared to close observation until progression.

The primary endpoint of the trial is progression-free survival.

Take home messages

In conclusion, now for the disease control we can consider two different strategies; the metronomic chemotherapy approach or the maintenance approach.

The combination of oral vinorelbine and platinum demonstrates similar results to other regimens containing platinum but the convenient route of administration of oral vinorelbine makes this agent a good candidate not only for maintenance strategies but also for the metronomic treatment.

Thank you for your attention!

Thank you very much for your attention.