AP: Dear colleagues, dear friends, it’s a great pleasure for me to welcome you to this ecancer forum today, discussing tepotinib as second-line treatment for patients with non-small cell lung cancer with a MET exon skipping mutation. It’s my great pleasure today to share the stage with Professor Raffaele Califano from the Christie and Manchester University Hospital in the UK. Welcome Raffaele.
RC: Welcome everybody, thanks Antonio.
AP: So the format of today is very, very interactive, Raffaele will discuss with all of us a clinical case dedicated to understanding more about the efficacy, the safety, of tepotinib in this particular driver positive non-small cell lung cancer, and then we have all the time to generate questions, impressions and, of course, key points for the future of the treatment of this kind of patient. So it’s my pleasure now to introduce Raffaele with his case, Raffaele, the stage is yours.
RC: Thank you very much. Thank you Antonio, and these are my disclosures. So this is a real case. When I met Margaret she was 78, she is Caucasian, was a former smoker and retired maths teacher. Her prior medical history only included tinnitus and osteoarthritis of the knee. There was no family history of lung cancer but she had a cousin with breast cancer and she was only taking paracetamol as needed due to the osteoarthritis of the knee. She presented with a two-month history of worsening shortness of breath and also had four episodes of haemoptysis. She went to see her GP, a chest X-ray was organised and was abnormal with an abnormality on the right lower zone.
This prompted a referral to the respiratory team in the University Hospital where she had a diagnostic workup. In particular, she had a CT scan of the chest and abdomen, this is January 2022, which showed a right lower lobe mass with small right hilar nodes and two liver metastases. The staging was T2 N1 M1c. She underwent a percutaneous liver biopsy which retrieved adenocarcinoma non-small cell lung cancer which was TTF-1 positive and the material was quite scanty. The material was sent for molecular markers.
Molecular testing was negative for EGFR, immunohistochemistry was performed for ALK and ROS1 and was negative. Immunohistochemistry for PD-L1 was positive with 45% of the cells staining for PD-L1. Unfortunately, there was insufficient material for next generation sequencing. So she came to see me in clinic to plan palliative systemic anticancer therapy. When reviewed in clinic she was visibly well with a performance status of 1. She had a good organ function despite the presence of liver metastases. I did explain that unfortunately I had an incomplete molecular profile due to the failure of the NGS for insufficient material. She wasn’t keen to have another biopsy as she didn’t want to delay treatment and therefore we agreed to start first-line chemoimmunotherapy with carboplatin, pemetrexed and pembrolizumab.
This is a slide that shows the baseline and the re-staging CT scan after four cycles of chemoimmunotherapy, showing a response with shrinkage of the lung mass and also of the disease in the liver. After four cycles we embarked on maintenance pemetrexed and pembrolizumab and she was reviewed regularly in clinic.
In terms of toxicity, she mostly experienced mild rash and dry skin on the back which we managed with emollients; she had intermittent grade 1 diarrhoea and mild nausea. She continued with treatment every three weeks but unfortunately on a re-staging CT scan in November 2022 there was disease progression with enlargement of the liver metastases and also new liver metastases and some minor changes in the thorax.
So, at that point we met again in clinic, I explained that unfortunately her disease was progressing and I had to stop the chemoimmunotherapy. I also stressed the importance of the rebiopsy due to the incomplete molecular profile. We therefore referred her again to the respiratory team who performed EBUS with a fine needle aspiration of the hilar nodes which was adequate and the material was sent for next generation sequencing. The NGS panel showed a MET exon 14 skipping mutation. Before I reviewed her in clinic I explained the results of the molecular testing and the fact that I was going to offer her a targeted therapy called tepotinib. We started tepotinib in December 2022 and I reviewed her regularly in clinic with safety bloods and, once established, she was reviewed in my clinic every month.
In terms of toxicity she had some mild oedema in her feet and ankles, also diarrhoea and mild nausea. She had a restaging CT scan after three months of treatment showing partial response. She continued treatment with monthly visits and only mild adverse events were noticed.
Unfortunately, after approximately 20-21 months on treatment she developed progressive disease in the brain with several brain metastases and also extracranially with multiple lung metastases and new liver metastases and I had to discontinue her tepotinib. At that stage, unfortunately, she had a decline in general fitness with worsening PS, now being PS3, and therefore I offered her best supportive care. Thank you.
AP: Thank you very much, Raffaele, for this very clear case that is a symbol of the general strategy that we apply in a clinical setting, particularly in European countries where inhibitors for MET exon skipping 14 are generally used in the setting. I think, discussing your case, there is the first most important question around the testing. So generally we discuss do we need NGS at the baseline but not all patients have tissue quality and quantity to perform all these kinds of analysis. But today we know that not only EGFR and ALK are the two major drivers. So in your clinic, Raffaele, and particularly considering your initial mindset as a KOL, so how important is the testing in this particular patient, not only patients with exon 14 but all patients without EGFR, ALK and ROS that are the three major pillars?
RC: Thank you very much. I think you touched on a very important point. In 2026, especially for non-squamous patients, it’s mandatory to have a complete molecular profile of the tumour. Of course there are a number of potential factors that may limit how feasible is this. As you mentioned, the material can be scanty and now we’re testing for a number of oncogenic drivers and we are performing, of course, the diagnosis so some of the tissue will be used up. We do do immunohistochemistry for some markers and then what is left over needs to be sent for an extensive NGS panel.
We know that even if you have a decent amount of tissue also the potential failure of the NGS depends on your cell content. It’s particularly important, especially in patients who are never or light smokers, to try and chase a rebiopsy and complete the molecular profile because what you don’t want is to miss an oncogenic driver and therefore you are giving them suboptimal treatment. Sometimes the treatment could be also potentially dangerous if you are missing an oncogenic driver, you're treating patients probably, let's say, with immunotherapy in the PD-L1 high setting as a single agent or chemoimmunotherapy, post them there may be a problem of sequencing and toxicity should you then discover the oncogenic driver.
So, in summary, as you said, we should endeavour to achieve a decent sample in terms of biopsy so that we can have an extensive molecular profile of the tumour and that’s the only way to give appropriate treatment.
AP: I complete agree. In addition, this is a very uncomfortable gene because it’s not one of the major genes that we discuss every time. But it’s also in the middle considered patient population so we have MET exon 14 in smoking people, in non-smoking people, and this, of course, is very difficult in the clinical setting sometimes with heavy-smoking people without KRAS that generally do not perform additional testing to identify, I don’t know NTRK, or MET exon 14 that are very, very important. Of course, this is also related to the first-line selection: chemo-I/O, I/O are two of the major options but smoking exposure could be another limitation.
But moving to the best side of the discussion, so when we have the opportunity to identify this predictive alteration we have, of course, important data for the application of MET TKIs and particularly here, as you discussed, tepotinib in patients progressing after first line. So the VISION trial was one of the most important trials in the story for us; what’s your feeling, what is your perspective, around tepotinib in patients with pre-treated stage?
RC: Thank you. If you are able to identify a MET exon 14 skipping mutation and, as you mentioned, these are different. Usually in terms of demographics these are different than, let’s say the EGFR, the ALK or ROS1 patients. These are usually elderly patients, about 70. We do see a bit more MET exon 14 skipping in the sarcomatoid subgroup which is, of course, a rare one. But you were stressing the importance to test independently on the smoking status because some of these patients are smokers.
Regarding tepotinib, if you identify a MET exon 14 skipping mutation in the pre-treated setting this is the way to go because, clearly, the outcomes in terms of response rate and progression free survival and potentially, potentially, overall survival are going to be better than your standard second-line with docetaxel, let’s say, or docetaxel- nintedanib. No doubt.
AP: Raffaele, in patients with more than 50% of PD-L1 with an exon 14 alteration what’s your preference in first line? Regardless of the limitation, the approval, in your country, but to understand the view.
RC: So, if there is a driver like these I tend to use chemoimmunotherapy if I can, unless, and this goes back to the demographics, unless these are elderly patients and you are concerned about the potential adverse events in an elderly person where you need to give platinum plus immunotherapy, or they don’t want the side effects from the chemotherapy. At that point I may need to compromise with single agent immunotherapy. I will be a bit less concerned if they’ve been smokers; if they are never-smokers, PD-L1 high, I will offer chemoimmunotherapy because we know from retrospective data that the never-smokers also PD-L1 high may do less well compared to chemoimmunotherapy. But at the end it’s always a discussion with the patients and their preferences and the pros and cons and the adverse events profile, that needs to be individualised.
AP: Of course this is a very important point to open our vision over the MET exon skipping alteration with the need to include a smoking history in our record because that is a very, very important clinical factor to discriminate patients for immunotherapy. I think that the last point for our discussion that is a crucial point is the evaluation of safety profile, as you anticipate. We know from the VISION trial that tepotinib showed a very manageable toxicity profile characterised by oedema, peripheral oedema, that is a class adverse event for all the MET inhibitors. But it is important also here to have a discussion around, and I am very, very curious of your experience here, is this drug is toxic, not toxic and how is the feeling from patients?
RC: Yes, so as you mentioned, it is the MET-driven adverse events. So mostly fluid retention, oedema, we do see also some low albumen. The low albumen, most of the time, is not a major concern. The oedema varies in terms of grading. We know from the study that the vast majority of patients experience grade 1 and 2 oedema so that’s, of course, milder and you may have some supportive medications and you may also encourage the patient to be mobile because, of course, immobility will increase the risk of oedema. In the case of grade 3+ oedema, together with the supporting medication, sometimes diuretics work, sometimes they don’t, I think you need to be prompt to reduce the dose because what you want is to make sure that the patient stays on drug for as long as you can whilst balancing the adverse events. You don’t want to stop unnecessarily because you have not managed the side effects proactively and then the patient can cope.
AP: Yes, this is an important point. Dose reduction for patients that receive a TKI is always a smart and effective measure to reduce the long-term toxicity, in particular peripheral oedema that is a very chronic adverse event for all patients that receive a MET inhibitor, not only MET TKIs, as we are discussing today.
So I think we had a great discussion, Raffaele. We know that these are very strong, well-renowned genes with many, many data in the literature, very strong manuscripts and important trials published, but globally we have no new big alert here. Of course this is not a great message for patients. But we need to test, we need to prioritise testing, particularly for those patients also with a smoking history and this is a point that you underlined in our discussion. In particular because MET exon TKI, in particular tepotinib, very, very effective, a low rate of grade 3 toxicity and we need to try to prioritise these kinds of drugs in the clinical setting, not only for patients with adenocarcinoma, sometimes also sarcomatoid or squamous. So please test, improve your testing, because this is really key.
So I personally would like to thank you, Raffaele, for your presentation, for your insight and your expertise discussing the role of tepotinib in second line for patients with non-small cell lung cancer harbouring exon 14 mutation. And, of course, I would like to thank ecancer for this opportunity that we have today. Thank you.
RC: Thank you.
