Management of Adverse Events Associated with MET TKIs in Patients with Advanced NSCLC: A Podcast Discussion

Abstract

MET exon 14 (METex14) skipping is observed in approximately 3–4% of patients with non-small-cell lung cancer (NSCLC). These patients are typically older and may or may not have a history of tobacco use. Several small molecule MET tyrosine kinase inhibitors (TKIs) have been developed, showing clinical efficacy in trials targeting the MET pathway in these patients. Among these MET TKIs, tepotinib and capmatinib are globally approved and have demonstrated robust and durable efficacy in patients with METex14 skipping NSCLC in the VISION and GEOMETRY mono-1 trials. While MET TKIs have provided an important therapeutic option for patients with METex14 skipping NSCLC, they are associated with some challenging treatment-related adverse events (TRAEs). Across studies investigating MET TKIs, peripheral edema (49–68%) was reported as the most frequently observed TRAE and is widely recognized as a class effect of MET TKIs in patients with METex14 skipping NSCLC. Nausea (23–44%) and blood creatinine increase (22–34%) were other commonly reported TRAEs observed with treatments in this class. Effective treatment with MET TKIs relies on early recognition of AEs, regular monitoring, patient and caregiver education, and tailored supportive care interventions to ensure treatment continuity and optimal outcomes. Dose reductions have proven effective in mitigating AEs while preserving efficacy, by allowing patients to continue to receive efficacious targeted therapy. In this podcast article, the authors will discuss safety considerations with MET TKI treatment for patients with METex14 skipping NSCLC. They will also share their perspectives on the current landscape of MET TKIs in METex14 skipping NSCLC, commonly reported TRAEs in clinical practice, management strategies for these TRAEs, and safety considerations when switching one MET TKI to another. In addition, authors will discuss two patient cases to illustrate effective management of TRAEs associated with MET TKIs in patients with METex14 skipping NSCLC.

Supplementary Information

The online version contains supplementary material available at https://doi.org/10.1007/s11523-026-01242-z.

Plain Language Summary

Lung cancer is one of the most common cancers in the world. In ~3–4% of people with a type of lung cancer called non-small-cell lung cancer, the tumor cells contain a specific change in a gene called MET. This change is known as MET exon 14 skipping, and it is more often found in older patients with non-small-cell lung cancer.

Two oral medicines, tepotinib and capmatinib, have been approved in the USA and many other countries to treat people whose lung cancer has this MET change. These medicines, called MET tyrosine kinase inhibitors (MET TKIs), block the faulty signals that help the cancer grow. Many patients with tumors that MET TKIs target respond well, potentially allowing patients to stay on treatment.

However, MET TKIs can cause side effects. The most common side effect is swelling of the legs, ankles, or feet (called peripheral edema), which happens in roughly five to seven out of ten patients. Other common side effects include gastrointestinal issues (e.g., nausea and diarrhea) and changes in a kidney waste product called creatinine. Most side effects can be monitored and managed, often allowing patients to stay on treatment.

In this podcast, two lung cancer specialists discuss how these side effects can be detected early, monitored, and managed by supportive care and/or treatment changes. They also discuss the roles of nurses and caregivers in supporting patients experiencing side effects with MET TKIs and whether patients can switch from one MET TKI to another. Lastly, the physicians provide two real patient examples that show how careful management can help patients stay on treatment and maintain quality of life.

An extended version of the Plain Language Summary is included as an Electronic Supplementary File with the online version of the article.

Supplementary Information

The online version contains supplementary material available at https://doi.org/10.1007/s11523-026-01242-z.

Key Points

Targeted treatment with MET TKIs such as tepotinib and capmatinib has shown benefit in patients with METex14 skipping NSCLC

Adverse events are common with these treatments, with swelling/edema being the most frequent, along with nausea and changes in creatinine levels; these adverse events are usually manageable with close monitoring and supportive care

Optimal management in these patients’ cases depends not only on choosing the appropriate targeted therapy but also on identifying side effects early, educating patients and caregivers, and adjusting the dose when needed so treatment can continue without compromising benefit.

The podcast and transcript can be viewed below the abstract of the online version of the article. Alternatively, the podcast can be downloaded here: https://doi.org/10.6084/m9.figshare.32999450.

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Transcript

Wade Iams: Hello, I’m Wade Iams. I’m the Director of Lung Cancer Research at Tennessee Oncology in Nashville, Tennessee. Welcome to this podcast that’s called “Management of Adverse Events Associated with MET TKIs in Patients with Advanced Non-Small-Cell Lung Cancer,” hosted by Targeted Oncology.

And we’re going to be discussing safety considerations specifically for MET TKIs; tepotinib and capmatinib, in particular, [are] going to be our focus for this discussion. We’ll talk about safety considerations generally and in the context of switching, and with a couple patient cases.

So, I’ll turn it over to my colleague, Dr. Florez.

Narjust Florez: I’m so delighted to be your co-host for this very important discussion about MET exon 14 [skipping NSCLC]. My name is Dr. Narjust Florez. I’m a thoracic medical oncologist at the Dana-Farber Cancer Institute and the co-director of the Young Lung Cancer Program here as well. So, let’s do this, my friend.

Wade Iams: So, when we think about MET exon 14 skipping mutations in general, the first thing I typically think about is epidemiology or the frequency of occurrence. So, this is about 3–4% of our patients with non-small-cell lung cancer [1–4]. And one of the most important things that I think about with MET exon 14 skipping is the epidemiology or patient population characteristics are a little different here than EGFR, ALK, ROS-1 [mutations] [5]. In this case, patients are often older, and there’s a little bit more of a mix of men and women, although I see men and women with EGFR, ALK, ROS-1 [5]. I think we can get led down the wrong path if we stick to those stereotypes too much.

But MET exon 14 skipping, especially, is known to occur in patients with even sometimes significant smoking history [5]. So, the epidemiology here is key. And as we all know in oncology, next-generation sequencing is really the technology that’s opened the door for all these therapeutic advances [6–8].

So, when we think about different therapeutic strategies, Dr. Florez, and targeting MET pathways in particular, can you walk us through the currently available MET TKIs and their efficacy?

Narjust Florez: So, these small molecules, MET TKIs, have been developed to be particularly clinically effective in these patients with MET exon 14 skipping mutations [9]. The first approvals of these drugs date back to the years of the pandemic. We have tepotinib, which is a highly effective MET TKI. It’s approved globally for patients with MET exon 14 skipping non-small-cell lung cancer [10–15]. In all patients with more than 3 years of follow-up in the VISION study, tepotinib demonstrated an objective response rate of 52% via median duration of response of 18 months. In patients that were treatment-naive, however, the overall response rate was 58% with a median duration of response of 31.7 months, while in previously treated patients overall response rate was 45%, and the duration of response was 12.6 months [16].

And it’s important to parse this to see that this is not new or unique to MET exon 14 skipping mutations. Patients that are treatment-naive tend to have more prolonged responses and higher overall response rate if the MET TKI is used first line. And that is something that is important to discuss because we have seen other therapies that could have efficacy in MET exon 14 [skipping], but starting with the TKI, I think, is key, not only for the duration of response but also for keeping patients very close to a near-normal lifestyle via oral regimen versus something that’s [intravenous] IV.

The other agent that has been around as well is capmatinib, another globally approved MET TKI. This was evaluated as well in MET exon 14 skipping mutation non-small-cell lung cancer, in this case in the GEOMETRY mono-1 trial [17]. The final analysis showed an overall response rate of 68% with a median duration of response of 16.6 months in treatment-naive patients and overall response rate of 44% via median duration of response only 9.7 months in those patients that were previously treated. And this is for a total follow-up of nearly 67 months. So, the same thing that we saw in tepotinib we see in capmatinib, in which always have a better and more prolonged response when used first line [17].

However, there [are] new kids in the block. And these are other three MET TKIs that have been approved only in China and Japan for the treatment of patients with the same alteration. These drugs that we actually have heard about for a little bit [are] savolitinib, [which] has demonstrated overall response rate of 62% in a Chinese patient population with a median duration of response of 12.5 months [18]. The other agent is gumarontinib, which is also approved mostly in China and in Japan from the GLORY study. This one also has a decent overall response rate of 66% with a median duration response a little bit lower than some of the other TKIs, with 8.3 months [19]. So, we have the other, and the third one of these new agents is vebreltinib, which was investigated in China in the KUNPENG trial. It has an overall response rate of 75% with disease control of 96% and a duration of response of 15.9 months [20]. Vebreltinib was also studied in a global population in the SPARTA 2 trial. While this trial has not been published separately, a combined analysis of patients with centrally confirmed MET exon 14 skipping mutations from KUNPENG—the first trial that was done in China and Japan—and SPARTA 2, showed that this agent had an overall response rate of 66% with a duration of response of 16.5 months in [patients who were] treatment-naïve [and] lowered overall response rate in patients that were not treatment-naïve [21].

Despite it being a rare mutation, it’s very exciting to see that there are other things cooking down the pipeline.

Wade Iams: Thank you, Dr. Florez. As we focus on safety in this discussion, we’re going to specifically focus on the safety of US [Food and Drug Administration] FDA-approved drugs, namely tepotinib and capmatinib.

Narjust Florez: It’s time to talk about safety events associated with MET TKIs. The advent of selective MET TKIs has provided an important therapeutic option for patients with MET exon 14 skipping non-small-cell lung cancer. However, as with any targeted agent or any cancer therapy in general, there are underlying safety concerns, and there are ways in which we can optimize the management of these safety concerns to have the better clinical outcomes, the longer duration of therapy, and most importantly, preserve our patient’s quality of life, because it’s about surviving and living lung cancer at the same time [9]. Across key clinical trials, MET TKIs have demonstrated a distinct pattern of adverse events compared to other TKIs. These safety profiles vary in between agents as well, but they have a class effect associated with MET inhibition [9, 16, 17].

Dr. Iams, why won’t you walk us through some of the overall safety profile observed with tepotinib in the VISION trial and with capmatinib in the GEOMETRY mono-1 study?

Wade Iams: Absolutely. In VISION, the median duration of tepotinib treatment ended up being 7.5 months. And as of the last data cut off from VISION, there was still ongoing treatment in 18 patients. A majority, about 92% of patients, reported treatment-related adverse events, but Grade 3 or greater treatment-related adverse events were about 36% of patients. These treatment-related adverse events led to dose reduction, treatment interruption, and permanent treatment discontinuation in 33%, that was the dose-reduction cohort, 44% treatment-interruption [cohort], and 16% permanent-treatment-discontinuation cohort [16]. In these patients who had dose reductions or interruptions, the median duration of tepotinib use was still about 10.7 months [22]. So, despite the dose reduction or interruption, they were still on the drug for over 10 months on average. Peripheral edema was the most common treatment-related adverse event. It occurred in 68% of patients. Grade 3 or greater peripheral edema, you know, clinically the even more difficult cohort to manage—that was 12% of patients [16]. Hypoalbuminemia, nausea, diarrhea, and creatinine increases were also seen in patients [in] the VISION study with tepotinib. They all occurred at rates of generally 22–25% across the board for hypoalbuminemia, nausea, diarrhea, and creatinine elevation [23]—so nearly a quarter of patients each.

In the final analysis of the GEOMETRY mono-1 study that was looking at capmatinib, the median duration of drug exposure was about 35 weeks. Grade 1–2 and 3–4 treatment-related adverse events were 38% for Grade 1–2 and 54% of patients for Grade 3–4, respectively [17]. A similar pattern of toxicity to what was seen with tepotinib—peripheral edema, nausea, creatinine elevation, vomiting, dyspnea—[were the] most commonly reported treatment-related adverse events [16, 17]. Across the MET TKI studies, peripheral edema was the most frequently observed treatment-related AE. That’s known to be a class effect with all MET TKIs [9].

Narjust Florez: Could you briefly explain the proposed pathophysiology behind MET TKI-induced peripheral edema? I think this is helpful context for the discussion that follows and also what we deal with in practice every day.

Wade Iams: Yeah, when we encounter any MET-directed treatment, the TKIs and also the [antibody-drug conjugates] ADCs, these all have risk for peripheral edema [24–27]. So, one proposal is that vascular endothelial cells are being hit by that MET inhibition. It’s blocking MET signaling in those vascular endothelial cells, and then, that results in increased vascular permeability and capillary leak [24]. So, kind of a capillary leak syndrome in the peripheral tissues is the way that I think of it. That may impair, obviously, vascular homeostasis but also lymphatic drainage. And then you have peripheral edema [24].

So unlike edema induced by cardiac or renal dysfunction, MET TKI-related edema typically develops gradually, due to slow increases in vascular permeability, [and] decreased lymphatic return of that interstitial fluid. So, it’s very systemic. It is reversible, but, importantly, use of diuretics is often [of] limited benefit. So, we’ve got to use supportive measures, almost managing [it] like lymphedema [9, 24, 28–30].

So, Dr. Florez, in the absence of head-to-head data between these MET TKIs, tepotinib and capmatinib, can you explain how indirect comparisons help us understand the relative safety profiles?

Narjust Florez: So, after we look at matching adjusted indirect comparisons of safety outcomes between the primary MET TKIs that were discussed in tepotinib and capmatinib, there [are] some insights about these adverse events profile that hope to help with the therapeutic decision-making, particularly when we don’t have these head-to-head data, and then, you have two agents that are approved in the same setting [31]. I think in this indirect comparison method, particularly, it’s important when we are looking at treatments evaluated separate[ly] in clinical trials when there is no standard comparator arm. So, for safety outcomes, taking [into] account all the bias and all the limitations of these types of comparisons, tepotinib in comparison with capmatinib in patients with MET exon 14 [skipping non-small-cell lung cancer] demonstrated lower rates of treatment-related adverse events, leading to less treatment discontinuation with tepotinib compared to capmatinib. We’re talking about 15% for tepotinib versus 21% for capmatinib in the first line. And for second line, it was 14% for tepotinib and 20% for capmatinib [31].

However, I think it’s very important to mention that one TKI became available before the other one. So, we may have been a little bit more comfortable managing these adverse events. So, the summary of this indirect comparison is that tepotinib potentially has a better side effect profile with lower discontinuation rates.

Wade Iams: Another important consideration with treatment-related adverse events of these TKIs is potential impact by patient ethnicity. So, when we look at MET TKI toxicity, for instance, we see that, in Asian patients, particularly the Japanese patients enrolled in these trials, treatment-related adverse events did have variation when compared with the global-trial patient population [17, 32–36]—creatinine elevations, in particular, which we suspect [are] due to inhibition of renal tubular transporters; that’s more frequently reported in Asian patients, particularly the Japanese patient populations [17, 32, 34–36]. Also, even more interesting, among serious adverse events, interstitial lung disease [ILD] was notably observed in Asian patients, including Japanese patients [34, 35, 37, 38]. There is a broader observation that there’s a higher reported frequency of ILD exacerbations during lung cancer treatment in general in Japanese patients [39]. But overall, it should be noted that, in clinical practice in Japan, tepotinib is overall generally well tolerated, but we see those little pockets of increased frequency toxicity, reported creatinine elevations and ILD [33]. Patients in this space, of course, who are treated with tepotinib or capmatinib have often received multiple lines of therapy, including immunotherapy [22, 30]. And so, we have to be on the lookout for late immune-related toxicities as well. But overall, tepotinib has demonstrated a consistent adverse event profile in patients previously treated with immunotherapy [40].

Narjust Florez: I think we can summarize the safety profile of MET TKIs: they’re considered manageable if they are addressed early. The edema, if you left [it] creeping up, it can be harder to treat. Treatment-related adverse events leading to death have been reported only between 1 [and] 4% [16, 17], with most adverse events managed through dose adjustment and supportive care. However, some adverse events will persist, requiring patient education day 1, as well as alternative measures to help them cope with these adverse events in daily life. There is no easy solution. And the management of adverse events for these TKIs require[s] involvement by the two parties: the treatment party—the physician, the nurse, the nurse practitioner—and by the patient—the patient, the family member, the neighbor—because these adverse events will persist. And with durations of response of 36 months, these adverse events are going to be around [16, 17].

Narjust Florez: Effective management of treatment-related adverse events is crucial to ensure treatment continuity and preserve the patient’s quality of life.

Wade Iams: Yes, we’re going to get into the weeds here with some more peripheral edema details that we’ve learned. This will be just quoting the clinical trial data. So, it’s usually mild-to-moderate in 50–63% of patients, but as we said earlier, the most common toxicity overall [9]. So, peripheral edema is the most important to be aware of. We start treating that at the time of initiation of prescription, lymphedema management, as proactively as possible. But when we hear those high overall rates, we need to hone in on Grade 3 or greater rates, which are anywhere from 5 to 10% in trials. But we all know it can be very uncomfortable and disruptive to have bad peripheral edema. It certainly does, in my experience, start without symptoms and does become more serious over time [9]. Patients have impaired mobility; obviously, weight gain as they pick up the interstitial fluid; and quality-of-life decreases [29]. The time of onset, an interesting feature that we’ve learned from clinical trials with tepotinib—it’s been reported as early as 8 weeks following initiation [30]. With capmatinib, it’s reported about 3.5–5 months after initiation [in] clinical trials [9].

But we can say weeks to a few months in general when we’re thinking about edema from these MET TKIs. And again, proactive management initially, we think, is the key to help avoid this.

But the variability and difference in potential progression with symptom burden—that makes monitoring key because we need to try to differentiate what’s related to the drug versus what’s related to the cancer, which I usually distill with patients. That’s a lot of, you know, all of our toxicity visits: is it drug-related, is it cancer-related, or could it be something else? Many of these patients have other diseases as well. Management of the edema involves supportive care for lymphedema, lower extremity elevation, compression stockings, [and] physical activity [9]. Those are key components to try to limit peripheral edema, and those can be effective for many patients. But when we think about Grade 3 or greater peripheral edema, in my experience, as well, it’s going to take something more than those conservative measures. You’re likely going to have to interrupt the dose and then reduce the dose to manage the peripheral edema and make sure that the patient’s quality of life isn’t severely impaired [24]. So, we know that therapeutic exercises we’ve talked about in combination with compression [are] valuable. But we have to acknowledge there [are] not any randomized trials specifically investigating exercise in this context [9, 24, 27].

But we’re going to shift gears a little now, Dr. Florez, over to [gastrointestinal] GI side effects. How do you approach those GI side effects?

Narjust Florez: Well, I think the gastrointestinal side effects are some of the ones that we see first [17, 36]. I think particularly nausea can be one of the things that we first see, followed by vomiting if the nausea is not addressed properly, and the diarrhea. They’re often manageable [9, 30], but the patient needs to have good control of the nausea. And it depends on what nausea is presented. I think it’s very important to characterize when the patient feels nauseous because that will help us address the problem. I think if the patient is nauseous right after taking the medication, then we do pre-medication 30 min before with antiemetics. So, if you’re taking your MET TKI at 8 in the morning, you can have an alarm at 7:30, and then, you take your antiemetic, and then you would take the TKI. It’s important to understand that a lot of these antiemetics also have side effects, but in this case, if the patient is having nausea and diarrhea, it’s “two for one” because medications like ondansetron produce constipation as a side effect. Take your ondansetron for the nausea, and that will help with the diarrhea at the same time, compared to using other antiemetics that may make them tired. So, you’re trying to combat the edema, but you’re giving an antiemetic that makes them tired so they’re not walking because they’re tired. So, I tend to use ondansetron if they have diarrhea.

However, many disturbances to the GI tract do not require dose reduction or interaction. It just requires [having a] very good handle of this, as there are many options. So, for nausea, we have to determine when the patient is nauseous. Vomiting tends to happen when the nausea is not controlled. In timing of the medication, if the patient is very, very nauseous, I ask them to take it at bedtime, right? Tepotinib is dosed in a way that it can be taken at bedtime if you need it [10]. The thing is consistency—that the patient doesn’t forget any doses. And for diarrhea, I think it’s particularly among older patients this is a very common side effect [41]—so having instructions [and] taking antidiarrhea medication after liquid bowel movements. And it’s very important to define what diarrhea is to patients and the caregivers. So, it has to be volume, consistency, and frequency for the diarrhea before we, like, get crazy, because otherwise you make them constipated if they’re just taking a lot of loperamide.

So now, can you discuss other clinically relevant adverse events that we should keep in mind, like pleural effusions, hepatotoxicity, or hypoalbuminemia, which can be scary at times?

Wade Iams: Absolutely. Yeah, so a little, certainly, less common than the peripheral edema and the GI side effects, but still important toxicities with MET TKIs. And if the patient with lung cancer has a pleural effusion, we’re always wondering “Is it worsening disease or is it treatment-related?” So, and particularly regardless for pleural effusions, if it’s symptomatic or if the diagnosis is going to change management, then I’ll recommend thoracentesis and identify if it’s non-small-cell lung cancer or [whether it’s] treatment-related [9, 30]. It tends to be more symmetric and bilateral if it’s due to systemic therapy versus disease, but not always. So, sampling can be helpful.

Hepatotoxicity, defined as elevated liver enzymes, certainly warrants close monitoring. We can follow the labels in our recommendations for our MET TKIs. And, very rarely, studies show that we may have to discontinue the drug for Grade 3 or greater hepatotoxicity, but that’s rare with MET TKIs [9, 30]. I’ve never seen it.

Hypoalbuminemia can be observed in patients with MET TKIs [36]. To me, that does go hand in hand with their increased peripheral edema, their vascular leak syndromes. Of course, that lab finding is asymptomatic. And then, the time of onset for hypoalbuminemia is 9.4 weeks with tepotinib [30]. And certainly, as I’ve said previously, I think it’s linked to their edema [9]. The hypoalbuminemia certainly lowers plasma oncotic pressure. And that can then further exacerbate hypoalbuminemia with the protein leak from the vascular system. So, we also must be aware of underlying kidney and liver dysfunction that may lead to hypoalbuminemia. So, that can exacerbate it and prolong recovery for our patients who experience hypoalbuminemia [9, 30].

Certainly, we should monitor that. That’s typically on our comprehensive metabolic panels that we’re getting through surveillance and toxicity checks for our patients, but especially in patients with worsening edema or just generally clinically worsening. So, we know that the potential mechanisms of hypoalbuminemia relate to the MET TKI drugs. Dietary protein supplement alone is probably just going to be limited benefit and, when we think about albumin, short half-life, also limited benefit similar for diuretic therapy with the edema and the likelihood of benefit. So, supportive care as if it’s lymphedema starting from Day 1 is the most effective way to manage this peripheral edema we run into with MET TKIs [9]. And not surprisingly, that’s accompanied by hypoalbuminemia, but it’s more about the patient’s symptoms, their clinical status, than chasing lab value[s].

And shifting over to the creatinine elevations, another key insight about knowing you’re going to tolerate that, and you don’t want to worsen edema—certainly, that’s the main takeaway is we don’t want to worsen edema for these patients on MET TKIs in any way, shape, or fashion—but how do you interpret blood creatinine in these patients on MET TKIs?

Narjust Florez: Let’s break it down, right? So, we have to understand that the elevation in creatine in these patients is partially induced by the drug. So, yes, it can cause renal impairment. However, 20–25% of that rise in creatine is by the inhibition of the creatinine transporters, and that’s very important because you may not see these often [9]. You have a few MET exon 14 patients. So, 20–25% indicates that the creatine increase in these cases may not be a true reflection of kidney dysfunction [9].

It is so important to know it’s not a common thing. And close and more frequent monitoring in the early months of treatment is key because we’re going to see this increase of creatinine, particularly in the first few months that the patient has started the MET exon 14 skipping mutation agent. And you have to have a correlation with the clinical aspect [17, 36]. If it’s 20–25%, I follow it, and I see how the patient does. Eventually, if the patient gets to a point of significant creatinine dysfunction, I do [a] little bit of investigation because these are older patients. There are other reasons why older patients may have an increase in creatinine, and just dating back to edema, they may have actually decreased the oral intake to deal with edema, and I see that all the time. So, 20–25% is induced by the reduction in the creatinine transporters. It’s very important to eliminate or investigate all the causes before we blame it on the drug. But if the case is directly [related] to the drug, then dose reduction or dose interruptions can help. But a lot of education [is needed] and [there are] a lot of interactions [9, 42, 43]. A lot of these patients may be on an ACE inhibitor. A lot of these patients may be on other medications with comorbidities that can be causing the creatinine increase. So, a little bit of investigation is worth it [43].

So, now let’s talk a little about another side effect that’s a little scary, which is ILD or pneumonitis. This is very infrequent, but it could be a potential serious treatment-related adverse event. Temporary discontinuation and initiation of corticosteroids is the standard of care in these cases with permanently discontinuation in patients that have confirmed cases, but these have to be confirmed [9, 30]. There are other reasons that can give you pneumonitis. [In] Some of these patients, if they reach the MET TKI after immunotherapy, you want to make sure you don’t blame it on the MET TKI, because you can have delayed pneumonitis if you have immunotherapy. So, I will be vigilant for pneumonitis. When in doubt, hold the drug, [and] proceed with steroids, and imaging is very important.

Some MET TKIs, like capmatinib, may cause photosensitivity. In the GEOMETRY mono-1 trial, patients were advised to use sunscreen or protective clothing during capmatinib [use] [44]. I think this is actually more a family drug class adverse event, I think other TKIs also produce photosensitivity. And if you ask me, everybody should be using sunscreen [45].

In other patients, very rare[ly], at least frequently, they may have some severe allergic reactions. While very rare, there are embryo fetal toxicities, so contraception is very key. And there’s also hepatotoxicity that can be seen with the MET TKIs [9]. A multidisciplinary evaluation is very important; [it’s] important that every team member is involved in the discussion. And when I say team member, the patient and their family are part of the team.

Wade, what have been some of your experiences with these adverse events that we talk about, and what do you do to proactively treat them?

Wade Iams: Yeah, I think the key takeaway is focusing on treating the edema early. So just being proactive from Day 1 I found to be really the most important strategy. And in sum, we know that MET TKIs are associated with a range of toxicities. We’ve talked about the edema, the GI side effects, the less common ILD, [and] hepatotoxicity that can occur, but we’ve got to have on the radar [though] not as common. And early recognition, consistent monitoring, patient and caregiver education, individualized strategies, as you’ve elucidated already—those are the keys to maintain patients on the treatment for as long as possible with as good of quality of life as possible. And we know that we’re trying to minimize dose interruption and discontinuation. We can keep those rates low, but we know that, [in] the clinical trials, patients still ended up getting a lot of treatment, even if they had to dose reduce. So, counseling our patients to not worry too much about that if we do have to reduce the dose, I think, is a huge part of our job with all targeted therapies, and a frequent point of discussion. But just to clarify those dose reductions with MET TKIs, for tepotinib it’s 450 mg [active moiety] once daily [and] capmatinib 400 mg twice daily. Those are our starting doses, maximum doses. And then, if we do need to dose reduce, tepotinib can go down to 225 mg once a day. Capmatinib can go down to either 300 mg twice a day or 200 mg twice a day [10, 44].

Narjust Florez: I think one [example] of what not to do, I think, is to discontinue drug without further investigation for the creatinine, for the hepatotoxicity, because then we are removing the patient from effective therapy without a foolproof that, in fact, it is the TKI. For pneumonitis, stop because the consequences are very large. But for the other ones, I think a little bit of investigation [is needed].

Narjust Florez: Dr. Iams, optimal AE management is a team effort. Could you describe the role of oncology nurses, physician assistants, nurse practitioners, caregivers, and anybody involved in the care of patients with lung cancer?

Wade Iams: Yeah, exactly. I think maybe the easiest way is just starting with, you know, a patient experiencing a toxicity. And who are the supports, folks along the way who are going to help us identify that and help remedy the problem? So, caregivers are key [42]. I think the reality with patients is obviously every individual is different. And then, there are certain patterns we see with patients sometimes wanting to underreport side effects for fear of being taken off their cancer drug. So, caregivers, I think, the first line of defense to make sure that we’re getting everything reported to our teams. Of course, when we think about calling into the clinic, our nurses are critical. [The] first-response system, they’re taking these calls, helping triage these calls. And then, sometimes they’ll be triaged to our nurse practitioners and physician assistants in the practice—you know, [the] next line of defense—and trying to react and monitor patients on these medications and responses to their toxicity and, then, ultimately sometimes triage[d] to the physician, and then, they’re involved in making decisions about what to do with the study drug. So, it’s really various lines of support for patients as they may or may not experience these toxicities. We also have, you know, standard check-in time points where our specialty pharmacists reach out to call patients to see what toxicities they may be experiencing on their targeted therapies. But are there any other kind of systems features that you work with to help integrate all the support mechanisms that we have for patients?

Narjust Florez: I think if your nurse is concerned, you should listen to them because our nurses have more experience taking this call. Many of them have been a nurse for longer than we have been an oncologist. And that’s my number one rule. If my nurse—her name’s Michelle—tells me she’s worried, I’m worried too because she has seen everything and anything.

And also, it is very important that we also involve other specialties if the patient has an organ damage. Before doing anything, I think we have to work very closely with cardiologists and nephrologists for patients that have chronic kidney disease or may have any of their cardiac history because these patients, the majority, are older.

Wade Iams: And when we think about patients experiencing problematic adverse events, is switching MET TKIs a viable strategy?

Narjust Florez: I think it could be a viable strategy depending on the adverse event. Evidence suggests that, in patients with MET exon 14 skipping non-small-cell lung cancer who previously experienced adverse events with one MET TKI, switching to another MET TKI may be a viable strategy for continuing successful treatment [46–49]. However, the data [are] mostly limited to case reports; long-term follow-up of these patients is lacking. And also what is the role, or when do you really switch? We don’t have the specifics, but it is an option. Like, we talk about early—the longest benefit is when used in first line. So, switching may be a better option, and patients will always prefer to be on oral therapy [more] than on chemo-immunotherapy, which gets them closer or tied up to their geographic location. And a lot of these patients want to have a life and travel. I encourage my patients to travel, so oral treatments allow that.

There is a case report describing a patient receiving a standard dose of tepotinib following advanced capmatinib-induced pneumonitis without recurrence of pneumonitis, but it’s one case report [46]. And with pneumonitis, I like to be very careful. Similarly, there are some cases of tepotinib treatment after capmatinib-induced ILD was reported in one patient [47]. These outcomes—I would take them with a grain of salt because they’re limited to case reports, but it’s a possibility. In a few cases, I have switched patients. So, I did switch a patient from capmatinib to tepotinib, in part because his diabetes was very challenging. He was gaining a lot of weight, a lot of edema. It was becoming very challenging. So, I was able to switch the patient from capmatinib to tepotinib, and the patient was able to ride the tepotinib for 8 more months. So that’s 8 more months not getting infusions, which is very invaluable. However, I did have some issues trying to get it approved—the reality of oncology with these very expensive TKIs—but eventually with good discussion and peer-to-peer, I was able to get it approved.

Another thing that has allowed me to do more than switching is holding, [which] allows the patients to improve a little bit; especially if you have control of disease, just to take a treatment holiday has been successful. Have you ever been able to swap a patient from one TKI to another?

Wade Iams: Yeah, I have switched. I’ve had resolution of toxicity with some other TKI classes. I have tried switching between capmatinib and tepotinib; one particular case with severe edema comes to mind where they had tripling [of] the size of their lower extremities on capmatinib—maybe pushed too hard there. [We] switched over to tepotinib. And then within a few months, they ran into similar issues with tepotinib as well. So, I think it’s worth a try to switch TKIs. And I think of that broadly for all of our targeted therapies. In the case of MET TKIs, it may or may not be successful. Just from the anecdote, I wouldn’t generalize. I would still try switching, see if you can have resolution of the toxicity, and keep our patients on these drugs for longer.

So, we’re now going to discuss two anonymized cases, just illustrating in specific terms management of the treatment-related adverse events that we’ve been discussing so far. So, I’ll jump right in with the first case.

Let’s talk about a 65-year-old woman who worked in a plastics factory, actually right at retirement at 65 [years]. She has Stage 4 MET exon 14 skipping non-small-cell lung cancer, adenocarcinoma histology. She started on tepotinib [in the] upfront setting. We know the upfront data with response; durability of response is best upfront for both tepotinib and capmatinib. But let’s say 3 weeks after initiating, she develops trace to 1+ bilateral lower extremity edema. She’s having a harder time putting on her shoes. Labs showed no kidney or liver dysfunction, and her albumin is already mildly reduced. And so, we advise her to use compression stockings and elevate her legs. As you and I have said from the beginning, I think we should be proactive and advise that right from the start. And maximal—while being safe, I always add—but maximal physical activity is also the best thing we know.

But for the sake of this case, let’s say we’re a little bit reactive. We waited that few weeks. She’s already developing some edema. But she comes in 1 week later, [and] says her lower extremity edema is worsening. She’s re-evaluated. Let’s say she does say that she is using compression stockings for most of the day. And she’s still trying to walk as much as possible, although it’s still difficult to put on her shoes. She’s now having mild pain. You can have stress on the nerves in the lower extremities. Edema is variably painful but can be painful for some patients. And you can develop that neuropathy as well from just loss of the interstitial functioning as normal. And then that can result in loss of balance. So, she’s starting to lose her balance. Edema is now classified as 1+ to 2+. It is bilateral and symmetric. Nonetheless, we have a patient with advanced cancer. We should always rule out thrombosis. So, lower extremity ultrasound shows no [deep vein thrombosis] DVT. And let’s say, at that point, it’s clearly worsening. She’s compliant with her conservative measures, exercise, compression, [and] elevation. So, we hold the drug for 2 weeks and the lower extremity edema improves—not right away, certainly not within a day or 2, but within a couple of weeks, it improves. Her balance comes back to normal. Her foot and leg pain is better. Her shoes are fitting like normal again. And let’s say we reduce her dose down to 250 mg daily, and she’s advised to continuing doing that compression stockings and leg elevation and exercise. That’s key. And then fortunately, after 8 weeks, we’re starting to see an excellent response on treatment.

So, with close monitoring and guidance like this, this is a good example where, if we have a patient who’s having worsening edema and we saw it was impairing balance, risk for falls, obviously uncomfortable for the patient, [and] causing pain despite those conservative measures, you may need to just interrupt the dose and reduce the dose, and patients can still be on the drug for a long period of time with good clinical benefit and quality of life.

Narjust Florez: I think this is a very good example of how many things can be done to allow these patients to remain in effective therapy, in my opinion.

Alright, so let’s talk about our next case, which is a 69-year-old man, a former nurse, with Stage 4 MET exon 14 skipping mutation non-small-cell lung cancer, adenocarcinoma. Four weeks after initiating tepotinib, the patient develops persistent nausea, reduced appetite, and weight loss of 3 kg. He describes feeling full after a few bites and notes a metallic taste that makes food unappealing. No vomiting is reported. Lab tests show no hepatic or renal abnormalities, [and] no evidence of disease progression. And he also notes mild diarrhea, 3 to 4 stools per day, particularly in the morning, and intermediate loss of appetite.

He has been using [an] antidiarrheal, like loperamide, with some benefit. Treatment with tepotinib is briefly interrupted for 7 days, followed by a dose reduction to 250 mg daily [225 mg active moiety] [and] continued use of loperamide as needed for diarrhea. Close follow-up every 2 weeks is arranged for weight, symptom diary, and quality of life assessment. I think close follow-up is very important, and [with] these patients, having this every 2 weeks, we are sure that the patient does not continue to lose weight and also to troubleshoot with the patient. And the patient always knows he has a follow-up in 2 weeks. So, that also allows with some of the mental health issues that come with side effects. The patient meets with nutritionists for small, frequent, high-protein meals and hydration guidance. Everything is written down for the patient for nutrition, and he follows the diet that he eats. That is also key. Don’t bring the patient a diet that doesn’t work. Antiemetic therapy, ondansetron, is used as needed before meals because that’s when the nausea is more prominent for this patient. He’s encouraged to increase his physical activity and do some short post-meal walks to stimulate the appetite. And they can change the taste issues by using more cold foods, citrus food, and some flavor enhancers. The gastrointestinal effects in this patient include nausea, anorexia, [and] changes in taste. They’re common for MET TKIs and can affect adherence and nutrition. Nutrition or eating is one of the pleasures of our life. So, early intervention is key. Finding many things—antiemetics, nutritional support, and individualized dose adjustments—often allow[s] for these patients to manage these side effects while maintaining quality of life.

Wade, what do you think about this patient, and what would you do in your practice?

Wade Iams: Yeah, I think the keys, I think, that you’ve articulated very well are close follow-up and then patient diaries. I love the use of patient diaries, and I need to have my patients do it more. It helps patients to give insight and really empower them to take action around their diet and those aspects that may contribute to GI toxicity and managing loss of taste. As you’ve noted, it’s a very disruptive side effect and certainly would impair my quality of life severely if I had a loss of taste. So, I think those are really good gems that you’ve described in helping manage GI toxicity that can occur with MET TKIs. And I’m definitely going to take some to my practice as well.

Narjust Florez: Well, we’re coming to the end of this wonderful conversation. I think you and I can talk for days about how to manage these patients. But let’s just summarize for our audience. We want to thank everybody for listening. Targeted treatment with MET TKIs such as tepotinib and capmatinib has shown benefits in patients with MET exon 14 skipping mutations.

Wade Iams: Absolutely. Thank you all for listening.

And we also know that adverse events are common—peripheral edema far and away the most important—and be very proactive in managing that, followed closely by GI toxicities like nausea, and then other class effects like elevated creatinine. But overall, these toxicities with MET TKIs are certainly manageable with close monitoring and supportive care.

Narjust Florez: Like we discussed, the optimal management of these patients depends not only on choosing the appropriate targeted agent but also identifying side effects early, providing a lot of patient education early and continuously, not only once, to the patient and their caregivers, and adjusting the dose when needed, and also maximizing supportive care for these patients. It has been a wonderful discussion. Thank you so much.

Wade Iams: Yes, always a pleasure. Good to see you, Dr. Florez.

Supplementary Information

Below is the link to the electronic supplementary material.

Funding

This podcast manuscript is funded by EMD Serono Research & Development Institute, Inc., Billerica, MA, USA, an affiliate of Merck KGaA (https://ror.org/027zrs220).

Declarations

Competing interests

Wade T Iams: Consulting or advisory role: Sanofi, Elevation Oncology, AstraZeneca, NovoCure, Catalyst, Janssen, Takeda, Bristol Myers Squibb, Mirati, Chardan Consulting, Curio Science, Defined Health, G1 Therapeutics, Genentech, Jazz Pharmaceuticals, Outcomes Insights, and EMD Serono Research & Development Institute, Inc., Billerica, MA, USA, an affiliate of Merck KGaA. Narjust Florez: Research funding from Genentech, AstraZeneca, Daiichi Sankyo, Johnson and Johnson, American Society of Clinical Oncology, Lungevity Foundation, and International Association for the Study of Lung Cancer and consulting fees or honoraria from: AstraZeneca, Daiichi Sankyo, Genentech, Bristol Myers Squibb, Jazz Pharmaceuticals, Johnson and Johnson, Novocure, Pfizer, Sanofi, MSD, Takeda, Catalyst Pharmaceuticals, and Regeneron.

Ethics approval, consent to participate, consent to publish

Not applicable.

Data availability, code availability

Not applicable.

Authors’ contributions

Narjust Florez and Wade Iams: validation, writing—review and editing, and visualization.