Toxicity Management and Patient Quality of Life

Whitney Lewis

Hi Liz. I’m glad to be back talking with you about NSCLC treatments. We have so many options to choose from for treating metastatic EGFR mutations in the front-line setting, which is a great “problem” to have. But it can be difficult to know where to start. One regimen we’ve been leaning toward for younger patients with brain metastases is from the FLAURA2 trial, when researchers looked at adding chemotherapy to osimertinib.¹

We’ve been using these drugs for a long time and are familiar with their toxicities. For years we’ve been telling patients they don’t have to have chemotherapy if we find a targeted mutation. How are you broaching the topic of combination targeted therapy and chemotherapy with them? 

Elizabeth Waxman

Absolutely, this can be a bit of a challenge. I always try to explain that single-agent TKI therapy is an option, but that for some specific populations, like patients with brain metastases, adding chemotherapy up front can delay progression in the brain and in the rest of the body. We can always adjust the doses and frequency of chemotherapy per patient tolerance as well, so although it’s more aggressive it is somewhat customizable. I explain that we typically give 4-6 cycles of chemotherapy with a platinum, usually with pemetrexed, after which the patient can be maintained on just pemetrexed alone, which is a quick 10-minute infusion every 3 weeks. So the patient would need to allot for a dedicated half-day for labs, follow-up appointments, occasional scans, and the treatment itself. I let the patient know that the major side effects of this chemotherapy include infectious complications, fatigue, some skin rash, nausea during the cycles with carboplatin, and the potential for neuropathy.

Whitney Lewis

Those side effects can be tough on a patient’s quality of life, especially the younger patients who may be trying to balance career and family along with their cancer treatment.

Elizabeth Waxman

Right, we want patients to lead as normal of a life as they feel able to, so I tell them to make sure they’re hydrating and enjoying meals, and to try to stay active to help fight off fatigue. Once osimertinib is added, I highlight the classical EGFR inhibitor side effects like acneiform rash and counsel on the importance of skin care and hydrating their skin. We talk about dry skin, dry eyes, diarrhea, and paronychia. Along with the more common side effects related to the administration of the drug and drug-drug interactions, I also discuss the rare chance of cardiomyopathy and interstitial lung disease.

Whitney Lewis

It’s so much for patients to absorb! I focus on the same things, usually starting with chemotherapy side effects and management, and then I summarize that before moving on to the targeted therapy. I include an overview of the prior authorization process, which many patients are unfamiliar with, and how a patient may acquire the drug since it’s not something that can just be picked up from their local pharmacy. I talk about the side effects and their management and then recap everything. I’ve found informational pamphlets to be really helpful during these discussions as well so patients can take notes and have the reassurance of something tangible that says a lot of what we are telling them. In my opinion, the more ears the merrier.

Studies show patients forget up to 80% of what we tell them almost immediately which is why I try hard to summarize the information at the end to reinforce key messages.² Patients should be encouraged to reach out to the clinic, to know that it can take a village. We’re here to help and support them, and while technology has come a really long way we certainly aren’t able to read their minds yet!

Elizabeth Waxman

You’re right. I know you do a lot of the patient counseling on amivantamab in our clinic. That’s an EGFR inhibitor, but since it’s an IV and has the additional mechanism of MET inhibition it’s a little more complex to explain than osimertinib. How do you approach those conversations with patients?

Whitney Lewis

I usually start with a brief overview of the mechanism of action, how amivantamab targets both MET and EGFR and has some immune mechanisms like trogocytosis and antibody-dependent cell-mediated cytotoxicity. It triggers the immune system to destroy the cancer cells. Then I’ll talk to the patient about the schedule and explain that eventually the drug can be given every 2 weeks (or every 3 weeks if patients are on chemotherapy plus amivantamab) and they should expect it to take about 3 hours of chair time. However, until we get to that point they will be here 2 days in a row to get the first dose split up and then be here another 4 weeks in a row as we ramp up the infusion rate until it’s that 3-hour infusion in the second cycle. That can be a lot for patients to wrap their minds around, especially the first 2 days of chair times that last between 5 and 7 hours! It’s a lot for the younger patients who are still working, and can be a challenge for some community infusion centers to accommodate as well. It’s likely there will be a subcutaneous formulation soon, but that product is not yet FDA-approved or available.³ We’re hoping to be able to decrease the time burden on patients in the near future.

Elizabeth Waxman

Thank you, Whitney. What about the infusion reactions? That’s always difficult for patients to hear as well. It can be hard to explain that although what they’re experiencing may feel like an allergic reaction, it very likely isn’t. Is there anything we can do to help reduce the chances of an allergic reaction?

Whitney Lewis

I probably spend at least 5 minutes on this with every patient! I think it’s so important to emphasize to patients that they should expect to have a reaction to amivantamab on day 1 because it is so common. There’s rarely a repeat of that or a first-time reaction on day 2. A reaction doesn’t mean they are allergic to the drug; true allergies are <1% of patients. If a reaction happens they should remain as calm as possible and let the infusion team know ASAP to stop the drug. Additional medications like hydrocortisone should be administered. Amivantamab can be resumed at a lower rate following package insert recommendations⁴ and almost always the patients are fine and don’t react again. It’s such an interesting phenomenon and we really don’t know what causes it, but it’s a great educational point for providers as well. We don’t treat this like a classic taxane reaction or hypersensitivity at all!

We also need to make sure patients are getting the first three exposures via peripheral line, that the drug isn’t primed in the tubing, and that dexamethasone is given as a pre-med day 1 and day 2 and can be discontinued after that if there’s no reaction. This is according to the package insert.⁴ Results from the phase 2 SKIPPirr study just came out, demonstrating that giving patients dexamethasone 8 mg twice daily starting 2 days before amivantamab (day -2 and day -1) greatly reduced the rate of infusion-related reactions.⁵ This is something we’re beginning to implement in our practice as well. Again, once the subcutaneous formulation comes out I think this will be less and less of an issue, but until then the current treatment can greatly contribute to a patient’s anxiety and the infusion center burden, so we want to do everything we can to reduce the chances for infusion reactions.

Liz, in my experience there’s also quite a bit of rash and paronychia with amivantamab. Can you comment on this and how you help your patients manage?

Elizabeth Waxman

We are a lot more aggressive about early referrals to oncodermatology for patients being treated with amivantamab. We see a lot of rash with this drug and at a higher grade than with previous EGFR TKIs. I’m also seeing more scalp rash/folliculitis for patients that topical clindamycin and oral tetracyclines are not strong enough to handle on their own. These patients often require topical steroids, sometimes at different strengths for different parts of the body like the face vs. the torso, occasionally in addition to acitretin to really control the rash. We may offer to hold therapy for a week or go with a dose reduction to help reduce the rash to a manageable level. Rashes can be particularly distressing for young female patients and can affect their self-esteem. We are also seeing a lot more paronychia and nail fissures that may require liquid bandages and/or a referral to an oncodermatologist to help manage this, as care may need to be escalated beyond Aquaphor and gloves, vinegar or bleach nail soaks, and good general nail hygiene. As data from the COCOON trial continue to evolve, we may begin to be more aggressive with prophylactic rash management vs. our current more reactive plan.⁶

Whitney, what else is unique about amivantamab and how do these side effects change with the addition of lazertinib?

Whitney Lewis

Liz, it’s important to remember that amivantamab also has MET inhibition so we see quite a bit of peripheral edema and some low levels of serum albumin. Amivantamab can also cause some peripheral neuropathy and myalgias. Lazertinib is similar to osimertinib in its mechanism of action and therefore we expect similar side effects between the two drugs. But there’s less cardiotoxicity with lazertinib compared to osimertinib, which opens up a niche for this combination therapy.

One unique side effect we should spend a moment on is the potential for venous thromboembolisms, specifically with the combination of lazertinib and amivantamab. We don’t necessarily see this with a single agent drug or with amivantamab plus chemotherapy; it's unique to amivantamab and lazertinib. Patients need to be on prophylaxis for VTEs for the first 4 months of therapy, and that prophylaxis can be a direct oral anticoagulant or low-molecular-weight heparins, although most patients prefer something oral like apixaban or rivaroxaban that they can take once or twice daily. Results from the phase 3 MARIPOSA trial showed that VTEs occurred in 37% of patients in the amivantamab-lazertinib arm compared to 9% in the osimertinib arm and the majority of patients were not on anticoagulation.⁷ After prophylaxis, we don’t see breakthrough recurrent VTEs and VTE rates went down.

Elizabeth Waxman

We give patients rash and nausea medications with osimeritnib and chemotherapy, or rash and anticoagulants with amivantamab and lazertinib. It can feel overwhelming to patients who are starting therapy. It’s important to take a step back and try to empathize with them about everything that’s changing in their lives. We need to give the patient and family a moment to breathe and process at the end of counseling, before we summarize and wrap up.

Whitney Lewis

Absolutely. I think it’s also kind to acknowledge their burden, and offer to be a resource for any questions and concerns that pop up. The good news is patients are likely to be on therapy for a long time but it still takes time to adapt to a “new normal” regardless of which therapy they may pursue up front. 

Whitney Lewis

Speaking of wrapping up, I think it’s that time for us as well, Whitney.

Whitney Lewis

I’ve really enjoyed working on this series with you, Liz. I’ve learned a lot from you.

Elizabeth Waxman

Same here! I’m so glad we could do this.