Forde Discusses AE Management With Dual Checkpoint Inhibition Plus Chemotherapy in NSCLC

Targeted Oncology Staff;

PARTICIPANT LIST: Bety C. Ciobanu, MD | Mohamad K. Khasawneh, MD | Melhem S. Jabbour, MD | Stanley Nabrinsky, MD

CIOBANU: In terms of tolerability, I think there is not much difference [between] 2 cycles of chemotherapy or 4 cycles. If the patients tolerate 2, they can tolerate 4. This is not the major issue. The major issue that I still struggle with is doublet [vs single] immunotherapy for these patients.

FORDE: That’s definitely an issue. The patients in whom I’ve used dual checkpoint inhibitors have tended to be the ones who I think will [tolerate] chemoimmunotherapy worse, but I have quite a few of them who are [being treated] a long way out at this point. It’s completely anecdotal, but I suspect patient selection makes a big difference…. Some of my colleagues sometimes will use the CheckMate 227 [NCT02477826] regimen, which is ipilimumab/nivolumab without chemotherapy, for patients with more frailty. If they have a severe immune toxicity, they’re still going to have problems, but you also have patients who have very little or no toxicity with ipilimumab/nivolumab. Approximately 20% to 30% of patients will not have major toxicity, so I have seen some of my colleagues use that regimen or…for some reason, defer the chemotherapy. There are a lot of nuances to help people use these regimens, which is a big difference from 15 years ago when we just had platinum doublets.

My personal feeling is that it doesn’t make too much difference, although I think that the 4-drug regimen would be tough to go through for 4 cycles. I haven’t used the POSEIDON [NCT03164616] regimen except for 1 patient, but I find that with nivolumab/ipilimumab plus chemotherapy after 2 cycles, most patients are ready to give the chemotherapy up, but it’s a smaller advantage.

MODERATOR SIDEBAR

Q: What is the safety profile of ipilimumab (Yervoy), nivolumab (Opdivo), and chemotherapy in the CheckMate 9LA trial (NCT03215706)?

FORDE: [In terms of] the treatment-related adverse events [AEs], you'll see skin toxicity and endocrine toxicity [Figure 1²]. GI [gastrointestinal] toxicity is going to be more common with a CTLA-4 [inhibitor], so colitis, gastritis, those sorts of things. You also tend to see more hepatic and renal issues than you would with pembrolizumab [Keytruda]-based regimens.

However, you see less chemotherapy toxicity: a bit less anemia, less neutropenia, less thrombocytopenia, a little bit less alopecia, depending on the regimen, but probably not a major difference there. Because they're given 2 cycles here vs 4 cycles, plus or minus maintenance pemetrexed, you're seeing a bit less of the other chemotherapy-related toxicities.

One concern that has been raised regarding CTLA-4/PD-1 inhibitor regimens is, will it make my patient have to stop therapy and not receive the immunotherapy over time? There are some patients who have a severe autoimmune event with a CTLA-4 inhibitor, which leads them to have to stop therapy. Now, what I sometimes will do in that situation is stop the immunotherapy, and then if and when they have progression, restart only the anti–PD-1 therapy at that point.

Patients who discontinued all components seem to do well, which is something we see with patients with immunotherapy. Sometimes if you have toxicity, you'll do well, but it’s somewhat reassuring that in those patients who discontinue it, overall survival is double that…of the fully enrolled population [Figure 2³]. There are usually not terrible outcomes if you have to discontinue due to treatment-related AEs.

KHASAWNEH: Typically, I offer the anti–CTLA-4/PD-1 combination, especially in patients with low PD-L1 and central nervous system [CNS] metastasis because that confers a worse prognosis. So you need to get your best regimen up front because those patients might not have the opportunity to see a second- or third-line regimen. In addition to that, I think the data from CheckMate 9LA were reassuring in patients with CNS metastasis and PD-L1 less than 1%.¹

FORDE: It’s relatively uncommon to have brain metastasis with squamous lung cancer. But for those patients, I think this is also a good option. Though a small group, they tend to have quite aggressive tumors when patients with squamous [non–small cell lung cancer] present with brain metastasis, so this is probably their best shot.

For CTLA-4, my general approach is, if the patient’s tumor is responding…to [anti–PD-1/CTLA-4]and they have a significant toxicity, I’ll try to take a break and let things cool off, and if and when we have to restart, I’ll tend to restart with the anti–PD-1 plus or minus chemotherapy.

This comes up with mesothelioma, which is another disease I treat for which nivolumab/ipilimumab is…one of the main options. Those patients can have severe autoimmune events, but I give them a long break because their diseases tend to be relatively indolent.

JABBOUR: You need to be sure they don’t have colitis from immunotherapy because this can be miserable. I will stop [therapy] and scan, and sometimes get a gastroenterologist on board. I would start prednisone if I need to right away. [I would] rule out [Clostridioides difficile] or any infection before doing anything like that, do a stool culture for C difficile to be sure and start prednisone if the culture is negative.

FORDE: That sounds very reasonable. We tend to bring these patients to urgent care, and ideally, if the symptoms are consistent with grade 3 colitis, then we will get a CT scan and just confirm that there’s radiographic evidence and also rule out other causes, either infectious or C difficile. Usually, if this turns out to be the autoimmune colitis, you’ll end up holding the therapy and starting a steroid course over 6 or 7 weeks. If the patient has to be admitted to the hospital, it becomes a bit more serious, and we sometimes end up giving intravenous steroids, initially methylprednisolone or something along those lines at a higher dose for a couple of days. At our institution, we have a gastroenterologist who has a particular interest in this area, so he will often weigh in specifically on the patient if there are questions regarding second-line or third-line management of colitis with drugs such as natalizumab [Tysabri].

JABBOUR: For people who get infliximab [Remicade] or treatment for [colitis] refractory to prednisone, will you rechallenge with immunotherapy?

FORDE: I have done it occasionally. I’ve had a couple of patients, but they’ve been patients who’ve had a sustained response to their initial immunotherapy, have had a toxicity… requiring infliximab, and 6 months, a year, or 2 years down the line, they’ve had progression. I’ve done it in those situations.

One of my colleagues had an unusual situation where she was giving immunotherapy for the cancer…but at the same time giving infliximab, which was [unusual], so there are rare situations. In the majority, I try to avoid giving further immune therapy, unless you’re out of options. There are situations, such as patients with transplants, [that are challenging].

The situations where I don’t tend to rechallenge would be [toxicities] such as myocarditis and severe autoimmune events such as myasthenia gravis, where if something happens again, the patient is likely going to die from that toxicity. There’s always a chance you can rescue colitis, but if you get a myasthenic crisis or myocarditis or something like that, you’re in serious trouble.

JABBOUR: We [serve] a rural area where it’s sometimes not easy to get everybody on board, and we have to manage [irAEs] ourselves most of the time. If [the patient is] not admitted to the hospital, by the time you call a gastroenterologist to see the patient, it’s going to be a problem. But the irAE I [struggled with] was hepatitis [where] liver function test results were very high, and I had to stop for a period. I had one severe case of dermatitis where I sent [the patient] to the dermatologist, and they told me it’s celiac [skin rash]…and they had never seen a case [with cancer immunotherapy], so I had to stop it. This was colon cancer, not lung cancer. Those are the 2 I faced where I had to totally stop the treatment. For colitis, I was OK with it, and [the same for] thyroid problems, but I had bad experiences with hepatitis and dermatitis.

FORDE: We’re a bit spoiled at [Johns Hopkins Medicine] that we have this immune toxicity team [from whom] you can get input. Even having said that, I have found particular areas can be difficult, such as nephrology. There are relatively few nephrologists who have any knowledge or interest in this area, whereas you can usually find a gastroenterologist who does colitis. There’s an increasing number of pulmonologists who [specialize] in this area, and cardiologists have a whole section at their national conference on cardio-oncology.

More refractory management gets quite difficult when you get to second-, third-, and fourth-line management of pneumonitis. Our pulmonologist favors intravenous immunoglobulin as a second-line therapy, but he doesn’t like to give it, so we end up having to give it in the infusion center, and then you have to deal with insurance, getting approval for it. It’s a nice therapy and not immunosuppressive, but it’s sometimes difficult to get through the oncology clinic.

NABRINSKY: As an oncologist, if we are leading physicians in the management of the case, we have to be careful who we invite for the [consultation]. We had a number of instances where if there were any neurological complications, whether it’s paraneoplastic or from chemotherapy, they have always been blamed by neurologists on… immunotherapy. For peripheral neuropathy—not myasthenia gravis, that’s pretty obvious—I’m talking about when it’s paraneoplastic or maybe chemotherapy-induced, or lifestyle-induced. But if immunotherapy is part of the regimen, it’s always been blamed on that, too. Then patients and family get upset that we never informed them about neurological AEs as a part of the informed consent, and if you look at the AEs, neurological AEs are [sometimes] being passed by. When nurses do teaching, neurological AEs are rarely commented on. Everybody knows about dermatology, GI [gastrointestinal], pulmonary, and so on. But recently we’ve seen a number of cases where nonspecific polyneuropathy and mononeuropathy [are attributed to] immunotherapy, even though there is no clear evidence. Patients get upset about that, [and] there is no guidance on that. Neurological complications of immune oncology are an undiscovered territory.

FORDE: That’s a great point, especially with the increasing use [of immunotherapy] in earlier-stage disease. I had a patient recently who developed type 1 diabetes on adjuvant pembrolizumab for lung cancer, and that was a tough situation because his chance of cure up front was probably 70% because he had a fully resected tumor. Awareness of those toxicities [is important and] it’s hard to be exhaustive when you’re doing the consent for these because there are so many rare toxicities they could have. I agree that our neurology colleagues [may report this]. We have a neuroradiology group, and I’ve yet to have an MRI of the brain performed with normal [results]. There’s nearly always something vaguely abnormal in an MRI of the brain. Those scenarios can be difficult.

_{1. Reck M, Ciuleanu TE, Dols MC, et al. Nivolumab (NIVO)+ ipilimumab (IPI)+ 2 cycles of platinum-doublet chemotherapy (chemo) vs 4 cycles chemo as first-line (1L) treatment (tx) for stage IV/ recurrent non-small cell lung cancer (NSCLC): CheckMate 9LA. J Clin Oncol. 2020;38(suppl 15):9501. doi:10.1200/JCO.2020.38.15_suppl.9501}

_{2. Carbone DP, Ciuleanu TE, Schenker M, et al. First-line (1L) nivolumab (N)+ ipilimumab (I)+ chemotherapy (C) vs C alone in patients (pts) with metastatic NSCLC (mNSCLC) from CheckMate 9LA: 4-y clinical update and outcomes by tumor histologic subtype (THS). J Clin Oncol. 2023;41(suppl 17):LBA9023. doi:10.1200/JCO.2023.41.17_suppl.LBA9023}

_{3. Paz-Ares LG, Ciuleanu TE, Cobo M, et al. First-line nivolumab plus ipilimumab with chemotherapy versus chemotherapy alone for metastatic NSCLC in CheckMate 9LA: 3-year clinical update and outcomes in patients with brain metastases or select somatic mutations. J Thorac Oncol. 2023;18(2):P204-222. doi:10.1016/j.jtho.2022.10.014}