Toxicity Management Remains Key With Expanding Frontline Treatment Options in Lung Cancer

Antoinette Wozniak, MD, FACP, FASCO

Best practices for managing treatment-related toxicities with frontline targeted therapy and immunotherapy is still being determined in patients with lung cancer, said Antoinette Wozniak, MD, FACP, FASCO. She added that careful data consideration and monitoring of patients is critical in the up-front setting as novel therapies, such as antibody-drug conjugates (ADCs) and combination regimens, enter the arena as potential first-line options.

“We have to analyze [the data from] these trials and put into practice what is most important and what will work best for patients. We need to be careful with some of these new agents in terms of adverse effects [AEs] and balance the delivery of the agents with toxicity,” Wozniak, a visiting professor of medicine, associate director of clinical research at the University of Pittsburgh Medical Center (UPMC) Hillman Cancer Center, director of the Lung Cancer Disease Unit, and co-director of the UPMC Lung Cancer Center of Excellence in the Division of Hematology/Oncology at UPMC, said in an interview with OncLive® during an Institutional Perspectives in Cancer (IPC) webinar on lung cancer.

“Everything that was discussed supports the importance of participation in clinical trials. Without those trials, we wouldn’t have these new agents. However, we need to be critical of the information and make sure that we don’t venture too far outside the box. We don’t know what some combinations might do in terms of toxicities,” Wozniak added.

Faculty who spoke during the virtual meeting covered frontline considerations with single-agent vs combination immunotherapy, targeted options against ALK-mutated non–small cell lung cancer (NSCLC), and treatment options in small cell lung cancer (SCLC), as well as how to navigate the paradigm among novel targeted therapies directed toward EGFR exon 20 insertion and KRAS mutations.

In the interview, Wozniak spoke to the topics covered by her colleagues, highlighted the importance of monitoring patients with lung cancer for toxicities, and significant advances on the horizon that are expected to further expand the lung cancer armamentarium.

OncLive®: What novel agents are emerging that you are intrigued by?

The ADCs are interesting, and a number of trials are ongoing [evaluating] ADCs. The whole idea is to identify a target. The agents [utilize] an antibody [directed] to the target, a linker, and a cytotoxic payload. It’s a fairly complicated process. ADCs have to be very specific so that they don’t cause significant systemic effects and that they get delivered primarily to the tumor. That is where we are heading in the future in terms of new agents.

Targeted agents specific for HER2 [are also emerging]. That will be interesting, particularly in the lung cancer paradigm, but not all of them work or have acceptable safety profiles. For example, an ADC called rovalpituzumab tesirine [was tested] in SCLC, but didn’t work and was fairly toxic. We have a lot of work to do with these agents, but they represent some of the more interesting agents.

Also of interest are clinical trials [exploring] agents [to use] after patients progress on immunotherapy. That’s a huge space. When we have patients who progress on immunotherapy or patients who responded for a while and then progress, it is difficult to try to figure out what to do next. Several trials are looking at why patients progress. A few molecules are interesting, such as those that target TIGIT and LAG3, as well as CTLA-4, which is still of interest. This is an area in which we are going to see a lot of clinical trials and development of new agents.

During the IPC meeting, Liza C. Villaruz, MD, of the UPMC Cancer Institute, discussed frontline immunotherapy in NSCLC. How are you selecting between utilizing single-agent immunotherapy vs combination chemoimmunotherapy in the frontline setting?

Wozniak: Regarding single-agent immunotherapy vs combination chemoimmunotherapy, we’ve been struggling [with what is best to choose]. Everyone likes the idea of using just one drug, but there are certain instances where we need [chemotherapy as well].

In patients with a PD-L1 status below 50%, the consensus right now is to use [chemoimmunotherapy]. Pembrolizumab [Keytruda] is FDA approved as a single agent, even in patients with a PD-L1 status of 1% to 49%. In that group, however, we feel we need more. In the over 50% group, a lot of [treatment selection] depends on the volume and aggressiveness of the disease. The survival curves [in the pivotal trials that evaluated immunotherapy] cross because it takes a little time for immunotherapy to work. Therefore, in patients who have what may be more aggressive disease or a high volume of disease, it may be worthwhile to combine chemotherapy with immunotherapy to get a better response earlier. That is where we are at.

The INSIGNA trial [NCT03793179] is ongoing, looking at sequencing, even in the 1% to 49% group. That trial may give us more information on how we can use single-agent [immunotherapy] vs combination [chemoimmunotherapy].

Shirish M. Gadgeel, MD, of the Henry Ford Health System, spoke to the frontline management of ALK-mutated NSCLC. What considerations are you making when selecting between available ALK inhibitors in this patient population?

We have a couple of very active agents [for ALK-mutated NSCLC]. We have alectinib [Alecensa], brigatinib [Alunbrig], and lorlatinib [Lobrena]. It’s hard to do cross-trial comparisons, so most of us use what we feel comfortable with. In the case of [ALK-positive disease], most people likely use alectinib because it was the first next-generation inhibitor to show benefit over crizotinib [Xalkori] and we feel comfortable with the safety profile of that agent.

We’ve seen increased use of brigatinib because the dosing is easier [than alectinib]. Also, there is at least a suggestion in trials that [brigatinib] is quite active [against] brain metastases. Then again, we can’t say one is better vs another, especially when the [activity] looks similar.

We are seeing that we can [use the agent] we feel comfortable with but sequencing them is a little more complicated because we really don’t [have data on how to do that]. More information about resistance mechanisms for ALK inhibitors [is emerging]. For instance, ALK G1202R mutations seem to be popping up occasionally. Lorlatinib has activity there, so many of us are using lorlatinib in the second-line setting right now. There is more to come in terms of [understanding] the best way to sequence ALK inhibitors.

Taofeek K. Owonikoko, MD, PhD, of the UPMC Cancer Institute, highlighted advances made in frontline SCLC. What were some of the key points from his presentation that apply to clinical practice, and what is next for the field of SCLC?

SCLC is still very difficult to treat, so we have a lot of work to do. Dr Owonikoko was quite clear about that.

We saw the first advance in probably 20 years with the addition of immunotherapy to [chemotherapy in] extensive-stage disease. [In] World Series [speak], this was a base hit, not a home run. There was improvement [with the addition of immunotherapy], but it is difficult with SCLC because we don’t have any biomarkers. It’s a very complicated disease with a lot of mutations and abnormalities but not 1 driver mutation. We have to understand the disease to be able to divide it up into subtypes. Within the subtypes, we will hopefully be able to determine which patients are more likely to respond to immunotherapy vs some of the other drugs that are being [evaluated].

In terms of limited-stage SCLC, we have to wait for the results of clinical trials before we incorporate the use of immunotherapy [into the paradigm].

Finally, Timothy F. Burns, MD, PhD, of the UPMC Cancer Institute, spoke to recent advances with targeted therapy for patients with EGFR exon 20 insertion mutation– and KRAS mutation–positive NSCLC. How has your experience been with the novel targeted options, and what considerations should be kept in mind when utilizing the agents in clinical practice?

[Targeted therapies against EGFR exon 20 insertion mutations and KRAS mutations] are relatively new, so we don’t know how successful they are going to be in common clinical practice. They are excellent [additions] because EGFR exon 20 insertion mutations and KRAS mutations have been very difficult to drug. I used to call them undruggable targets.

EGFR exon 20 has been very frustrating because we see such good results when we treat exons 19 and 21. However, now we have 2 drugs [for patients with these mutations]. I have used both of these agents on expanded access. Both agents are approved as second-line treatments, so patients generally get chemotherapy first with or without immunotherapy.

Mobocertinib [Exkivity] is one of those drugs. It is oral, so it has that advantage. It’s a small molecule TKI. We have to be aware of the [AEs associated] with that drug, including gastrointestinal toxicities like diarrhea. Patient education with regard to the development of diarrhea and nausea is important to manage AEs. We also have to follow the recommendations for dose reduction. [Mobocertinib] does cause QT prolongation, so we have to be careful which drugs are combined with it. That is for not only anti-nausea agents, but also other drugs patients might be on. [As an example,] a patient [I treated] was on medication for anxiety and depression, some of which cause QT prolongation. We have to be really careful and monitor patients.

Amivantamab-vmjw [Rybrevant] is the other drug [approved for patients with EGFR exon 20 insertion mutant–NSCLC]. It is a bispecific antibody [directed against] MET and EGFR that is given intravenously. At the initial time we give the drug, we see a lot of infusion-related reactions, so we must be cognizant [of those events]. They usually happen with the first infusion and is why the infusion is split over 2 days. [These reactions] don’t tend to happen later, but they can be fairly significant initially.

It wouldn’t be a bad idea to pre-treat patients [who will be receiving amivantamab] with steroids and H2 blockers, such as famotidine, and of course, diphenhydramine [Benadryl]. Pretreatment is important.

[Mobocertinib and amivantamab] are approved as second-line treatments, so which one is better? Which should we use? It’s dealer’s choice; one isn’t better than the other. They haven’t been compared directly. The toxicities are different so we have to consider that. If a patient wants to try an oral drug vs an IV [intravenous] drug, that might make our decision.

KRAS mutations represent the most common mutation, [occurring in] approximately 25% of adenocarcinomas. They are very rare in squamous cell [carcinomas]. Although KRAS was discovered a long time ago, we have not been able to target it. Now we have 1 drug available: sotorasib [Lumakras]. We also have 1 drug, adagrasib, in clinical trials, which is probably going to be approved soon.

Some of the toxicities to be aware of with sotorasib include diarrhea, some skin toxicities, and liver toxicities, which I ran into [with a patient]. We have to monitor patients carefully, but sotorasib seems to be reasonably well tolerated. The response rate is just around 37%, and the drug is being used in the second-line setting. The response rate is not as high as we see with ALK and EGFR inhibitors though.

First-line trials are planned [with sotorasib], likely in combination with chemotherapy or immunotherapy. We will see where this drug lands in the future, but for now, it is a second-line agent that has some activity. It’s reasonable to try sotorasib, or if we can [enroll patients onto] clinical trials, that’s the way to go.

Additionally, more drugs [targeting EGFR exon 20 insertion mutations and KRAS mutations] are being evaluated in clinical trials.