Emerging Targeted Therapies Continue to Shift Paradigm in EGFR Exon 20–Mutated NSCLC

Amivantamab-vmjw (Rybrevant) and mobocertinib (Exkivity) have been integrated into treatment for patients with non–small cell lung cancer (NSCLC) harboring EGFR exon 20 mutations in the metastatic setting. As these agents continue to be explored, moving them into earlier lines of treatment could provide more benefits for this patient population, according to Edward Kim, MD, MBA.

“Targeted therapy has been a true renaissance in lung cancer. I still remember the days when we used doublet chemotherapy and were arguing about which adverse effects were better or worse, and in which patients. You would feel so helpless as a practitioner if that’s the only thing you were really discussing [instead of treatments] with greater efficacy. Now though we have made some incremental progress. Precision medicine [has led to] this integration of targeted therapy,” Kim said in an interview with OncLive® following an Institutional Perspectives in Cancer (IPC) webinar on lung cancer.

In the interview, Kim, the chair of the IPC meeting, discussed the facets of each presentation from the meeting, featuring other emerging targeted therapies in NSCLC, biomarker testing in the space, frontline immunotherapy in NSCLC, and the current management of small cell lung cancer (SCLC). Kim is the physician-in-chief at City of Hope Orange County, and vice physician-in-chief at the City of Hope National Medical Center.

OncLive^®: What are some of the exciting emerging areas for targeted therapy in NSCLC?

Kim: I had the pleasure to speak about several emerging areas in lung cancer. The first one is EGFR exon 20 [mutations]. We know that EGFR is expanding as far as the types of mutations that we’re finding, and now we have more drugs that are inclusive in this area that are FDA approved, including osimertinib [Tagrisso], amivantamab, and mobocertinib. These are drugs that are being implemented when we find these EGFR exon 20 mutations and have now become part of the armamentarium in lung cancer. [We are also aware that we] have to make sure we get comprehensive [genomic] testing in each patient.

I also covered osimertinib and its approval in the frontline setting and how it has changed targeted therapies. It is a drug that has high potency and high penetration into the central nervous system and is now being implemented in earlier-stage, surgically resectable disease. That excites me because this means we’re taking our wisdom, our scientific knowledge [that has been utilized] in the metastatic setting and moving it to the early-stage setting. We are following [the trend of] the breast cancer paradigm, which is exciting.

Finally, [I discussed] KRAS mutations. KRAS was something that, if you asked [clinicians] in the early 2000s, we would have assumed that this was the first biomarker that would have been relevant clinically. It hasn’t been until recently that we finally have a drug that’s FDA approved for KRAS G12C–mutated lung cancer [in sotorasib (Lumakras)], and that’s an exciting area. We expect other [mutations] to follow suit.

Given the exponential growth we’ve seen with targeted therapy, where do you see the field headed?

We want to measure the genomics of each individual’s cancer to see what comes up. Our menu of drugs that we can offer for specific targets has greatly expanded, and that’s exciting. However, it’s also daunting because there are so many targets and so many drugs now. Lung cancer is still in the middle of this change where we will continue to find more targets and more drugs. We have been a poster child for precision medicine.

Could you expand on the importance of genomic testing and the timing of that testing?

I consider genomic testing of one’s cancer essential, and I wish we would [include it] as part of the staging process. When you hear staging, you think of what CAT scans, PET scans, or MRIs you have to conduct in order to stage [the cancer]. Then you think of what the diagnosis is, and the diagnosis is a histological diagnosis of NSCLC or SCLC and whatever subtype it is.

Biomarkers is a third bucket, but I would hope that we could put biomarkers and genomic testing in one of those two areas, as either part of staging or part of histological diagnosis. If you think of breast cancer, when patients get a diagnosis, it is not complete until you have the hormone markers, the HER2 status, and now other markers.

I hope lung cancer now shifts in that direction that it [would be considered] incomplete staging or an incomplete diagnosis unless you have these genomic findings.

What options are currently available for patients with KRAS G12C–mutated NSCLC?

KRAS G12C mutations are a new area. It’s a subset of the KRAS gene, so it does not make up the entire 25% to 30% of lung cancer that harbors KRAS mutations. [KRAS] has multiple subtypes as well.

We have identified treatments that target KRAS G12C. The first agent is sotorasib. That is a drug that has been FDA approved and is utilized in previously treated patients based on the phase 1/2 CodeBreaK 100 trial [NCT03600883]. I’m glad we have a treatment, and we have other treatments down the road that are coming.

I also mentioned the phase 1/2 KRYSTAL-1 trial [NCT03785249] that evaluated adagrasib, which is coming as well. We’re hopeful that other drugs in the pipeline will cover some of these other KRAS subtypes down the road.

Your colleague, Michelle Afkhami, MD, of City of Hope, spoke on biomarker testing in lung cancer. How has this testing evolved over time?

Dr Afkhami gave an elegant talk on the perspective from pathology on the importance of biomarker testing. The things we always focus on are the technology platforms and how much tissue or blood we need, how quickly we can run the markers, and how many markers we can run. [The speed of these tests has been] increasing, and [the amount of blood or tissue needed has been] decreasing. It’s a rapidly changing area. The technology continues to improve. The types of specimens we are testing are changing, and the number of markers that we as clinicians want to have, not only to treat our patients in the clinic, but also to measure for research purposes, [are changing, too].

It is like a microcosm of what we’re doing with telescopes in space. We have a great telescope, we launch it, we can see things we’ve never seen before, but then we need a new one to see deeper and find other things. This is a similar type of paradigm, except we’re moving faster.

[Genomic testing] is of the utmost importance. We’re still trying to emphasize to our clinical colleagues that you have to do this up front. There’s still data that’s being reported that [genomic testing rates are] no [higher] than 90%, and that needs to change. We also understand that we have to make it easier to do this testing. There are hurdles in some rural areas, community-based areas, and even metropolitan areas where it is challenging to get this done. We need to work on both sides: the attitudes and beliefs [on genomic testing] and the processes. We need to make it all better.

Erminia Massarelli, MD, PhD, of City of Hope, spoke on frontline immunotherapy. How has immunotherapy changed historical approaches to treatment?

Dr Massarelli is the section head of lung cancer at City of Hope, and she talked about frontline immunotherapy, another great frontier that has been crossed in patients who we are treating for lung cancer. She talked specifically about the phase 3 CheckMate 277 trial [NCT02477826] and the phase 3 CheckMate 9LA trial [NCT03215706], as well as the phase 3 EMPOWER-Lung 1 trial [NCT03088540]. We know that the established frontline regimen is a combination of chemotherapy and immunotherapy. We have multiple options on the table. We still use the phase 3 KEYNOTE-189 trial [NCT02578680] regimen of pembrolizumab [Keytruda] plus chemotherapy; that’s the most popular. But [these trials] have advanced the options of what we had with doublet chemotherapy or even with bevacizumab [Avastin] in previous iterations.

We’re now at a point where immunotherapy has completely changed not only how we treat patients but what our expectations of their outcomes are. I love the fact that we can use lesser toxic chemotherapies but also empower [a patient’s] immune system to help battle the cancer. This has changed the paradigm of our treatment approach.

Nishan Tchekmedyian, MD, of City of Hope, gave a presentation on targeted therapy. Are there any other key areas of targeted therapy that you want to highlight?

Dr Tchekmedyian has worked in a community-based system and is now one of our faculty members at City of Hope. He and his group previously have done a lot of research in a regional-based setting. Additionally, he has recently [coauthored] the Journal of Clinical Oncology publication on poziotinib [in the phase 2 ZENITH20 trial (NCT03318939)] in patients with NSCLC harboring HER2 exon 20 insertion mutations.

He gave us an update on RET and ALK. ALK was the second targeted therapy class in lung cancer, but now it has multiple generations of drugs. Most recently, the phase 3 CROWN trial [NCT03052608] was reported, and [lorlatinib (Lorbrena)] is being integrated into our treatment paradigms.

He discussed RET, which is an area that is new for lung cancer, and it is exciting as well. It is another marker that we’re measuring so that we can implement the appropriate treatments. There are a lot of changes, even in these rarer markers. There are more drugs and more options, which leads us down the road of how we sequence these drugs in patients who have this biomarker. What works best first? What works best in overcoming resistance? These are the questions that we’re now asking, whether it’s with targeted therapies or immunotherapies because we want to be able to treat patients as long as possible and overcome resistance mechanisms that the cancers are constantly trying to fight us with.

Lastly, Jyoti Malhotra, MD, MPH, of City of Hope, spoke about current management of SCLC. What recent updates in this field have been exciting to hear?

Dr Malhotra has now joined us at City of Hope to be our lung lead in our Orange County Campus. She spoke on SCLC, and we should not forget SCLC and leave it behind. For years, NSCLC and SCLC were equally frustrating in the treatments that we would offer with doublet chemotherapy. Just because one of our areas has advanced a lot, which is NSCLC, we shouldn’t leave the other behind.

SCLC is getting the attention that it deserves. We’re trying to find biomarkers and targeted therapies. You’ll hear people say that we’re not going to find [these biomarkers and targeted therapies], but we said that about NSCLC for many decades. It finally happened [in NSCLC], and I believe it will happen in SCLC as well.

Dr Malhotra gave a nice overview of the phase 3 CASPIAN trial [NCT03043872], the phase 3 IMpower133 trial [NCT02763579], as well as what we do in the second-line setting of SCLC. It’s important to continue to include SCLC in our dialogues, discussions, and research because it constitutes about 15% of lung cancer. That puts it in line with an EGFR incidence or some of these other markers, such as KRAS G12C. This is an equally important population, and we need to continue to pursue and find the best treatment options because our patients are still being diagnosed with SCLC, and SCLC can tend to be more aggressive. We urgently need to find these therapies.

What do you believe is the biggest highlight to come out of the IPC meeting?

These meetings are great. They provide a great service to people who are trying to keep up with all the data. These days, everyone’s so busy, but over a 2-hour period, you can get updated with all the latest and the greatest in a particular disease type. These types of formats are great for learners, and great for folks who are busy.

I really enjoy the fact that we can cover so many topics from pathology and biomarkers all the way through the different treatments for lung cancer right now. The format is great. I do believe that the right messages are being taken home. It’s like a summary of what the current state of the data is, and that’s why you continue to see a lot of participation and a lot of interest by experts in the field who want to use this type of format to convey this important information and timely updates for the community at large.