“Exciting Year” for Targeted Therapy Options for Mutated NSCLC, Experts Say

Julia K. Rotow, MD

Clinical Director at the Lowe Center for Thoracic Oncology, Physician at Dana-Farber Cancer Institute, and Assistant Professor at Harvard Medical School

Hatim Husain, MD

Medical Oncologist, Associate Professor of Medicine at UC San Diego Health

Wade T. Iams, MD

Assistant Professor of Medicine at Vanderbilt-Ingram Cancer Center

In this Around the Practice®program, experts in the field of lung cancer came together to discuss treatment options for patients with non–small cell lung cancer (NSCLC). The panel touched upon different trials presented at the 2023 European Society for Medical Oncology (ESMO) Annual Meeting, which tested the effects of different drug combinations in this population. For example, the clinicians discussed the preliminary findings of the the phase 3 FLAURA2 trial (NCT04035486), which compared the standard of care of third-generation tyrosine kinase inhibitor (TKI) therapy with osimertinib monotherapy. Based on data presented at the conference, the doctors believe these trials could potentially change the standard of care in the treatment of NSCLC. Specifically, the experts highlighted the difficulties in treating mutations within NSCLC, such as EGFR mutations, and preliminary data efficacy in these studies.

The panel was led by Julia K. Rotow, MD, clinical director at the Lowe Center for Thoracic Oncology, physician at Dana-Farber Cancer Institute, and assistant professor at Harvard Medical School; she was joined by Hatim Husain, MD, medical oncologist, associate professor of medicine at UC San Diego Health; and Wade T. Iams, MD, assistant professor of medicine at Vanderbilt-Ingram Cancer Center.

Biomarking Testing

Rotow: Could you take me through your strategy for biomarker testing in lung cancer?

Iams: This is an important issue, and the way I test for all targetable biomarkers in my practice is that I do a circulating tumor DNA [ctDNA] liquid biopsy, as well as tumor-based next-generation sequencing [NGS] at the time of diagnosis for all patients with NSCLC, regardless of histology or smoking history. This is also independent of stage since we need to know EGFR for the patients with surgically resectable disease and, at the time of progression, typically only in patients with oncogene-driven NSCLC. It’s rare that I’ll repeat molecular testing at progression in patients who don’t have an oncogenic driver.

Rotow: Do you encounter challenges in getting this testing done in those patients where you can’t get NGS? How often does this come up in your practice?

Iams: There are challenges. The biggest challenge is having sufficient tissue to do a tissue-based NGS, which I consider the gold standard. However, our liquid biopsy technology is continuing to evolve, and the specificity is so high. So, if I have an actionable finding in the liquid biopsy, I act on that. Repeat biopsies do occur around 10% to 20% of the time in my practice. Fortunately, within our practice, our NGS has a very generous financial assistance program. There are very few cost concerns, but I know that we are on the more fortunate side. Not all practices can do testing that easily.

Rotow: Is a negative liquid biopsy enough to rule out something actionable for our patients?

Husain: That’s a key point. The field has recognized the fact that the FDA approval for liquid biopsies was when tissue is insufficient or not available.¹ That’s hinged upon the fact that a negative liquid biopsy does not exclude the possibility of finding an oncogenic driver. This is critical because we don’t want to leave any patient behind. Having that information early and upfront can help guide the treatment strategy for the patient. We call this the effective testing rate, meaning having the results before the first line of therapy.

Emerging Therapy Updates from 2023 ESMO

Rotow: Stepping forward, we’ve done our testing. We found an EGFR-activating mutation. We’re addressing a patient in clinic with a newly-diagnosed metastatic EGFR mutant lung cancer. We’ve seen a lot of changes and new regimens in this space in the last several months. Could you take us through what you see in the first-line treatment landscape?

Husain: This year has been exciting in the landscape of EGFR-mutant disease. Over the last several months, we’ve seen a number of abstracts that helped us provide some flexibility for patients and helped us understand how combinations can be important in the upfront treatment strategy for patients. In the phase 3 FLAURA2 trial [NCT04035486], we saw an analysis of the addition of chemotherapy to osimertinib [Tagrisso].² We saw an improvement in progression-free survival [PFS], about a 25.5 month median PFS [in the treatment arm] compared with a 16.7 month median in the control arm. We saw that the addition of chemotherapy can be helpful in certain subsets that are more difficult to treat, such as patients with L858R mutations,² as well as patients with brain metastases. At this ESMO, we have seen some unique data with other combinations. We’ve seen the addition of [VEGF inhibition] as one strategy.³ We’ve also seen the addition of the bispecific antibody, amivantamab-vmjw [Rybrevant], which is FDA approved for patients with exon 20 insertion mutated NSCLC in second-line therapy.⁴ We have now seen upfront data in the first-line space as well as the second-line space.

Rotow: It’s been very exciting. Until 3 or 4 months ago, for new diagnoses, our standard had been third generation tyrosine kinase inhibitor [TKI] therapy with osimertinib monotherapy. It’s been our benchmark for several years. We’ll see in these trials that many include that [treatment regimen] as the control arm in comparing some strategies for novel upfront combination therapies. Now, this doesn’t apply to all EGFR mutations. These are the classical or common mutations. Regarding the FLAURA2 trial, this was the first of our major updates in the combination therapy strategy space, which looked at adding platinum double chemotherapy upfront in combination with osimertinib in the first-line setting rather than introducing it at acquired resistance. This was a randomized study comparing osimertinib and monotherapy as a control option. We saw an increase in PFS by about 8 months, and the best benefits in patients with known central nervous system [CNS] disease. We’ve also seen a number of others come through. We’ve heard about the phase 3 MARIPOSA trial [NCT04487080].⁵ Could you take us a bit through that?

Iams: The MARIPOSA trial is an important trial looking at therapy escalation in the treatment-naive setting for patients with common EGFR mutations, such as exon 19 deletion and L858R. The design of MARIPOSA was a randomized, phase 3 trial where patients were randomly assigned 2:2:1 to: amivantamab plus lazertinib [Leclaza], osimertinib monotherapy, and then the lazertinib monotherapy group was the smaller subgroup within the 3. It was a very large trial approaching 1000 patients total, so several hundred patients in each treatment arm. Regarding some of the key findings from the study, there was PFS in the amivantamab plus lazertinib arm of 23.7 months, and median PFS in both the osimertinib and lazertinib arms were about 15 to 16 months, showing an improvement in PFS. Response rates were high in all cohorts, between 80% to 90%. The durability of response reflects the PFS with essentially the same numbers there. Hopefully, we get mature survival data as soon as possible. That’s going to take some time, but it’s the survival data that is the key. The HR was 0.70 [95% CI, 0.58-0.85; P <.001] when you compare amivantamab plus lazertinib with osimertinib. There’s a trend towards improvement in survival, and the survival curves are intriguing at this point and certainly need some maturation. When I’m in the clinic, I’m thinking about the toxicity of the therapy, the impact on quality of life, and, conversely, the impact on quantity of life. Time will tell the impact on quantity of life and whether it is enough to justify the impact on quality of life. This is the same thing with FLAURA2. How do you anticipate articulating a PFS improvement with immature survival results to your patients?

Rotow: My takeaway from this has been that now I have this conversation with my patients [detailing their treatment options]: the option for monotherapy upfront, the options for combination therapy upfront, and the options for, assuming we see approvals come through, several different types of combination therapy upfront. We did see a few other combination therapy strategies come up during a meeting at ESMO and at the World Conference on Lung Cancer, which looked at adding various VEGF-targeted agents into upfront EGFR TKI therapy. VEGF has always been an exciting area in lung cancer. We’ve seen its benefits for a long time in the metastatic setting. This data from the OSIRAM-1 trial and the ATTENTION with that apatinib [Rivoceranib] combined with aumolertinib.^6,7 In one of these, we saw more limited benefits in PFS, and in the other, we saw some PFS gains. This is a good example of needing to see overall survival [OS] data as well. I worry that the VEGF story has contained a lot of positive PFS data without a lot of positive OS data. This reminds us of the need for caution. We’re considering introducing additional toxicity, so we need to understand impact on long term survival. I’m excited to see as this data matures for all these strategies.

Husain: In the trials that were presented, the amount of time that the patients stayed on the VEGF inhibitor had some implications in terms of the PFS that was seen [by investigators]. Understanding [the effect of] the duration of therapy and the continuation of medicines on patients is important. Another key point for patients is understanding truly how these agents will affect the brain and how bevacizumab [Avastin] or ramucirumab [Cyramza] and other VEGF antibodies or TKIs may impact the CNS response. It’s an active area of interest.

Rotow: For our patients with lung cancer, especially if our patients with EGFR mutations have CNS metastases, there are significant clinical challenges. Many of our laser-line therapeutic options don’t offer effective CNS control. We’re left thinking about radiation-based strategies, which we can exhaust, or you will have to move to whole brain [radiation] with the associated toxicities that come with it. We did see some interesting CNS data at this conference as well. We’re familiar with pemetrexed and carboplatin as a potentially CNS-active regimen. That did ring true in the FLAURA2 study, where patients with CNS disease had better outcomes and a greater gain in PFS of 11 months compared with those without CNS disease. Some of the surprising data we saw looked at the phase 3 MARIPOSA-2 trial [NCT04988295] in the CNS subsets from there.²

Iams: In the MARIPOSA-2 study, the CNS observation was intriguing for a couple different reasons. MARIPOSA-2 was an evaluation of patients with typical EGFR mutations in the second-line setting after acquired resistance to third-generation EGFR-TKI. It was randomized in a 2:2:1 fashion. The groups in this setting were amivantamab plus platinum-based doublet chemotherapy plus lazertinib vs platinum-based doublet chemotherapy, which is our standard second-line, post-acquired resistance to EGFR TKIs. Then there was a group that was amivantamab and chemotherapy, which was the slightly smaller group. The study had over 100 patients in each group, with almost 500 patients total in the trial. This is a strong evidence base that we’re evaluating here. What we’re seeing in the CNS was a significant improvement in CNS PFS in both amivantamab groups compared with platinum-based doublet chemotherapy, so both groups that had lazertinib, which we would think as CNS active, [as well as] the group that [did not receive] lazertinib. We can speculate about the amivantamab in our evaluation of contributing components which seemed to be the active thing. Most of us would have thought that the lazertinib, the third-generation EGFR TKI, would be what provides CNS control. How do you interpret that?

Husain: This ESMO has challenged some of our thinking about firstly whether large molecules contribute to CNS efficacy. There’s been a lot of speculation that large molecules may not be as effective for contributing to CNS response, but we’re now seeing counterpoints. We also have a lot to learn in terms of the breakdown of the blood brain barrier and how that may be relevant for the distribution of the medicines, as we see with the impact of chemotherapy. CNS data was presented for the FLAURA2 trial as well. One unique thing about that was just the number of complete responses that were seen in the brain. That helps me understand the concept of whole brain radiation for these patients. We now have other alternatives that may not necessarily always translate to the need for whole brain radiation. This is a dialogue that we can have with our radiation oncologist, regarding how that message gets communicated around the impact of CNS efficacy in the EGFR space, particularly through combinatorial strategies. This conversation is one that can impact both medical oncology as well as our radiation oncology colleagues.

Rotow: This speaks to the importance of including patients with CNS metastases in clinical trials because sometimes you can be surprised by the efficacy and find patients who can benefit from these sorts of strategies. Another agent where we had some CNS data come through this ESMO was with the phase 2HERTHENA-Lung01 trial [NCT0461900] looking at patritumab deruxtecan [HER3-DXd], and this is another large molecule where, for bispecifics, there was some question as to whether we are going to see CNS activity or if it can cross the blood brain barrier.⁸ We saw reported CNS activity of these compounds, very similar to the systemic activity. This suggested that blood tumor barrier may be very different from the blood brain barrier and could require different sorts of assessments to understand activity.

References

1. FDA approves liquid biopsy NGS companion diagnostic test for multiple cancers and biomarkers. FDA. June 11, 2021. Accessed December 13, 2023. http://tinyurl.com/2ajhhyhu
2. Phase 3 MARIPOSA-2 Study Meets Dual Primary Endpoint Resulting in Statistically Significant and Clinically Meaningful Improvement in Progression-Free Survival for RYBREVANT® (amivantamab-vmjw) Plus Chemotherapy With and Without Lazertinib versus Chemotherapy Alone in Patients with EGFR-Mutated Non-Small Cell Lung Cancer after Disease Progression on Osimertinib. News release. Johnson & Johnson. September 6, 2023. Accessed December 19, 2023. https://tinyurl.com/yp73edvn
3. Zhao Y, Chen G, Chen J, et al. AK112, a novel PD-1/VEGF bispecific antibody, in combination with chemotherapy in patients with advanced non-small cell lung cancer (NSCLC): an open-label, multicenter, phase II trial. EClinicalMedicine. 2023;62(102106):102106. doi:10.1016/j.eclinm.2023.102106
4. RYBREVANT (amivantamab-vmjw) Receives FDA Approval as the First Targeted Treatment for Patients with Non-Small Cell Lung Cancer with EGFR Exon 20 Insertion Mutations. News release. Johnson & Johnson. May 21, 2021. Accessed December 19, 2023. https://tinyurl.com/3p7kdp6h
5. Planchard D, Jänne PA, Cheng Y, et al. Osimertinib with or without chemotherapy in EGFR-mutated advanced NSCLC. N Engl J Med. 2023;389(21):1935-1948. doi:10.1056/nejmoa2306434Landmark phase 3 MARIPOSA study meets primary endpoint resulting in statistically significant and clinically meaningful improvement in PFS for RYBREVANT® (amivantamab-vmjw) plus lazertinib versus osimertinib in patients with EGFR-mutated NSCLC. Janssen. September 28, 2023. Accessed December 19, 2023. https://tinyurl.com/bdfebue6
6. Nakahara Y, Kato T, Isomura R, et al. LBA70 OSIRAM-1: A multicenter, open label, randomized phase II study of osimertinib plus ramucirumab versus osimertinib alone as initial chemotherapy for EGFR mutation-positive non-squamous non-small cell lung cancer (TORG1833). Ann Oncol. 2023;34:S1313. doi:10.1016/j.annonc.2023.10.071
7. Hu Y, Zhang F, Zhao M, et al. LBA69 Aumolertinib plus apatinib versus aumolertinib as first-line treatment in patients with EGFR mutation positive locally advanced or metastatic non-small cell lung cancer (NSCLC): A randomized multicenter study. Ann Oncol. 2023;34:S1312. doi:10.1016/j.annonc.2023.10.070
8. Yu HA, Goto Y, Hayashi H, et al. HERTHENA-Lung01, a phase II trial of Patritumab deruxtecan (HER3-DXd) in epidermal growth factor receptor–mutated non–small-cell lung cancer after epidermal growth factor receptor tyrosine kinase inhibitor therapy and platinum-based chemotherapy. J Clin Oncol. 2023;41(35):5363-5375. doi:10.1200/jco.23.01476