CE / CME
Physician Assistants/Physician Associates: 1.50 AAPA Category 1 CME credits
Nurses: 1.50 Nursing contact hours
Physicians: maximum of 1.50 AMA PRA Category 1 Credits™
Pharmacists: 1.50 contact hours (0.15 CEUs)
Released: November 17, 2023
Expiration: November 16, 2024
Targeting EGFR ex20ins Mutations in Advanced NSCLC
Matthew Gubens, MD, MS:
Next, we will look at a subset of EGFR mutations that was not covered by the 3 trials we just discussed: exon 20 insertions (ex20ins). Tumors with these mutations are not as responsive to osimertinib or the earlier-generation EGFR TKIs that are currently available for the treatment of EGFR-mutated NSCLC.
There are currently 2 FDA approvals for EGFR ex20ins–positive advanced NSCLC. Amivantamab-vmjw, a bispecific EGFR-MET antibody, is approved for treatment of adult patients with locally advanced or metastatic NSCLC with EGFR ex20ins mutations whose disease has progressed on or after platinum-based CT.21 Mobocertinib, an EGFR TKI, received accelerated approval in this setting22 but is being voluntary withdrawn from the US market—and eventually across the globe—following the confirmatory randomized phase III EXCLAIM-2 trial indicating a failure to meet the primary endpoint of IRC-assessed PFS per Response Evaluation Criteria in Solid Tumors version 1.1 criteria (NCT04129502).
However, a new generation of investigational agents is under development for this population with an unmet need for new options, one of which we will discuss next.
FAVOUR: Furmonertinib in EGFR ex20ins–Positive Locally Advanced or Metastatic NSCLC
Matthew Gubens, MD, MS:
Furmonertinib is an oral, irreversible, brain-penetrant, selective third-generation EGFR TKI that has shown clinical efficacy and tolerability at doses up to 240 mg in EGFR T790M–mutated and EGFR ex20ins–positive NSCLC.23-26
Updated efficacy and safety data from the phase Ib FAVOUR trial were reported at WCLC 2023.27 Patients with EGFR ex20ins–positive advanced or metastatic NSCLC received furmonertinib at a dose of 160 mg daily (n = 28 previously treated) or 240 mg daily (n = 28 treatment naive and n = 28 previously treated). Patients with asymptomatic stable CNS metastases were allowed to enroll. Treatment continued until progression, unacceptable toxicity, or death. The primary endpoint of the study was ORR by IRC, with secondary endpoints including DCR, DoR, PFS, OS, depth of response, safety, and QoL.
FAVOUR: Efficacy
Matthew Gubens, MD, MS:
A very impressive ORR was seen with furmonertinib in the cohort of patients who were treatment naive (78.6%). Furthermore, the median DoR in the treatment-naive setting was 15.2 months (95% CI: 8.74-24.84), which I think speaks to good first-line efficacy.
Even the patients who had received prior systemic anticancer therapy (86%-96% CT, 32%-39% IO, and 7%-14% EGFR-targeted therapy) had an ORR of 46.2% with the 240-mg dose and 38.5% with the 160-mg dose.
FAVOUR: Safety
Matthew Gubens, MD, MS:
As with any EGFR TKI, particularly those addressing the EGFR ex20ins mutation, there is a potential for significant treatment-related AEs (TRAEs). Although the majority of patients experienced a TRAE of any grade (89%-100%) with furmonertinib, the rate of grade ≥3 TRAEs (13%-29%) was relatively reasonable for this drug class.
Compared with mobocertinib, which is considered to have a very high discontinuation rate (10%-17%) because of EGFR on-target effects such as diarrhea,28 the rate of furmonertinib discontinuations due to TRAEs was low—none in the treatment-naive cohort and only 4% in the previously treated cohorts—with reasonably acceptable dose interruption and dose reduction rates.
FAVOUR: Most Frequent TRAEs
Matthew Gubens, MD, MS:
When you look at the AEs with furmonertinib in greater detail, similar to other EGFR TKIs, diarrhea was very prominent, and rash and mouth ulceration also are going to be very frustrating for patients. Fortunately, very few of these TRAEs were grade ≥3.
This is not dismissing the fact that grade 1/2 AEs can be very frustrating, especially over the long term that patients are receiving these TKIs, but the safety profile for furmonertinib compares favorably with other EGFR ex20ins–specific TKIs.
FAVOUR: Clinical Implications
Matthew Gubens, MD, MS:
Dr Yu, what are your thoughts on a role for furmonertinib within the treatment paradigm for EGFR ex20ins–positive advanced NSCLC? I want to emphasize that furmonertinib is one of a few EGFR TKIs in this generation, and we are going to see some mature studies come out.
Helena Yu, MD:
First, I think having options for our patients is really important. As you mentioned, we currently have 2 approved agents in the EGFR ex20ins space, with reasonable efficacy—but flaws, as well. Despite the fact that it is going to be withdrawn from the market soon, I have patients who are receiving mobocertinib and are doing reasonably well. So, I eagerly await confirmatory global phase II studies in larger populations of other investigational agents targeting EGFR ex20ins mutations that will, I hope, lead to the approval of some new options.
Overall, furmonertinib looks very promising, and data from the previously treated cohort looks in line with that for sunvozertinib, zipalertinib, and other next-generation EGFR ex20ins inhibitors.29,30 Regarding the toxicity profile, it would be ideal if we could get less EGFR wild-type inhibition for agents targeting EGFR ex20ins mutations. There is also a big question about sequencing, that is, can you sequence EGFR antibodies and then TKIs? Can you start with amivantamab-vmjw and then perhaps move to furmonertinib next? We also need to understand the CNS penetration of these next-generation drugs, which we hope will improve on the limited efficacy of the initially approved drugs. However, I am very excited about this study and looking forward to seeing more data.
Matthew Gubens, MD, MS:
I agree with you that understanding how these drugs work relative to one another—particularly how to manage their sequencing around amivantamab-vmjw—is going to be very important.
Helena Yu, MD:
Another interesting point is that response rates with furmonertinib were higher in treatment-naive disease vs in later lines. This is something we have seen with many targeted therapies, and it makes sense to some degree when we think about tumor heterogeneity progressively increasing with more treatment. Of course, we need more data, but what we have seen so far does suggest that using these targeted therapies earlier in the treatment sequence makes sense.
Matthew Gubens, MD, MS:
I agree. Leading with your best foot forward is usually a good strategy, although it is interesting—and perhaps a quirk of EGFR ex20ins drug development—that both drugs currently on the market have approval for the second and subsequent lines. We will see if these next-generation drugs are more efficacious and safe enough to be approved in the front line.
TRIDENT-1: Phase I/II Study of Repotrectinib in Patients With ROS1 Fusion–Positive Advanced NSCLC
Matthew Gubens, MD, MS:
Next, we will discuss a new treatment option under investigation for ROS1 fusion–positive advanced NSCLC.
ROS1 has some homology with ALK, another important targetable genomic aberration in NSCLC. The first-line SoC treatment for ROS1 fusion–positive advanced NSCLC is crizotinib or entrectinib.31-33 However, there is no approved next-line agent, although the ALK/ROS1 TKI lorlatinib is recommended as a subsequent therapy option after progression in clinical guidelines.31 Lorlatinib is approved by the FDA for treatment of adult patients with metastatic NSCLC whose tumors are positive for an ALK rearrangement.34
Repotrectinib is a next-generation ROS1/TRK/ALK TKI with known preclinical activity against ROS1-resistant mutations, a decreased potential for development of resistance, and favorable characteristics for enhanced intracranial activity.35 Repotrectinib showed preliminary clinical activity in patients with ROS1 fusion–positive advanced NSCLC who were TKI naive and TKI pretreated in an initial report of the multicohort open-label phase I/II TRIDENT-1 trial evaluating repotrectinib in patients with locally advanced or metastatic solid tumors with ROS1 or NTRK1-3 gene fusions.36 Patients with asymptomatic CNS metastases were allowed to enroll. The primary endpoint was confirmed ORR by BICR, with key secondary endpoints including DoR, clinical benefit rate (CBR), time to response, PFS, OS, intracranial DoR, and safety.
At WCLC 2023, Cho and colleagues37 presented updated data from TRIDENT-1 with a focus on patients with ROS1 fusion–positive NSCLC who were ROS1 TKI naive (n = 71) or who had received 1 prior ROS1 TKI but no prior CT (n = 56).
TRIDENT-1: Baseline Characteristics
Matthew Gubens, MD, MS:
The baseline characteristics of patients in this updated analysis from TRIDENT-1 were as expected, including a younger patient population (median age: 57 years).
The ROS1 TKI–naive cohort was majority Asian (58%) and patients who never smoked (63%), with 28% having received some prior systemic therapy (CT with or without IO). In terms of the cohort of patients who received prior ROS1 TKI therapy, 82% had received crizotinib, 16% entrectinib, and 2% ceritinib.
Brain metastases were identified in 24% and 46% of patients who had not received a ROS1 TKI and who had received prior ROS1 TKI therapy, respectively, speaking to ROS1-positive NSCLC being a relatively CNS-tropic disease.
TRIDENT-1 RIKI–Naive Cohort: Response
Matthew Gubens, MD, MS:
As mentioned, we might expect to see better response rates in patients who are naive to prior treatment. In the ROS1 TKI–naive cohort, with a median follow-up of 24.0 months, the ORR was 79%, with a DoR of 34.1 months. These results compare very favorably, in a decent-sized patient population, with the currently approved SoC, crizotinib and entrectinib.
TRIDENT-1 ROS1 TKI–Naive Cohort: Survival
Matthew Gubens, MD, MS:
In terms of survival in the ROS1 TKI–naive cohort, the median PFS was 35.7 months, and the median OS was not reached as of the data cutoff (December 19, 2022).
TRIDENT-1 Cohort With 1 Prior ROS1 TKI, No Prior CT: Response
Matthew Gubens, MD, MS:
In those patients who had been treated previously with 1 ROS1 TKI and no CT, with a median follow-up of 21.5 months, the confirmed ORR and median DoR were lower than in the ROS1 TKI–naive cohort at 38% and 14.8 months, respectively.
TRIDENT-1 Cohort With 1 Prior ROS1 TKI, No Prior CT: Survival
Matthew Gubens, MD, MS:
In this cohort, median PFS was 9.0 months (95% CI: 6.8-19.6), and median OS was 25.1 months (95% CI: 17.8-NE. It is possible that efficacy in this cohort was lower because the patients already had received treatment and perhaps had developed some resistance at this point.
TRIDENT-1: Intracranial Efficacy in Patients With Measurable Baseline Brain Metastases
Matthew Gubens, MD, MS:
These are small patient numbers, but intracranial response was seen both in the ROS1 TKI–naive cohort (n = 9; intracranial ORR: 89%; intracranial DoR range: 1.9+ to 25.8+ months) and in the ROS1 TKI–pretreated cohort (n = 13; intracranial ORR: 38%; intracranial DoR range: 3.0+ to 17.5+ months).
We already mentioned the importance of intracranial efficacy for these TKIs, and based on these results, repotrectinib does appear to be CNS active.
TRIDENT-1: Emergence of ROS1 Resistance Mutations
Matthew Gubens, MD, MS:
It is important to note that no on-target resistance mutations developed in patients in the ROS1 TKI–naive cohort who progressed on repotrectinib—and only did so in 14% of patients in the ROS1 TKI–pretreated cohort.
Efficacy with repotrectinib also was reported in 17 patients from the ROS1 TKI–pretreated cohort who had a ROS1 G2032R resistance mutation at baseline, showing a confirmed ORR of 59%, with a median DoR of 7.6 months and median PFS of 9.2 months.
TRIDENT-1: Safety in Patients Treated at the Recommended Phase II Dose
Matthew Gubens, MD, MS:
In terms of safety, repotrectinib compares favorably with the ROS1 TKIs currently in the clinic.
Safety was reported in all patients in all cohorts who received the recommended phase II dose regardless of tumor type, ROS1 or NTRK fusion status, or prior treatment (n = 426). Grade ≥3 TRAEs were seen in 29% of patients, serious TRAEs were seen in 9%, and there were no TRAEs that led to death (TEAEs leading to death in 4%). In broad terms, the discontinuation rate (7% for TEAEs, 3% for TRAEs) was comparable to other ROS1 TKIs in this space.
One of the most common AEs was dizziness (any grade: 62%; grade ≥3: 3%), but it did not result in any treatment discontinuations. This is not in the usual suite of toxicities we expect with drugs for ROS1 or other actionable genome alterations in NSCLC, so it is important to proactively counsel about it.
TRIDENT-1: Clinical Implications
Matthew Gubens, MD, MS:
ROS1 fusion–positive advanced NSCLC represents another relatively small patient population, and we have 2 approved drugs on the market. Dr Yu, how will the TRIDENT-1 results and a potential approval of repotrectinib affect your approach to disease management in these patients?
Helena Yu, MD:
These data are interesting, particularly considering the activity of repotrectinib after progression on either crizotinib or entrectinib. Furthermore, as you get better on-target inhibition, you actually see less on-target resistance, and seeing the lack of acquired ROS1 alterations in the patients who have not received a ROS1 TKI helps us understand what resistance will look like in the future with better and better drugs.
I will add that I find the TRK-related AEs with entrectinib—the associated weight gain, paresthesia, and dizziness, and then the requirement to often have to taper down at discontinuation to avoid a potential flare effect—to be quite challenging for my patients. So, that is something we will need to keep an eye on with repotrectinib.
Matthew Gubens, MD, MS:
I have had similar experiences and think it will be important to counsel patients about these toxicities and proactively manage them. I think it is also important to note that the toxicity profile with crizotinib is not the easiest to manage, either.
Phase I CHRYSALIS Update: Amivantamab in Expanded Cohort of Patients With Advanced
NSCLC and MET Exon 14 Skipping Mutations
Matthew Gubens, MD, MS:
Another area of drug development has been for MET exon 14 (METex14) skipping mutations, which are found in approximately 3% of NSCLC adenocarcinoma cases.38 Currently, 2 treatments are approved by the FDA in this space: capmatinib and tepotinib.39,40
Despite the availability of these drugs, acquired resistance via secondary MET mutations or activation of bypass signaling remains a concern.41
The dose-escalation/dose-expansion phase I CHRYSALIS trial (NCT02609776) evaluated amivantamab in multiple cohorts of patients with advanced NSCLC, including the MET-2 cohort of patients with METex14-positive metastatic or unresectable disease. The primary endpoint was ORR, with key secondary endpoints including PFS, OS, DoR, CBR, and safety. We already mentioned that amivantamab-vmjw is a bispecific MET-EGFR antibody approved for treatment of adult patients with locally advanced or metastatic NSCLC with EGFR ex20ins mutations whose disease has progressed on or after platinum-based CT.21
Preliminary results from the MET-2 cohort of CHRYSALIS suggested encouraging antitumor activity with amivantamab monotherapy in patients with advanced/metastatic NSCLC and a METex14 skipping mutation.42,43 The report at WCLC 2023 focused on an expanded MET-2 cohort of patients (n = 97) who had progression on, declined, or were ineligible for SoC treatment and received amivantamab-vmjw monotherapy in dose expansion.44
CHRYSALIS Expanded METex14 Cohort: Baseline Characteristics
Matthew Gubens, MD, MS:
Within cohort MET-2, 16 patients were treatment naive, and of the 81 patients who had been previously treated, 53 had received a MET inhibitor.
CHRYSALIS Expanded METex14 Cohort: Response
Matthew Gubens, MD, MS:
At a median follow-up of 10 months, ORR (50% vs 21%) and CBR (88% vs 68%) were higher in the 16 patients who were treatment naive compared with the 53 patients who received prior MET inhibitor therapy.
CHRYSALIS Expanded METex14 Cohort: Antitumor Activity
Matthew Gubens, MD, MS:
This waterfall plot clearly shows continued antitumor activity with amivantamab-vmjw in this expanded cohort of patients with METex14-positive advanced NSCLC.
CHRYSALIS Expanded METex14 Cohort: DoR
Matthew Gubens, MD, MS:
The median DoR with amivantamab-vmjw in this patient population was 11.2 months, with 38% of patients remaining on treatment as of the data cutoff (June 19, 2023).
CHRYSALIS Expanded METex14 Cohort: Survival
Matthew Gubens, MD, MS:
In the overall cohort, the median PFS was 5.4 months, and the median OS was 15.8 months.
CHRYSALIS Expanded METex14 Cohort: Safety
Matthew Gubens, MD, MS:
As expected for a MET-EGFR bispecific antibody, the toxicity profile of amivantamab-vmjw included both EGFR on-target toxicities and those associated with MET inhibition. EGFR-associated AEs included paronychia, dermatitis, and rash. MET-associated AEs included hypoalbuminemia and peripheral edema, a significant toxicity that must be proactively anticipated and actively managed. TRAEs leading to dose interruption, reduction, and discontinuation occurred in 24.7%, 12.4%, and 9.3% of patients receiving amivantamab-vmjw, respectively.
CHRYSALIS Expanded METex14 Cohort: Clinical Implications
Matthew Gubens, MD, MS:
As mentioned above, 2 oral MET TKIs are approved for first-line use in patients with advanced NSCLC harboring METex14 skipping alterations. Amivantamab-vmjw does appear to have some activity even after progression on a prior MET TKI, although at a lower PFS and response rate than observed in the first-line setting or in patients who did not receive a prior MET inhibitor. Dr Yu, do you think this is promising for possible future use?
Helena Yu, MD:
The efficacy of amivantamab-vmjw in the treatment-naive setting was comparable to what we see with first-line capmatinib or tepotinib, but considering their more favorable toxicity profile and ease of oral administration, I would continue to use those as first-line treatment. I was most intrigued to see some response following treatment with an oral MET TKI, and that is the population with whom I really would want to dig deeper. Is there a biomarker that could potentially select for patients who would benefit from that sequencing?
Matthew Gubens, MD, MS:
That would be great.
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