CME
Physicians: Maximum of 1.25 AMA PRA Category 1 Credits™
Released: November 18, 2021
Expiration: November 17, 2022
Thomas E. Stinchcombe, MD:
EGFR ex20ins mutations are found in approximately 2% of NSCLC cases and are associated with a poor response and poor survival outcomes with first-, second-, and third-generation EGFR TKIs, so there is a strong need for new therapies for this patient population. Two drugs, amivantamab and mobocertinib, have recently been approved for patients with advanced/metastatic NSCLC with an EGFR ex20ins mutation and disease progression on or after platinum-based chemotherapy, so this mutation is quickly becoming targetable.29,30
In this setting, we will first talk about an analysis of 2 phase I trial of a new selective, irreversible EGFR/HER2 inhibitor, DZD9008.31 These trials were international phase I dose-escalation/dose-expansion studies. Patients with previously treated advanced NSCLC with an EGFR or HER2 ex20ins mutation were enrolled in dose-escalation cohorts from 50 mg to 400 mg daily. Subsequent dose expansion cohorts received DZD9008 200 mg, 300 mg, or 400 mg daily. This trial is ongoing, with the safety data set including 102 patients and the efficacy data set including 56 patients. Primary objectives are safety and tolerability, and secondary objectives are pharmacokinetics and preliminary antitumor activity, including ORR, duration of response (DoR), disease control rate, and PFS.
Thomas E. Stinchcombe, MD:
The baseline characteristics of the study population reflect what we would expect for this patient population. The median age was approximately 59 years, and a little more than one half of the patients were women. Forty‑six percent of patients in the study had received prior EGFR TKI therapy, including approximately 3% that received prior poziotinib and 1% that had mobocertinib. Looking at the other prior therapies, approximately one third of patients had received a PD‑1/PD-L1 inhibitor and approximately 5% had prior amivantamab. Approximately 40% of patients had brain metastases at baseline.
Thomas E. Stinchcombe, MD:
Safety was evaluated in all patients, and you can see there was a relatively small number of patients in the 50-mg and 100-mg cohorts and a larger number in the 200-mg, 300-mg, and 400-mg cohorts.
The safety profile of DZD9008 is similar to other EGFR TKIs, with low-grade diarrhea and rash. When we look at the grade 3 toxicity, as expected there is a somewhat linear relationship with more toxicity at the higher doses. At the 400-mg dose, the rate of grade 3 treatment-related AEs is approximately 70%. Looking at the AEs leading to dose reductions and dose interruptions, which are a rough estimate of the patients’ tolerance of the therapy, we see that a high percentage of patients required dose reductions or interruptions at the 400-mg dose, a more moderate number at the 300-mg dose, and just one patient receiving the 200-mg dose needed a dose interruption.
Thomas E. Stinchcombe, MD:
Looking at preliminary efficacy, I want to focus on the confirmed ORR, because I think that’s probably the best metric. Although recognizing that each cohort has only a small number of patients, DZD9008 begins to show antitumor activity at the 100-mg daily dose, with higher response rates at the 200-mg and 300-mg dose levels. The confirmed ORR is 44.7% in the expansion cohorts, which received the 200-mg dose and higher. With a more detailed look, doses ≥100 mg showed activity across all the EGFR ex20ins mutation subtypes, regardless of the presence of brain metastases at baseline, and in patients who had received prior amivantamab. Median DoR and PFS have not been reached, which just reflects that the data are relatively immature, since this study is still ongoing.
Thomas E. Stinchcombe, MD:
This slide gives a more detailed look at the response rates by presence of brain metastases at baseline and by type of EGFR ex20ins mutation. The ex20ins mutations were grouped into those in the near loop and those in the far loop, and DZD9008 was active in both groups with similar response rates. I think this is reassuring that the drug will be broadly active in patients with most EGFR ex20ins mutations.
Thomas E. Stinchcombe, MD:
These data are very preliminary. I’m really intrigued that there might be another agent for this subset of patients who have EGFR ex20ins mutations. As we get more data, we’ll have a better idea of the activity of DZD9008 after previous EGFR TKI therapy in tumors with specific mutations, but this agent looks very promising at this point.
Thomas E. Stinchcombe, MD:
In September, the oral EGFR TKI mobocertinib received accelerated FDA approval for patients with locally advanced or metastatic NSCLC with an EGFR ex20ins mutation after progression on platinum-based chemotherapy.30 This approval was based on a promising response rate demonstrated in an ongoing phase I/II trial, which includes several phase II dose expansion cohorts.32,33
At WCLC 2021, Spira and colleagues34 reported results from cohort 5, which enrolled 20 patients with an EGFR ex20ins mutation who had response or stable disease for at least 6 months on a prior EGFR TKI. The phase II primary endpoint is ORR by RECIST v1.1 criteria, and secondary endpoints include ORR by independent review, best overall response, DoR, time to response, survival, and safety and tolerability.
Thomas E. Stinchcombe, MD:
Looking at the patient demographics for this cohort, I want to focus on prior therapies. Of the 20 patients, 80% had received prior platinum-based chemotherapy and 65% had prior immunotherapy. Based on the cohort criteria, all had received a prior TKI, with 65% receiving prior poziotinib, 20% each osimertinib and afatinib, 10% erlotinib, and 1 patient received an investigational TKI. The median time on the prior TKI was approximately 8 months. Investigator‑assessed response rate on the prior TKI was 54% with poziotinib and 50% with osimertinib.
Thomas E. Stinchcombe, MD:
With a median follow-up of 14.2 months, the investigator‑assessed response rate was 20% (95% CI: 5.7-43.7) in these patients who had response or stable disease for at least 6 months on a prior EGFR TKI, with response rates relatively similar across the different prior therapies. These response rates are rather modest, but the median DoR of 13 months is really encouraging, suggesting that the patients who do respond to mobocertinib really get a clinically significant benefit.
Thomas E. Stinchcombe, MD:
This waterfall plot includes a lot of different information. The letters above each bar, AEIOP, represent each patient’s prior EGFR TKI therapies, and the coloration represents the different EGFR ex20ins mutations. You can also see the best change in target lesion size, as well as whether the patient had a partial response or stable disease. With just 20 patients it’s hard to be definitive, but we can see responses to mobocertinib across multiple EGFR ex20ins mutations as well as different prior EGFR TKIs.
Thomas E. Stinchcombe, MD:
The median PFS with mobocertinib in this small cohort of patients who had response or stable disease for at least 6 months on a prior EGFR TKI was 7.3 months and median OS was not yet reached.
Thomas E. Stinchcombe, MD:
One half of patients experienced grade ≥3 treatment-emergent AEs with mobocertinib, but the types of any‑grade treatment-related AEs, shown in the right column, are all consistent with prior data on EGFR‑related toxicities with mobocertinib. Diarrhea was the most common treatment-related AE; it was grade ≥3 in just 1 patient.
Thomas E. Stinchcombe, MD:
As multiple agents become available for our patients with advanced EGFR ex20ins–positive NSCLC, an inevitable question is, how should we sequence them? Do any of them have activity after prior EGFR exon 20 targeted therapy?
This cohort analysis provides preliminary data that mobocertinib does have some activity after prior EGFR exon 20–targeting agents and that some patients can get durable clinical benefit. I think the next step will be to expand to a larger number of patients, possibly with a more homogeneous population in terms of the exposure to prior therapies.
Anne Chiang, MD, PhD:
Amivantamab is an EGFR-MET bispecific antibody that is FDA-approved for patients with advanced NSCLC with EGFR ex20ins mutations and progression on or after platinum-based chemotherapy. This approval was based on initial results from the CHRYSALIS phase I study, which reported an ORR of 40% and a median response duration of 11.1 months with amivantamab in 81 patients with advanced NSCLC and EGFR ex20ins mutations.35
In the current analysis of CHRYSALIS, Spira and colleagues36 evaluated the activity and safety of amivantamab in patients with primary MET exon 14 skipping mutations.
Anne Chiang, MD, PhD:
Patients in this study had received a median of 2 prior lines of treatment, and 42% had already received a targeted MET inhibitor. Only 4 patients (21%) were treatment naive.
Anne Chiang, MD, PhD:
Regarding AEs, grade 1/2 rash and infusion reactions were reported in most patients who were treated with amivantamab. Grade 3 or higher AEs occurred in 3 patients: 1 event each of dyspnea, hypoalbuminemia, and rash. Peripheral edema has been noted before with amivantamab, but in this small cohort of patients with MET exon 14 skipping mutations, there were no cases of grade ≥3 peripheral edema.
Anne Chiang, MD, PhD:
Amivantamab treatment was associated with a partial response rate of 64% in this patient cohort with MET exon 14 mutation–positive advanced NSCLC, with responses being observed in both treatment‑naive and previously treated patients, including in those previously treated with MET TKIs.
Anne Chiang, MD, PhD:
Responses with amivantamab appeared durable, with the median DoR not yet reached and 8 of 9 responding patients with ongoing responses and 11 of 14 response-evaluable patients remaining on treatment at the time of this analysis.
Anne Chiang, MD, PhD:
These data show that amivantamab has antitumor activity in patients with MET exon 14 skipping mutation–positive NSCLC, including in treatment-naive patients and those previously treated with MET TKIs. Patients also appear to be remaining on treatment, which along with the safety data, suggests that amivantamab is fairly well tolerated. Given this early promising evidence, I look forward to seeing more data in this setting. Enrollment onto this cohort is ongoing.
Anne Chiang, MD, PhD:
NTRK fusions have been detected in a wide range of tumor types, and occur in 0.1% to 1.0% of NSCLC.37,38 There are 2 TRK inhibitors, larotrectinib and entrectinib, approved for the treatment of patients with solid tumors that have an NTRK gene fusion without a known acquired resistance mutation, are metastatic or where surgical resection is likely to result in severe morbidity, and have progressed on standard therapy and are without other satisfactory alternative treatments.39,40
At WCLC 2021, Drilon and colleagues41 provided an update on the efficacy and safety of larotrectinib administered at 100 mg twice daily in 20 patients with TRK fusion-positive lung cancers enrolled on a phase I and a phase II trial.
Anne Chiang, MD, PhD:
In this updated analysis, larotrectinib was associated with an ORR of 87% in patients with advanced NSCLC overall and 88% in the subset of patients with CNS metastases.
Anne Chiang, MD, PhD:
The median DoR was not reached in the 13 responding patients in the overall population, with 64% of responses being maintained at 12 months. The 12-month PFS and OS rates were 62% and 86%, respectively.
Anne Chiang, MD, PhD:
Among patients with CNS metastases, the median DoR was 8.2 months in the 7 responding patients, with 21% of responses being maintained at 12 months. The 12-month PFS and OS rates were 18% and 71%, respectively.
Anne Chiang, MD, PhD:
Overall, larotrectinib is a well-tolerated drug; treatment-emergent AEs were primarily grade 1/2 with 2 dose reductions and no treatment discontinuations among the 20 patients evaluated.
Anne Chiang, MD, PhD:
In this updated analysis with longer follow-up, larotrectinib appears to have very good activity in patients with TRK fusion–positive lung cancer, including in patients with brain metastases. Patients seem to have been able to remain on treatment and it appears to be a well-tolerated therapy. Even though NTRK fusions are rare in advanced NSCLC, these results reinforce the importance of NTRK testing in our patients with newly diagnosed advanced NSCLC.
Thomas E. Stinchcombe, MD:
As we’ve advanced molecular testing into NSCLC, one challenge we have is making sure all patients get tested and results are obtained in a timely manner. Historically, the paradigm has been first to perform a tissue biopsy then to order molecular tests and assess PD‑L1 expression. The patient schedules an appointment with the medical oncologist, but their test results may or may not be available at that appointment—which can delay care and be a source of patient dissatisfaction.
This study by Thompson and colleagues42 enrolled patients with suspected stage IIIB and stage IV NSCLC based on imaging, who were undergoing an interventional biopsy with either pulmonology or interventional radiology and who didn’t have any evidence of concurrent malignancies. Molecular testing was performed at the time of the biopsy. Patients also underwent plasma genotyping using a next-generation sequencing (NGS) panel of 74 genes, after which their medical oncology appointment was scheduled. The primary endpoint of the trial was time to first‑line therapy compared with a retrospective cohort.
This was a small, single-center study that showed the number of oncogenic mutations was similar between cohorts, so we were not missing molecular alterations by this site selection. Of course, the turnaround time for the plasma testing was much shorter than for the tissue testing, 8 days vs 22 days, and a significantly higher number of patients in the NGS cohort had test results available at the time of the first medical oncology visit. When the plasma testing was done at the time of the biopsy, 85% of patients had their NGS results available at their first oncology appointment vs 9% of those who had tissue testing. I see this as a way to expedite the patient’s care and help reduce the anxiety that can be associated with waiting for test results which are needed to make a treatment decision.
I think this is a very innovative study. Obviously, it will have to be replicated in a larger, multicenter design, but I think this approach could be a good way to accelerate molecular testing, improve compliance with guidelines for testing, improve patient satisfaction, and make sure that every patient gets tested.
Anne Chiang, MD, PhD:
I agree that this study was interesting, and of course will need to be validated, but my concern is that it was a single-institution approach in a setting that involves multidisciplinary care, and so its results may not be applicable to community sites that don’t have access to interventional pulmonologists to order the studies.
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