During a Targeted Oncology™ Case-Based Roundtable™ event, Joshua K. Sabari, MD, discussed research supporting the use of amivantamab for patients with non–small cell lung cancer and an EGFR exon 20 insertion, including data comparing with real-world cohorts of similar patients treated with other agents.
Targeted OncologyTM: How did investigators study amivantamab-vmjw (Rybrevant) in patients with non–small cell lung cancer (NSCLC) in the phase 1 CHRYSALIS clinical trial (NCT02609776)?
JOSHUA K. SABARI, MD: In the phase 1 CHRYSALIS study, we studied all patients with EGFR mutations [in their disease] and we dose escalated from 140 mg to 1750 mg.1 The recommended phase 2 does is now 1050 mg for those patients weighing less than 80 kg. This drug was initially developed in South Korea, then when we brought the drug to the US we realized…we had to give a 1400 mg dose for those patients weighing greater than or equal to 80 kg.2 In cohort D we looked at patients with EGFR exon 20 insertion mutations who had prior platinum therapy.
The baseline characteristics of these patients [included a] heavily Asian patient population. Particularly in the efficacy population, [it was approximately] 49%.1 If we look at the smoking history, [it was] 53% nonsmoker, so [nearly] half of patients were active or former smokers. The median lines of [prior] therapy was 2, but there were patients with 6 or 7 lines of therapy on this initial expansion cohort.
What was the efficacy and safety for amivantamab in this cohort of the trial?
The objective response rate [ORR] by blinded independent review committee was 40%.1 The investigator-assessed ORR was 36%, so it was slightly higher when centrally reviewed. The disease control rate was 74%. It’s important to note that the median duration of response was quite good, 11.1 months, with a PFS [progression-free survival] of 8.3 months, and a median overall survival [OS] of 22.8 months at the time of presentation.
[When looking at] the safety profile of amivantamab, the most important thing to note is the [rate of] infusion-related reactions. About 65% to 70% of patients have a classic infusion-related reaction on cycle 1, day 1. It presents as flushing of the skin and redness. If the medicine is not stopped in time, or discontinued, or reduced, patients have chest pain, nausea, emesis, and even significant respiratory sequalae. It’s important to educate patients about this and to monitor them closely. The infusion reaction typically occurs between 35 and 45 minutes [after treatment . We do premedicate patients [and they] receive steroids, antipyretics, and they also receive medications that can prevent nausea and emesis.
Early on we noticed that when we split the dose, we were able to give a very low-test dose on cycle 1, day 1. In a patient getting 1050 mg, we give them 350 mg on cycle 1, day 1. If someone has an infusion reaction 35 to 40 minutes in, I personally stop the medication. They come back in the following day, cycle 1, day 2 and get the remainder of that 700 mg. The rate of the infusion-related reaction on day 2 is around 1% or less. We also do see some rash with this medicine, but if you look at grade 3 or greater [toxicity], it’s about 4%, so [it’s] very low; paronychia of grade 3 or greater was 1%. Because this…does inhibit MET as well as EGFR, we do see some hypoalbuminemia, low albumin and grade 3 or greater clinically significant in 3% of the patient population.
How does amivantamab compare with patients in the same setting who were treated with other agents?
[When looking at] real-world data of amivantamab vs what we see with EGFR exon 20 insertion mutations, data from CHRYSALIS [were] compared with cohorts from 6 US and European real-world datasets.3 Some of the limitations are that this is not a head-to-head study; it’s a real-world comparison. There are no safety data included in this analysis, and the efficacy end points in our analysis are not included in the label of amivantamab. When you look at some of the real-world cohorts, the data we saw in CHRYSALIS are relatively similar. A lot of patients are heavily pretreated of 2, 3, and even 4 plus lines of therapy. In the European set cohort, [when] adjusted, 30% or so had 3 or more lines which is similar to what we saw in the CHRYSALIS cohort D. It was common to see brain metastasis in this patient population. Twenty-five percent had brain metastases; all had treated brain metastases. In the real-world dataset, you see for the unadjusted 37.8% and for the adjusted, 25.5%. Age was very similar, and gender was very similar across both of these cohorts.
When you look at the amivantamab vs real-world data in the sense of what prior treatments they received, [19%] of patients have received prior immunotherapy. Patients received prior EGFR-TKI [tyrosine kinase inhibitor], and we know a lot of the first, second, and third generation EGFR-TKIs are ineffective in this patient population. Patients received non–platinum-based chemotherapy and VEGF inhibitor plus chemotherapy, 18% [in the European cohort] and 14% in [the US cohort]. All these patients in the frontline received platinum doublet with and without immunotherapy.
When you look at the OS analysis of the amivantamab group, this is the group treated in cohort D that we just [discussed] versus this real-world group, these are matched controlled patients with EGFR exon 20 [insertion] treated around the same timeframe. The median OS is almost double for amivantamab versus the real-world comparator. This is not 2 trials comparing 2 agents. This is comparing with real-world data. How do patients with EGFR exon 20 insertion mutations do? Clearly amivantamab has a significant improvement and the HR in the adjusted population was 0.47. When you look at the investigator-assessed PFS, PFS for amivantamab was 3 months better than the adjusted real-world cohort.
Time to next treatment is something we commonly use in a real-world dataset. When you look at time to next therapy, those patients who were treated with amivantamab had median time to next treatment of 12.4 months as opposed to the group in the real world, about 5 months on average in the unadjusted and adjusted group population.
How does mobocertinib (Exkivity) compare with amivantamab when it comes to adverse events (AEs)?
The major difference between these agents is the common AEs. Clearly, for amivantamab, it’s infusion-related reactions and rash.2 You [may] see paronychia, discomfort, nausea, fatigue. This is all in relation to the infusion-related reaction. Other AEs are relatively rare and the EGFR-mediated AEs are relatively rare. For mobocertinib, you more commonly are seeing diarrhea, rash, stomatitis.5 These are EGFR-mediated toxicities.
Both drugs do have some warnings and precautions. Amivantamab has the infusion-related reactions up front.2 There is a slight risk for interstitial lung disease [ILD] and pneumonitis. There is some issue of ocular toxicity, although very rare. For mobocertinib, the label does include a QTc [corrected QT interval] prolongation cardiac toxicity warning.5 We have also seen ILD pneumonitis, as well as severe diarrhea that could lead to electrolyte disturbances if you’re not managing patients appropriately and aggressively.
When you have shared decision making with your patient, it’s important to counsel the patient on all the positives as well as the negatives of both of these agents. For the GI and rash toxicities for mobocertinib, think about upfront topicals, dermatology referral, maybe GI prophylaxis. For amivantamab, the education on what to expect cycle 1, day 1 and the premedication is going to be critical.
1. Park K, Haura EB, Leighl NB, et al. Amivantamab in EGFR exon 20 insertion-mutated non-small-cell lung cancer progressing on platinum chemotherapy: initial results from the CHRYSALIS phase I study. J Clin Oncol. 2021;39(30):3391-3402. doi:10.1200/JCO.21.00662
2. Rybrevant. Prescribing information. Janssen; 2021. Accessed April 24, 2023. https://bit.ly/40yLRwa
3. Chouaid C, Bosquet L, Girard N, et al. An adjusted treatment comparison comparing amivantamab versus real-world clinical practice in Europe and the United States for patients with advanced non-small cell lung cancer with activating epidermal growth factor receptor exon 20 insertion mutations. Adv Ther. 2023;40(3):1187-1203. doi:10.1007/s12325-022-02408-7
4. Zhou C, Ramalingam SS, Kim TM, et al. Treatment outcomes and safety of mobocertinib in platinum-pretreated patients with EGFR exon 20 insertion-positive metastatic non-small cell lung cancer: a phase 1/2 open-label nonrandomized clinical trial. JAMA Oncol. 2021;7(12):e214761. doi:10.1001/jamaoncol.2021.4761
5. Exkivity. Prescribing information. Takeda Pharmaceuticals; 2021. Accessed April 24, 2023. https://bit.ly/3HadLrw