At the European Society for Medical Oncology (ESMO) Virtual Congress 2020 , lead study investigator Prof. Byoung Chul Cho (Yonsei Cancer Centre, Yonsei University College of Medicine in Seoul, South Korea) presented the interim findings of the Phase 1 CHRYSALIS study (NCT02609776), which evaluated amivantamab, in combination with lazertinib in patients with non-small cell lung cancer (NSCLC) with either gene epidermal growth factor receptor (EGFR) exon 19 deletions or L858R mutations [1]. Physician’s Weekly interviewed Prof. Cho to discuss the implications of the data which promise new studies to further evaluate the potential of amivantamab and lazertinib combination therapy.
The CHRYSALIS study is an open-label, multicenter study assessing the safety, pharmacokinetics and preliminary efficacy of amivantamab as a monotherapy and in combination with lazertinib in adult patients with advanced NSCLC. Amivantamab is a humanized bispecific antibody that targets epidermal growth factor receptor (EGFR) and mesenchymal epithelial transition factor (MET) mutations. Both MET and EGFR are known genetic drivers of NSCLC tumors, and MET amplification can develop as a resistance mechanism to EGFR inhibitors. Lazertinib is the third-generation EGFR tyrosine kinase inhibitor (TKI). The complementary modes of action between amivantamab and lazertinib underly the rationale of this combination therapy in patients with NSCLC bearing somatic mutation in the EGFR gene. In particular, deletion of exon 19 and the missense mutation L858R collectively account for 85% of all EGFR mutations in NSCLC and are the target of the current study [2].
The primary outcome of the CHRYSALIS study reported at ESMO 2020 was to determine the recommended Phase 2 dose of amivantamab (monotherapy), and to determine the recommended Phase 2 combination dose (RP2CD) (amivantamab with lazertinib combination therapy). Efficacy was assessed using overall response rate (ORR) according to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1), clinical benefit rate, duration of response and the safety profile of amivantamab and lazertinib.
In total, the study enrolled 91 patients with NSCLC harboring either an EGFR exon 19 deletion or L858R mutation, who received the combination of amivantamab and lazertinib. Of these, the first cohort of 26 patients without restriction on prior therapy participated in a dose escalation study, but dose-limiting toxicities were not observed. The RP2CD was the maximally assessed doses of 1050 mg (1400 mg, ≥80 kg intravenously) amivantamab together with 240 mg oral lazertinib, equivalent to the monotherapy doses together. For the 91 treated patients, the 93% of treatment-related adverse events experienced were Grade 1-2. The interim safety profile included rash (78%), infusion related reaction (61%), paronychia (42%), stomatitis (31%), pruritus (24%), and diarrhea (14%).
The second subset of patients in this study was a group of 20 treatment-naïve patients with EGFR-mutated NSCLC, who were enrolled to interrogate the safety, efficacy and tolerability in the first-line setting. The third subset was 45 patients whose disease had relapsed while taking osimertinib, but who had not yet received chemotherapy, trying this drug combination in the second-line setting.
Preliminary efficacy data was highly encouraging. With a median of 7 months follow-up (range 4 – 10), the 20 treatment-naïve patients who received the combination of amivantamab and lazertinib achieved a 100% ORR (95% CI 83-100).
Among the 45 osimertinib-relapsed, chemotherapy-naïve patients, the combination of amivantamab and lazertinib resulted in a 36% ORR (95% CI 22-51), with one complete response and 15 partial responses. The remaining endured stable disease. The clinical benefit rate for these patients was 60% (95% CI 44-74).
Looking forward, the Phase 3 MARIPOSA study (NCT04487080) will assess the amivantamab and lazertinib combination versus osimertinib in previously untreated advanced EGFR-mutated NSCLC. In addition, another Phase 1 trial (NCT04077463) has been initiated to examine the combination in patients who have progressed after treatment with osimertinib and chemotherapy.
Physician’s Weekly called the lead study investigator Prof. Cho to reflect on these results himself:
Early efficacy data
“Despite treatment advancements, lung cancer remains the leading cause of cancer deaths globally, and there are opportunities to improve treatment options for patients with non-small cell lung cancer with genetic factors such as EGFR mutations. CHRYSALIS is a phase 1 study to evaluate safety, tolerability, recommended combination phase 2 dose and efficacy of the combination of lazertinib and amivantamab. The key result of the CHRYSALIS phase 1 study is that we demonstrated a response rate of 36% in patients who had progressed while taking osimertinib, a third generation TKI,” says Dr. Cho. “The other important finding was that we demonstrated a response rate of 100% in treatment-naïve lung cancer. These two findings are really important because, as we all know, after progression on osimertinib, there is virtually no therapeutic option except for cytotoxic chemotherapy. Cytotoxic chemotherapy provides only a medium progression-free survival of 3 to 4 months, and a response rate of less than 20%.”
Besides poor outcomes, Dr. Cho says patients experience significant morbidity on cytotoxic chemotherapy, so this alternate novel approach is most welcome. Although longer follow-up data on these patients in CHRYSALIS are necessary, the response rate appeared rapid and robust, and he hopes those RECIST responses remain durable. “We are encouraged by these results that suggest amivantamab in combination with lazertinib may be a promising option in this specific disease cohort where a high unmet need remains for more targeted treatment options.”
Safety & Post-osimertinib
Dr. Cho and his team tested all patients for tolerability, regardless of prior treatment, the combination was well tolerated. The majority of toxicities was Grade 1 or 2. Expected side effects included skin rash and an itching sensation were most common adverse events, which are related to EGFR inhibition. Infusion-related reactions occurred in about 70% of patients, but only occurred in cycle 1, and were overall very low Grade and manageable.
“One important clinical implication of these data is the potential here in the second-line. Many patients will relapse because of acquired resistance to osimertinib, where the median progression-free survival is 16 to 18 months,” says Dr. Cho. “So with this combination, we hope that lazertinib together with amivantamab will improve progression-free survival not only for patients who face few options post-osimertinib, but eventually extend survival in treatment-naïve NSCLC. The reason why I say this is that lazertinib and amivantamab have complementary modes of action covering several pathways that feed into each other. Combining these two agents may prolong progression-free survival to an EGFR inhibitor by delaying or preventing the emergence of a resistance mechanism in our patients.”
Next steps?
“We just started a global randomized phase 3 study called MARIPOSA in treatment-naïve EGFR mutant advanced-stage lung cancer. The primary endpoint of this study is progression-free survival. We will compare the lazertinib and amivantamab combination with osimertinib in treatment-naïve NCSLC. We still have to wait for that data, but CHRYSALIS results have been very encouraging to pursue this drug combination.”
Sources:
- Cho BC et al. Abstract #1258O. Presented at: European Society for Medical Oncology Virtual Congress 2020; Sept. 19-21, 2020.
- Sharma SV, et al. Epidermal growth factor receptor mutations in lung cancer. Nat Rev Cancer. 2007 Mar;7(3):169-81.
