As new findings emerge in the lung cancer treatment paradigm, innovative strategies have resulted in impressive central nervous system activity and encouraging responses with acceptable tolerability.
Benjamin P. Levy, MD
As new findings emerge in the lung cancer treatment paradigm, innovative strategies have resulted in impressive central nervous system (CNS) activity and encouraging responses with acceptable tolerability. Additionally, novel bispecific antibodies and antibody-drug conjugates are showing early practice-changing potential.
In a special OncLive® video program, The Board, several experts met to examine important data that read out during the 2020 ESMO Virtual Congress. Benjamin P. Levy, MD, clinical director of medical oncology and associate professor of oncology at the Johns Hopkins Sidney Kimmel Cancer Center at Sibley Memorial Hospital, led the dynamic discussion, which featured insights from the following panelists:
As part of the conversation, the panel reviewed some of the promising findings on emerging agents presented during the meeting and shared how they might apply that information to their own clinical practice.
The third-generation EGFR TKI osimertinib (Tagrisso) was found to result in an 82% reduction in the risk of CNS death or progression (hazard ratio [HR], 0.18; 95% CI, 0.10-0.33; P <.0001) in patients with early-stage EGFR-mutated non–small cell lung cancer (NSCLC) after complete tumor resection, according to an analysis from the phase 3 ADAURA trial (NCT02511106).1
The double-blind, phase 3 trial enrolled a total of 682 patients aged 18 years or older with a World Health Organization performance status of 0-1, a confirmed primary nonsquamous NSCLC EGFR exon 19 deletions and exon L858R mutations, and who had complete resection with negative margins. Patients were randomized 1:1 to receive either osimertinib at a once-daily dose of 80 mg or once-daily placebo.
The primary end point of the trial was DFS per investigator assessment, and the secondary end points comprised DFS in the overall population; DFS at 2, 3, 4, and 5 years; overall survival, safety, and health-related quality of life.
Earlier findings from the trial showed that the median disease-free survival (DFS) with adjuvant osimertinib had not yet been reached versus 19.6 months with placebo (HR, 0.17; 95% CI, 0.12-0.23; P <.0001) in patients with stage IB/II/IIIA EGFR-mutated disease.2 In the overall study population, the median DFS had not yet been reached with osimertinib versus 27.5 months with placebo (HR, 0.20; 95% CI, 0.15-0.27; P <.0001). These data resulted in the December 2020 FDA approval of adjuvant osimertinib for select patients with EGFR-mutated NSCLC.
“We know that osimertinib is active in the brain, right? We shouldn’t reinvent this paradigm that was used in advanced disease,” said Peter. “Knowing all that, the DFS and this HR we’ve never seen in [our experience as] thoracic oncologists, plus the [benefit] in the brain, is it sufficient [enough] to convince the community to use it before longer follow-up [data are available]? I would say without a doubt.”
Scagliotti agreed that the ability of this approach to delay brain metastases is clinically relevant, but still stressed the need for more mature data.
Osimertinib is now under investigation with or without chemotherapy compared with chemotherapy alone as neoadjuvant therapy in patients with EGFR-positive NSCLC in the phase 3 NeoADAURA trial (NCT04351555).3 “That is something that is reassuring us,” said Scagliotti. “We believe that the neoadjuvant study, obviously having a lot of correlative science behind it, is something that should be done pretty early.”
The combination of the EGFR/MET bispecific antibody amivantamab (JNJ-61186372; JNJ-6372) and lazertinibwas found to elicit high response rates with favorable tolerability in treatment-naïve patients with advanced EGFR-mutated NSCLC who were resistant to osimertinib, according to data from the phase 1 CHRYSALIS trial (NCT02609776) presented during the meeting.4
At a median follow-up of 7 months in treatment-naïve patients, the objective response rate (ORR) and the clinical benefit rate (CBR) was 100% (95% CI, 83%-100%), comprised of 20 partial responses. In osimertinib-resistant, chemotherapy-naïve patient, the combination elicited an ORR of 36% (95% CI, 22%-51%) at a median follow-up of 4 months; this consisted of 1 complete response (CR), 15 PRs, and 1 pending confirmation of PR. A 60% CBR was observed in this subset (95% CI, 44%-74%).
The phase 1 trial enrolled a total of 26 patients with metastatic/unresectable NSCLC and EGFR exon 19 deletions or L858R mutations were enrolled to the dose-escalation portion of the trial. Here, patients first received a weight-dependent dose of intravenous amivantamab (700 mg, < 80 kg; 1050 mg, ≥ 80 kg) every week for 4 weeks and every 2 weeks thereafter plus 240 mg of oral, once-daily lazertinib. Patients were then escalated to 1050 mg (< 80 kg) and 1400 mg (≥ 80 kg) of amivantamab. The recommended phase 2 dose was determined to be 1050/1400 mg of amivantamab and 240 mg of lazertinib.
The expansion cohorts comprised patients with osimertinib-resistant, chemotherapy-naïve, EGFR-mutated NSCLC (n = 45) and treatment-naïve, EGFR-mutated NSCLC (n = 20).
“Median follow-up was pretty short here, at 7 months, but patients appeared to continue to benefit with the therapy,” said Lisberg. “Basically, the phase 1 trial really showed that this combination of these therapies is well tolerated and has nice efficacy, both in the frontline setting, as well as in the resistant setting.”
These findings led to the launch of a phase 3 MARIPOSA trial (NCT04487080), which will compare amivantamab/lazertinib head-to-head with osimertinib or lazertinib alone in patients with EGFR-mutated locally advanced or metastatic NSCLC with either treatment-naïve or advanced disease.5
“It’s not that we’ve never seen responses in that range before at this early point in development, and those were encouraging,” Wakelee noted. “But is it really better than other EGFR/EGFR combinations? I don’t know. How much are we adding with the MET inhibitor?”
Carbone and Scagliotti interjected to mention that a key limiting factor with the approach is the fact that it must be delivered intravenously. For the frontline setting, it would be a choice between 1 pill versus another pill plus an IV infusion given every 2 weeks, on top of additional toxicity, said Scagliotti, as such, the option may be better suited for the second-line setting.
“I think this is 1 of the drugs I’m must excited about in the resistant setting,” Piotrowska chimed in. “There’s a lot of enthusiasm; it’s really nice to see safety data with amivantamab in combination with a TKI, because I think prior to that, 1 of the challenges had been these patients who had CNS metastases who were controlled on osimertinib. You have to stop the TKI, put them on this monoclonal antibody, and their CNS may progress. Having the combination of a CNS-penetrant TKI together with this will be very clinically important.”
The HER3-directed antibody-drug conjugate (ADC) patritumab deruxtecan (U3-1402), when given at a dose of 5.6 mg/kg, continued to showcase clinically meaningful antitumor activity with an acceptable safety profile in patients with EGFR-mutated NSCLC, according to findings from a phase 1 trial (NCT03260491) revealed during the meeting.6
The ADC elicited a confirmed ORR was 25% (95% CI, 14.4%-38.4%), which was comprised of a 2% CR rate, a 23% PR rate, and a 45% stable disease rate. Sixteen percent of patients experienced progressive disease. The disease control rate reported with patritumab deruxtecan was 70% (95% CI, 55.9%-81.2%). The median time to response was 2.0 months with the ADC and the median duration of response was 6.9 months.
“This was a very highly pretreated patient population; 86% had received osimertinib, 90% had platinum-based chemotherapy, and half of them received immunotherapy,” said Peters. “Half of them had brain metastases, too, so 25% is an interesting signal.”
The dose-escalation portion of the phase 1 study enrolled 12 patients with metastatic/unresectable EGFR-mutated NSCLC who have either progressed on osimertinib or who were T790M negative following progression on erlotinib (Tarceva), gefitinib (Iressa), or afatinib (Gilotrif). These patients received the ADC at a dose of 5.6 mg/kg once every 3 weeks.
The dose-expansion cohort was comprised of patients with metastatic/unresectable EGFR-mutated disease who had received at least 1 EGFR TKI and a least 1 previous platinum-based chemotherapy regimen. The primary objective of the trial was to evaluate antitumor activity with the agent, while secondary objectives included safety and tolerability.
“We just opened the study at Massachusetts General Hospital, and we’ve had a lot of interest,” added Wakelee. “One of the nice things about this is that it’s a drug that seem to have some activity in the resistant setting that not specific to a particular resistance mechanism, which is an area of significant need…Although these are not earth-shattering responses, there is some activity, and I certainly look forward to seeing more data and whether we can find a biomarker that predicts response.”