【WCLC】Broken cocoon and turned into a butterfly and reborn | Amivantamab combined with Lazertinib in the first-line treatment of patients with EGFR-sensitive mutation PFS may exceed 28 months!

The treatment of non-small cell lung cancer (NSCLC) has achieved a leap from traditional therapy to targeted therapy, and the treatment of advanced epidermal growth factor receptor mutation-positive (EGFRm+) NSCLC has presented a situation of "three generations in the same family"

Osimertinib is one of the standard regimens for the initial treatment of EGFR-sensitive mutant NSCLC.

The CHRYSALIS study is a Phase I & Phase IB study to explore the efficacy and safety of the EGFR/c-MET dual-target specific antibody Amivantamab alone or in combination with the third-generation EGFR TKI Lazertinib in the treatment of NSCLC

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Research methods

This analysis included treatment-naïve NSCLC patients with EGFR exon19del and L858R mutations in cohort E of the CHRYSALIS study who received the combination regimen of Amivantamab + Lazertinib

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Research result

The 20 patients enrolled were all Asian, and 11 and 9 had EGFR ex19del and L858R mutations, respectively

With the extension of follow-up time, as of June 2022, the median follow-up time of patients is 28 months, and the mDOR and mPFS have not yet been reached, indicating that Amivantamab combined with Lazertinib is used for the first-line treatment of EGFR-sensitive mutated NSCLC, and the mDOR and mPFS will exceed 28 month!

The safety profile of the Amivantamab+Lazertinib regimen was consistent with previous reports, and no new safety events were observed

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Analysis conclusion

After a median follow-up of 28 months, the mDOR and mPFS of the treatment-naïve patients treated with the Amivantamab+Lazertinib regimen have not yet been reached, suggesting that the mDOR and mPFS may exceed 28 months

Lazertinib is a third-generation EGFR TKI that can penetrate the blood-brain barrier with high selectivity against EGFR-sensitive mutations and T790M mutations

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Research result

As of January 2021, 43 patients with NSCLC were followed up for a median of 28.

In a safety analysis, the most common TRAEs included rash (53.
5% for any-grade AEs), diarrhea (46.
5%; 7% for grade ≥3 AEs), and pruritus (46.
5%)
.

Analysis conclusion

In this phase I/II study, patients with EGFR mutations who received lazertinib 240 mg/day first-line treatment could achieve PFS over 2 years, showing very excellent anti-tumor efficacy, and the patient's safety was good
.

Currently, the phase III randomized multicenter study LASER 301 of lazertinib for first-line treatment is also ongoing
.

As an extremely important therapeutic target for advanced NSCLC, EGFR has always been the focus of clinical research
.

It is our pursuit to seek more efficient and safer new treatment options, including trying combination therapy or developing a new generation of TKIs
.

The above two studies have respectively explored a promising new combination regimen or a new third-generation EGFR TKI in the first-line treatment of patients with EGFR mutations, which is expected to further break through existing treatment strategies and further optimize the therapeutic efficacy of patients with EGFR mutations
.

It is particularly worth mentioning that this small sample I/II study shows that lazertinib single-agent first-line treatment can achieve more than 2 years of PFS, and mDOR of 23.
5 months, which is also close to 2 years
.

In terms of safety, the incidence of diarrhea above grade 3 with lazertinib first-line treatment was only 7%, no rash and itching above grade 3, and no treatment-related cardiac adverse reactions were reported.
In progress, the protocol blocks the MET pathway while blocking the EGFR pathway extracellularly and intracellularly
.

And then achieve three-point blockade, prolong the occurrence time of drug resistance mutation
.

Such a three-point blocking mechanism has also been confirmed in clinical studies.
At present, after 28 months of follow-up, mPFS has not yet been reached, and the results of future research are very worth looking forward to
.

Overall, we expect more and more novel and superior treatments to emerge that will bring more durable survival benefits to patients with EGFR mutations
.

Platinum-based chemotherapy is the current standard of care for osimertinib in advanced NSCLC after progression
.

Data from a real-world study released at this conference showed that 167 patients with sensitive EGFR mutations received first-line osimertinib therapy, 44% of patients received platinum-based chemotherapy after progression, and 20% of patients received osimertinib combined with other The regimen continued treatment, and the mPFS of the overall later-line treatment was only 3.
4 months
.

Once again, it shows that there is a large unmet clinical need for late-line treatment of osimertinib resistance in patients with EGFR mutations
.

【Oral MA07.
04】Amivantamab+Lazertinib combination regimen targeting EGFR and c-MET pathways combined with chemotherapy effectively overcomes osimertinib resistance with controllable safety⁴

From the CHRYSALIS cohort E data results, the combination of Amivantamab and Lazertinib is expected to bring more clinical benefits to patients with osimertinib resistance
.

And studies have shown that chemotherapy-mediated tumor cell apoptosis, releasing antigens to recruit more Fc-bearing immune cells, can enhance the immune cell-mediated toxicity of Amivantamab, so chemotherapy and Amivantamab have a synergistic effect in mechanism
.

The researchers hypothesized that the combination of Amivantamab + Lazertinib + platinum-containing chemotherapy in patients with EGFR TKI resistance is expected to further improve the efficacy of patients
.

This time, a preliminary analysis on the safety of the four-drug combination was conducted
.

Research design

The CHRYSALIS-2 LACP cohort (treatment regimens: lazertinib, amivantamab plus carboplatin, and pemetrexed) enrolled patients with previously treated EGFR-mutant NSCLC (up to 3 lines of therapy) with an EGFR TKI as the last line of therapy
.

Patients who received at least one efficacy evaluation after receiving study drug treatment were included in the efficacy analysis population
.

Research result

The median number of lines of treatment for enrolled patients was 2 (range: 1-3), including osimertinib (n=14), gefitinib (n=3), and afatinib (n=3)
.

To date, the median follow-up time was 7.
1 months (2.
4–10.
4)
.

Results of the efficacy assessment showed an ORR of 50% (95% CI, 27–73) and a CBR of 80% (95% CI, 56–94)
.

For patients with brain metastases at baseline (n=10), ORR was 50% (95% CI, 19–81) and CBR was 80% (95% CI, 44–98)
.

Seventy-five percent of patients remain on treatment, and the median duration of response, progression-free survival, and overall survival cannot currently be estimated
.

Of the 14 patients who progressed after osimertinib treatment, 5 were assessed as PR, 6 as SD, 2 as PD, and 1 did not participate in the assessment
.

Most AE responses were grade 1-2
.

AEs related to EGFR and MET inhibition were consistent with previously reported AE data for the amivantamab + lazertinib combination regimen, neutropenia was consistent with previously reported AE data for platinum-based chemotherapy, and no new safety signals were identified
.

The most common AEs during treatment included infusion-related reactions (73.
3%), neutropenia (66.
7%), rash (46.
7%), thrombocytopenia (40.
0%), fatigue (33.
3%), and nausea (33.
3%)
.

All infusion-related reactions (IRRs) were grade 1-2, and no treatment interruptions due to IRR occurred
.

Of the 5 patients who discontinued treatment, 2 were due to chemotherapy-related serious adverse events and 3 were due to disease progression
.

Analysis conclusion

Amivantamab and lazertinib combined chemotherapy regimen for EGFR TKI-resistant patients showed very high efficacy
.

In terms of safety, the toxic and side effects of the combination regimen were similar to those of each drug used alone, and no new safety events and cumulative toxicity were observed
.

At present, a large-scale phase III study MARIPOSA-2, which is exploring the combination of Amivantamab + Lazertinib + platinum-containing chemotherapy in the late-line treatment of osimertinib resistance, is ongoing
.

At this stage, platinum-containing chemotherapy has become the mainstream clinical treatment mode for patients who are resistant to osimertinib treatment
.

Genetic studies of osimertinib-resistant patients have found that MET amplification is an important pathway mediating osimertinib resistance.
By targeting both EGFR and MET pathway inhibition, it is expected to overcome osimertinib resistance
.

In the CHRYSALIS-2 study, cohort A explored Amivantamab combined with Lazertinib, that is, a macromolecule monoclonal antibody combined with TKI to overcome osimertinib resistance.
Previously published research data showed a better response rate and durable efficacy advantages
.

The LACP cohort reported at this conference is based on the treatment mode of Amivantamab combined with Lazertinib, combined with platinum-containing chemotherapy, which is expected to provide more effective treatment strategies for drug-resistant patients
.

It is worth mentioning that this combination regimen achieved a very high effective rate in osimertinib-resistant patients, with an ORR of 50%
.

This response rate is currently the highest in the unselected population after osimertinib progression
.

Although it was a four-drug combination regimen, no new safety events were observed
.

We believe that the exploration of different combination regimens can provide more treatment options for osimertinib-resistant patients.
We can choose the most appropriate treatment strategy for the patients based on their physical status after drug resistance and the mutation pattern of drug-resistant genes.

.

【Poster EP 08.
02-137】Ametinib for EGFR-mutant NSCLC intolerant to osimertinib therapy⁵

The Phase II and Phase III study data of the third-generation EGFR TKI ametinib showed that it can achieve good efficacy and safety in advanced NSCLC with sensitive EGFR mutations
.

In addition, a comparison of relevant study data found that the adverse reactions of almetinib and osimertinib were different, manifested in a numerically lower incidence of interstitial pneumonitis, cardiotoxicity, and hematologic toxicity
.

The aim of this study was to evaluate the efficacy and safety of almetinib in patients who could not tolerate toxicity after osimertinib treatment
.

Therefore, the study used the success rate of dressing change as the primary endpoint
.

Research design

This is a prospective, multicenter, single-arm clinical study of 40 patients with EGFR-mutant advanced NSCLC who experienced grade ≥2 hematologic toxicity or grade ≥3 other adverse events after receiving osimertinib
.

Patients started treatment with almetinib 110 mg/day after prior toxicity had decreased to ≤Grade 1 until discontinuation after disease progression, or when ≥Grade 2 hematologic toxicity or ≥Grade 3 other adverse events
.

All AEs were assessed using the Common Terminology Criteria for Adverse Event Assessment, 4th edition (CTCAE), with the primary endpoint being the 3-month switch success rate, defined as the absence of grade ≥ 2 within 3 months of switching to almetinib.
Proportion of patients with hematologic toxicity or other toxicity of grade ≥3
.

Secondary endpoints included PFS, ORR, OS, DOR, DCR and depth of tumor response (DepOR)
.

Currently, this research is still ongoing
.

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1.
 Amivantamab and Lazertinib in Treatment-Naive EGFR-Mutant Non-Small Cell Lung Cancer (NSCLC).
 2022 WCLC, P1.
16-01.

2.
 Lazertinib as a Frontline Treatment in Patients with EGFR Mutant Advanced Non-Small Cell Lung Cancer: Results from the Phase I/II Trial.
 2022 WCLC, EP08.
02-025.

3.
 Treatment Patterns and Outcomes Among Patients With EGFR-mutant Advanced NSCLC in the Frontline and Post-Osimertinib Settings.
2022 WCLC, EP08.
02-173.

4.
Amivantamab and Lazertinib in Combination With Platinum-Based Chemotherapy in Relapsed/Refractory EGFR-mutant NSCLC.
2022 WCLC, MA07.
04.

5.
Prospective Study of Aumolertinib in NSCLC Patients with EGFR Sensitive Mutations Who Are Intolerant to Osimertinib Treatment.
2022 WCLC, EP08.
02-137.

CRC code: MED-ONC-CN-3135

Approved Date 2022-08-08

Reviewer: Professor Lu Shun

Typography: Youshi

Execution: Traveller