Bispecific Combination Therapy Leads Paradigm Shift in Advanced NSCLC

As targeted therapy gets more precise, the treatment paradigms shift, particularly for patients with non–small cell lung cancer (NSCLC). This patient population has seen substantial changes in standard of care as more nuance is added to the understanding of how resistance and mutations within the tumor are targeted. This is most pronounced in treating patients with EGFR-mutated NSCLC who can also harbor other resistance mechanisms to treatment.

“If you know a patient has an EGFR mutation, the data clearly show the survival benefit for the addition of an EGFR-directed therapy,” Joshua K. Sabari, MD, thoracic medical oncologist at NYU Langone Health’s Perlmutter Cancer Center in New York, told a panel of oncologists while moderating a Case-Based Roundtable discussion on the case of a patient with EGFR-mutated NSCLC.

This is also in accordance with National Comprehensive Cancer Network (NCCN) guidelines, which recommend testing patients for actionable mutations, including EGFR, ALK, ROS1, BRAF, NTRK1/2/3, METex14 skipping, RET, KRAS, and HER2 (now known as ERBB2).¹ By confirming a patient’s mutation status using next-generation sequencing (NGS) prior to their first-line systemic therapy, the treatment path will become much clearer. In the case of patients with EGFR-mutated NSCLC, there is further nuance when looking at the kind of EGFR mutation their tumor is harboring prior to deciding on first-line therapy.

For example, in patients with NSCLC positive for an EGFR exon 19 or exon 21 L858R mutation, if the mutation was discovered during initiation of first-line systemic therapy, the NCCN recommends continuing the course of treatment along with maintenance therapy, following that with the preferred use of osimertinib (Tagrisso), an EGFR-targeting tyrosine kinase inhibitor (TKI). Osimertinib is also the preferred category 1 recommended therapy if the EGFR mutation is discovered prior to initiation of first-line therapy, alongside osimertinib combined with chemotherapy. The introduction of the bispecific therapy amivantamab-vmjw (Rybrevant) combined with carboplatin and pemetrexed for the patients who progress after osimertinib treatment is also recommended.¹ Amivantamab is also approved for the treatment of patients with EGFR exon 20 insertion– mutated NSCLC and is the immediate category 1 recommendation in this patient population.^1,2

Testing for EGFR-Driven Mutations

During the event he moderated, Sabari discussed the case of a woman aged 72 years who was a never smoker but presented to her primary care physician with a persistent, nonproductive cough and loss of appetite; she also experienced pruritus for 4 months. Her contrast-enhanced chest/abdomen/pelvis CT scan showed a 4.1 × 3.8-cm tumor in the left upper lobe with calcification and left hilar lymphadenopathy, but an MRI scan of her brain was negative for any intracranial activity.

After the patient underwent a transbronchial biopsy, her immuno-histochemistry panel came back negative for ALK and TPK1 mutations but was positive for TTF1 mutation, and an antibody assay came back with a PD-L1 measurement of 25%. Her concurrent tissue- and plasma-based next-generation sequencing (NGS) panel was positive for an EGFR exon 21 L858R mutation, and she was diagnosed with stage IV adenocarcinoma.

“The combination of tissue and plasma testing [is] acceptable [by the NCCN guidelines], in any combination: tissue first, liquid first, or the combination of the 2,” explained Martin Dietrich, MD, PhD, medical oncologist at The US Oncology Network and assistant professor of internal medicine at the University of Central Florida College of Medicine in Orlando, during the live virtual event he moderated. “Which test you use depends on the individual case; sometimes you have a beautiful big core biopsy from the liver and that’ll probably be OK in an asymptomatic patient, but the ideal plan is a fast and comprehensive tissue testing approach in the beginning.”

Testing patients for EGFR-driven mutations becomes vital, as EGFR mutation subtypes have different responses to therapy and are seen in 10% to 15% of NSCLC cases in White patients and up to 50% in East Asian patients.³ According to a literature review, about 1% to 2% of all NSCLC cases are EGFR exon 20 insertion mutations, and among cases of EGFR-positive NSCLC this mutation subtype makes up about 4% to 10% of all observed mutations in NSCLC.³

Knowing which mutation is present in the tumor becomes vital, as patients with EGFR-mutated tumors will generally have a low response to immune checkpoint inhibitors (ICIs), but not every subtype has the same outcome.⁴ For instance, in an analysis of outcomes with ICIs across 4 institutions in this patient population, patients with EGFR L858R and EGFR exon 19 deletions had better outcomes if they received 0 to 2 prior lines of therapy, especially so for patients with EGFR exon 19 deletions.⁴ However, when compared with patients with EGFR wild-type mutations (n = 212), those with EGFR exon 19 deletions (n = 76) had a significantly lower overall response rate of 7% vs 22%, respectively (P = .002). Further, progression-free survival (PFS) was significantly reduced for patients with EGFR exon 19 deletions compared with wild-type mutations (HR, 0.45; 95% CI, 0.412-0.811; P < .001) and in patients with EGFR L858R–positive disease (HR, 0.58; 95% CI, 0.41-.81; P = .001).⁴

“I’m seeing a lot of patients get chemotherapy and immunotherapy just carte blanche without having any NGS testing results, and that’s problematic,” Sabari said. “So, just like in the stage IV setting, we need to be thinking about doing broad-panel NGS as soon as we can.”

Starting Therapy

After discussing the testing result of the case, both moderators presented a polling question to the participants at their separate events: What are you most likely to offer this patient as first-line therapy, assuming that a clinical trial is not available? Eighty percent of the respondents chose single-agent osimertinib, with 20% choosing osimertinib plus carboplatin and pemetrexed chemotherapy. In another Case-Based Roundtable event focusing on the same patient case, led by Dietrich, participants had the same responses as the group Sabari led, with the majority choosing single-agent osimertinib and the rest looking to combine it with chemotherapy (Polls).

Initially approved in 2018 for patients with metastatic NSCLC whose tumors have EGFR exon 19 deletions or exon 21 L858R substitution mutations, osimertinib has also been approved in combination with chemotherapy for these patients.^5,6 Rationale for the use of osimertinib with chemotherapy in the first line for this patient population came from the results of the phase 3 FLAURA2 trial (NCT04035486), which randomly assigned 557 patients 1:1 to either 80 mg of osimertinib as a single agent or 80 mg of osimertinib alongside carboplatin or cisplatin.

The study met its primary end point of investigator-assessed PFS favoring osimertinib in combination with chemotherapy compared with single-agent osimertinib at a median of 25.5 months (95% CI, 24.7-not calculable [NC]) vs 16.7 months (95% CI, 14.1-21.3), respectively (HR, 0.62; 95% CI, 0.49-0.79; P < .001).⁷ This PFS benefit with osimertinib plus chemotherapy continued in patients with central nervous metastases at baseline with a median PFS of 24.9 months (95% CI, 22.0-NC) compared with 13.8 months (95% CI, 11.0-16.7) in the single-agent arm (HR, 0.47; 95% CI, 0.33-0.66).⁷

“The reason why I would continue osimertinib is that I would tell patients it was still working in 90% of their tumor cells, but also [important] for the intracranial activity,” Sabari said when explaining his rationale for previously continuing the use of the TKI. “But now we’re seeing that there are other therapeutics available that have unique mechanisms of action…. A lot of us were continuing osimertinib plus chemotherapy with the absence of any real data, until recently.”

Patients with EGFR exon 20–driven mutations in their tumor will have de novo resistance to EGFR TKIs, because of resistance to the binding mechanism.⁸ The development of targeted therapy against EGFR exon 20–driven mutations has brought new options to the forefront and more considerations for physicians. Further, it allows for options if patients progress on osimertinib to the use of amivantamab.

Bispecific Antibodies in NSCLC

Bispecific antibodies in solid tumors are separate from bispecific T-cell engagers and are constructs that recognize 2 antigens, allowing for multiple targets.⁹ According to Dietrich, amivantamab is the first bispecific antibody in solid tumor oncology and is double-blocking 2 oncogenic receptors that are important to EGFR signaling, including c-MET. Dietrich explained that c-MET is a major resistance factor to targeting EGFR mutations and that amivantamab’s construction allows it to better induce tumor cell lysis.

“I have patients who have an amplification of 50 MET copies, and those are patients who derive a lot of benefit from medicines like amivantamab, the EGFR and MET antibody,” Sabari said in his event. “It’s really a complex and exciting time for different resistance mechanisms, different mutations, but there have been no prospective data looking at…single-gene resistance mechanisms and approval of therapies. It’s mostly been broader in its development.”

In several studies, amivantamab has demonstrated its efficacy in this patient population. In the phase 3 MARIPOSA trial (NCT04487080), the combination of amivantamab and the third-generation EGFR TKI lazertinib (Leclaza) showed an efficacy benefit over single-agent osimertinib for patients with advanced NSCLC.¹⁰ Patients were randomly assigned 2:2:1 to either amivantamab plus lazertinib (n = 429), osimertinib (n = 429), or single-agent lazertinib (n = 216). At a median follow-up of 22.0 months, the median PFS with the combination regimen was 23.7 months (95% CI, 19.1-27.7) compared with 16.6 months (95% CI, 14.8-18.5) in the osimertinib arm (HR, 0.70; 95% CI, 0.58-0.85; P < .001).⁹

This PFS benefit with amivantamab and lazertinib was extended to patients with a history of brain metastases at a median of 18.3 months (95% CI, 16.6-23.7) compared with 13.0 months (95% CI, 12.2-16.4) for patients on osimertinib (HR, 0.69; 95% CI, 0.53-0.92).⁹ An exploratory end point on the study—extracranial PFS, defined as the time from random assignment to disease progression as detected by extracranial scans, or death—favored the combination regimen. Patients on amivantamab plus lazertinib had a median extracranial PFS of 27.5 months (95% CI, 22.1-not estimable) compared with 18.5 months (95% CI, 16.5-20.3) for patients on osimertinib (HR, 0.68; 95% CI, 0.56-0.83; P < .001).⁹ “This came up as a question in the clinical trial, and the observation is interesting that the patients who receive the large bispecific molecule seem to have benefit across the board in the brain metastatic patient population,” Dietrich explained.

This continued in the intracranial PFS in the phase 3 MARIPOSA-2 (NCT04988295) study that saw researchers assess the use of amivantamab alongside chemotherapy, similar to TKI and chemotherapy approaches in the front line, and found amivantamab to be more beneficial.¹¹ In the amivantamab and chemotherapy cohort, the median intracranial PFS was 12.5 months compared with 8.3 months for patients on chemotherapy alone (HR, 0.55; 95% CI, 0.38-0.79; P = .001). Further, the median intracranial PFS in the amivantamab, lazertinib, and chemotherapy arm was 12.8 months vs 8.3 months with chemotherapy only (HR, 0.58; 95% CI, 0.44-0.78; P < .001).¹¹

Further research has also led to the use of amivantamab and chemotherapy being considered a standard of care in the frontline setting for patients with EGFR exon 20 insertion–mutated advanced NSCLC. In the phase 3 PAPILLON trial (NCT04538664), patients were randomly assigned 1:1 to either platinum chemotherapy alone (n = 155) or amivantamab with platinum chemotherapy (n = 153).¹² PFS was significantly longer in the amivantamab and chemotherapy arm at a median of 11.4 months (95% CI, 9.8-13.7) compared with 6.7 months (95% CI, 5.6-7.3) in the chemotherapy arm (HR, 0.40; 95% CI, 0.30-0.53; P < .001).12 Responses also favored the combination regimen, which led to its approval,¹ and also exhibited a faster response (Table¹²).

When presented with these data, most physicians in Sabari’s and Dietrich’s groups chose amivantamab in combination with chemotherapy for patients who progress after osimertinib. In Sabari’s group, 75% elected to go with the combination regimen, compared with 50% in Dietrich’s group, showing the shifting change toward the use of the bispecific therapy in solid tumor oncology.

REFERENCES:

1. NCCN. Clinical Practice Guidelines in Oncology. Lung cancer, version 4.2024. Accessed April 18, 2024. https://tinyurl.com/2x5sukut

2. FDA approves amivantamab-vmjw for EGFR exon 20 insertion-mutated non-small cell lung cancer indications. FDA. March 1, 2024. Accessed April 18, 2024. https://tinyurl.com/3stckmx8

3. Hastings K, Yu HA, Wei W, et al. EGFR mutation subtypes and response to immune checkpoint blockade treatment in non-small-cell lung cancer. Ann Oncol. 2019;30(8):1311-1320. doi:10.1093/annonc/mdz141

4. Low JL, Lim SM, Lee JB, Cho BC, Soo RA. Advances in the management of non-small-cell lung cancer harbouring EGFR exon 20 insertion mutations. Ther Adv Med Oncol. 2023;15:17588359221146131. doi:10.1177/17588359221146131

5. FDA approves osimertinib for first-line treatment of metastatic NSCLC with most common EGFR mutations. FDA. Updated April 19, 2018. Accessed April 18, 2024. https://tinyurl.com/26n6p27y

6. FDA approves osimertinib with chemotherapy for EGFR-mutated non-small cell lung cancer. FDA. Updated February 20, 2024. Accessed April 18, 2024. https://tinyurl.com/ymju8yk2

7. Planchard D, Jänne PA, Cheng Y, et al; FLAURA2 Investigators. Osimertinib with or without chemotherapy in EGFR-mutated advanced NSCLC. N Engl J Med. 2023;389(21):1935-1948. doi:10.1056/NEJMoa2306434

8. Hastings K, Yu HA, Wei W, et al. EGFR mutation subtypes and response to immune checkpoint blockade treatment in non-small-cell lung cancer. Ann Oncol. 2019;30(8):1311-1320. doi:10.1093/annonc/mdz141

9. Carlisle J. The promises and challenges of bispecific antibodies in lung cancer. ASCO Daily News. November 2, 2022. Accessed April 18, 2024. https://tinyurl.com/4mvr4sfh

10. Cho BC, Felip E, Spira AI, et al. LBA14 Amivantamab plus lazertinib vs osimertinib as first-line treatment in patients with EGFR-mutated, advanced non-small cell lung cancer (NSCLC): primary results from MARIPOSA, a phase III, global, randomized, controlled trial. Ann Oncol. 2023;34(2):S1306. doi:10.1016/j.annonc.2023.10.062

11. Passaro A, Wang J, Wang Y, et al; MARIPOSA-2 Investigators. Amivantamab plus chemotherapy with and without lazertinib in EGFR-mutant advanced NSCLC after disease progression on osimertinib: primary results from the phase III MARIPOSA-2 study. Ann Oncol. 2024;35(1):77-90. doi:10.1016/j.annonc.2023.10.117

12. Zhou C, Tang KJ, Cho BC, et al; PAPILLON Investigators. Amivantamab plus chemotherapy in NSCLC with EGFR exon 20 Insertions. N Engl J Med. 2023;389(22):2039-2051. doi:10.1056/NEJMoa2306441