Papillon trial, a major advance in the management of patients with metastatic, mutated-EGFR exon 20 insertion non-small-cell lung cancer

The individualization of the molecular anomalies in patients with metastatic non-small-cell lung cancers (NSCLCs) and adapted therapies targeting those anomalies have led to remarkable progress over the past few years (1). However, not all patients with molecular anomalies have benefited from those advances to the same extent. For those with a so-called common activating mutation in the epidermal growth factor receptor (EGFR) gene, essentially in exon 19 and L858R, which represent 80% of those known, first- and second-generation tyrosine kinase inhibitors (TKIs) and even more specific third-generation TKIs have been developed (2). These third-generation TKIs achieve prolonged disease control for a non-negligible proportion of such patients. More recently, combining—as of first-line therapy—third-generation TKI with either platinum-based chemotherapy or anti-EGFR antibodies improved these patients’ prognoses, by adapting initial therapy to their clinical and biological profiles (2). This progress has also benefited patients with less frequent anomalies, like v-RAF murine sarcoma viral oncogene homolog B (BRAF)^V600E mutation, anaplastic lymphoma kinase (ALK) and rearranged-during-transfection (RET) translocations and, to a lesser extent, proto-oncogene tyrosine-protein kinase (ROS) translocations for which TKIs, with good efficacy and satisfactory tolerance, are available (3).

Unfortunately, advances in epidemiological knowledge and therapeutic management for other patient subgroups have been slower. That is the case for patients harboring an EGFR exon 20 mutation insertion (henceforth EGFRex20ins), the most frequent of the rare EGFR mutations. Its incidence was about 0.5% in large series of non-squamous NSCLCs and is almost never found in patients with squamous-cell cancers or large-cell neuroendocrine carcinomas (4).

Women, Asians and non-smokers are overrepresented among patients carrying the EGFRex20ins mutation, as for those with classical activating EGFR mutations. Its prognosis is poorer than that for those with classical activating EGFR mutations, with median survival ranging from 16.2 to 24 months and a 5-year overall survival (OS) rate at 8% (4-7). First-line therapy for patients with good Eastern Cooperative Oncology Group performance status has until recently relied on platinum-based chemotherapy. However, that regimen has only modest efficacy, with median progression-free survival (PFS) ranging from de 3.4 to 6.9 months. Immunotherapy, although not specifically studied prospectively in these patients, does not seem to have obtained convincing results (5-7).

The first therapeutic progress for this population of metastatic NSCLCs harboring EGFRex20ins was made in the phase 1 Chrysalis trial (8,9) that examined amivantamab efficacy. For patients previously treated with at least one line of chemotherapy and almost all exposed to platinum, the objective response rate (ORR) was 40%, with median response duration lasting 11.1 months, based on blinded, independent, central review, and median PFS of 8.3 months and median OS of 22.8 months. Amivantamab is a bispecific antibody targeting EGFR-mesenchymal-epithelial transition factor (MET), that has immune-cell-directing activity with multiple mechanisms of action, as defined in preclinical models. Those mechanisms include inhibition of ligand binding, endocytosis and receptor degradation, and macrophage, monocyte and natural killer-cell engagement via its Fc domain. Collectively, those mechanisms are able to bypass the ligand-site resistance against TKIs in patients with EGFRex20ins NSCLCs, to counter the MET bypass-resistance mechanism and recruit effector-anticancer cells (8).

Those very encouraging results were reinforced by indirect comparisons with real-world patient-management outcomes. Individual patient-data-based adjusted analyses compared Chrysalis trial participants to those with the same prognostic factors from seven European and US real-world sources (10). All the outcomes supported amivantamab over current standard-of-care, with respective ORRs of 36.8% versus 17.0%, and median PFS lasting 6.9 versus 4 months [hazard ratio (HR): 0.55; P<0.0001] and median OS lasting 22.8 versus 12.5 months (HR: 0.47; P<0.0001). Those results must nevertheless be interpreted as a retrospective analysis, with the technical limitations of indirect comparisons.

That brings us to the contribution of the recently published, phase-3 Papillon trial, whose data confirmed amivantamab efficacy in patients with metastatic EGFRex20ins NSCLCs (11). That phase-3, international, randomized trial evaluated amivantamab-chemotherapy-combination efficacy and safety compared to standard platinum-based chemotherapy alone as first-line therapy for metastatic EGFRex20ins NSCLCs. In that trial, 306 patients were equally distributed for the percentages of women, Asians and non-smokers into two arms. Insertion-mutation detection was done locally and confirmed at centralization. Blinded, independent, central review reported median PFS at 11.4 [95% confidence interval (CI): 9.8–13.7] months for the amivantamab-chemotherapy arm and 6.7 (95% CI: 5.6–7.3) months for chemotherapy-alone recipients, with a HR of 0.40 (95% CI: 0.30–0.53; P<0.001); the respective 18-month PFS rates were 31% and 3%. In contrast, at the time of the analysis, with 33% data maturity for mortality endpoints, no significant difference was found between the treatment arms (HR: 0.67, 95% CI: 0.42–1.09; P=0.11). It should be noted that 65 patients crossed-over from chemotherapy to combination therapy as part of the trial, and that amivantamab monotherapy was the first subsequent therapy off-protocol therapy for six additional patients, representing 66% of the chemotherapy-alone recipients whose disease progressed (11).

That observed efficacy gain was accompanied by toxicity characterized by an additive effect of chemotherapy- and amivantamab-linked toxicities. The majority of Papillon trial participants experienced at least one adverse event, primarily neutropenias (59%), paronychia (56%) and rash (54%) in the amivantamab-chemotherapy combination arm and anemia (55%), neutropenias (45%) and nausea (42%) in chemotherapy-alone recipients. The respective, infusion-related reaction rates were 42% for the combination arm and 1% for chemotherapy recipients. The most frequent grade-3-or-higher adverse events were neutropenia (33%), leukopenia (11%) and rash (11%) with the combination, and neutropenia (23%), anemia (12%), and thrombocytopenia (10%) for chemotherapy recipients. Serious adverse events occurred, respectively, in 37% and 31%, leading to treatment interruptions, dose reductions and discontinuations for 69%, 48% and 24% combination-arm patients and 36%, 23% and 10% of chemotherapy recipients. Those results opened the door to this combination therapy in a marketing authorization setting or early-access programs in many countries, especially in Asia, the US and Europe, and constituted a major advancement in improving the management of these patients (11).

Nevertheless, numerous challenges remain.

The first is that all patients managed for metastatic NSCLC have access to molecular testing. Under-prescription of testing persists, as shown by the SEER study in the US (12). Among 28,511 NSCLC patients analyzed, only 39.3% had benefited from diagnostic molecular testing, with particularly marked access disparities linked to race and place of residence. It is even more important that the same study confirmed that the risk of death was significantly lower for tested patients. Beyond access, management organization should also enable test results to be obtained in time compatible with starting first-line therapy. Rapid EGFR-mutation detection tests are usually not able to identify EGFRex20ins, for which the reference is next-generation sequencing (NGS) that requires more time to yield test results. A study on the large American Flatiron database (13) revealed that the median time between diagnosis and targeted-therapy onset for patients with EGFR-mutated NSCLCs was 1.6 months, with targeted therapy not started for 34% of the patients 3 months after the diagnosis of metastatic disease. Those authors also found a significant impact on survival between patients starting targeted therapy within the month following diagnosis versus the others.

The second challenge is managing toxicities. Clearly, toxicity was increased with the amivantamab-chemotherapy combination compared to chemotherapy alone, especially infusion-site reactions, skin reactions and digestive disorders. Intravenous amivantamab-infusion-related reactions can be considerably limited with adapted premedication, as shown by the results of the phase-2, SKIPPirr trial (14). Prophylaxis with oral dexamethasone (8 mg, bid) on the 2 days preceding chemotherapy and 1 hour before amivantamab infusion (5 doses total) resulted in an ~3-fold incidence-rate-ratio reduction (from 67.4% to 22.5%) compared with standard management. In addition, the availability in the months to come of a subcutaneous injection formulation should also improve injection tolerance and patients’ therapeutic pathways. Moreover, skin toxicities can be avoided with a proactive and multidisciplinary approach (15).

The third challenge is managing patients with brain metastases for whom little is known about amivantamab efficacy. Indeed, the phase-3 Papillon trial only included asymptomatic patients with treated brain metastases and not taking corticosteroids.

In the Chrysalis study (16), 38 (33.3%) of the 114 patients had brain metastases at study entry; for 13 (11.4%), those metastases were sole site of disease progression, and eight of them had had brain metastases at inclusion. The median time to progression for patients with only brain metastases was 4.5 months versus 5.5 months for those with systemic progression; six of the 13 patients with intracranial-only progression underwent stereotactic radiosurgery (SRS), while continuing on amivantamab. Adverse events temporally associated with SRS were nausea and fatigue. For these six patients, the median time on amivantamab after progression was 4.0 months. Those results indicate that SRS treatment of brain metastases while pursuing amivantamab would be feasible and tolerable (16).

Lastly, EGFRex20ins-NSCLC patients are a very heterogeneous population (17). Most often, they have 3–21 base-pair in-frame insertions or duplications (dup) between amino acid (AA)761 and AA775. While EGFRex20ins is also located in the TK domain, it presents unique challenges for targeted-drug development because of its distinctive “αC-in” constitutive conformation and its significantly larger ATP-binding pocket, thereby creating substantial steric hindrance. Structurally, EGFR exon 20 spans AA762–823, encoding the TK domain, and contains the regulatory αC helix (AA762–766) and adjacent loop (AA767–774). Based on the insertion site and the AA sequence, this insertion mutation can be further divided into three categories: in the αC helix, in the C-terminal near-loop (767–772) of the αC helix (Ex20ins-NL), and in the far-loop (773–775, Ex20ins-FL). Notably, these different insertion sites have been associated with varying degrees of sensitivity to EGFR TKIs. Better understanding of these subgroups should enable—in the future—better selection of patients who will benefit the most from amivantamab (17).

Finally, 16.6% to 37.9% of the patients, respectively, harbor a concomitant TP53 and an EGFR amplification. The impact of these co-mutations on amivantamab efficacy has not yet been clearly established.

Comprehensive genomic analyses showed frequent co-mutations of TP53 and H773dup and A767_V769dup, and RB1 and with H773_V774insAH, suggesting that tumorigenesis drivers of different EGFRex20ins-mutation subtypes may reflect distinct genomic backgrounds. The other factor that should also be considered is programmed death ligand-1 (PD-L1) expression. NSCLCs harboring EGFRex20ins are most frequently (~75% of the tumors) PD-L1-negative, with a low tumor-mutation burden. In these patients, elevated PD-L1 percentages could be an indicator of poor response to amivantamab (18,19).

In conclusion, the amivantamab-chemotherapy combination is a new standard-of-care to manage patients with metastatic EGFRex20ins NSCLCs. However, that said, it imposes having the molecular mutation results at the onset of first-line therapy, and mastering proactive and multidisciplinary management of toxicities, especially skin reactions with this combination. In the future, better knowledge of the mutation subgroups, the role(s) of co-mutations and PD-L1 expression should enable improved selection of patients most likely to benefit the most from this combination therapy. The cost-effectiveness ratio should also be taken into account before the dissemination of this innovation (20).

Finally, let us emphasize that new innovative therapies will very quickly complete the field of therapeutic possibilities (21).

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Chinese Clinical Oncology. The article has undergone external peer review.

Peer Review File: Available at https://cco.amegroups.com/article/view/10.21037/cco-24-100/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://cco.amegroups.com/article/view/10.21037/cco-24-100/coif). C.C. declares having received grants, travel expenses, consulting fees from AZ, BI, GSK, Roche, Sanofi Aventis, BMS, MSD, Lilly, Novartis, Pfizer, Takeda, Bayer, Janssen and Amgen. Jean-Baptiste Assié declares having received fees from AZ, MSD and BMS. Jean-Bernard Auliac declares having received fees from AZ, BI, Sanofi Aventis, BMS, MSD, Lilly, Takeda, and Janssen. The authors have no other conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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