Future Directions for NSCLC With PACC Mutations

Panelists discuss how new agents such as amivantamab, sunvozertinib, and zipalertinib are expanding therapeutic possibilities for uncommon 

Panelists discuss how these data may guide sequencing strategies, combining different targeted modalities to overcome resistance and extend patient benefit.

Panelists discuss how emerging non–tyrosine kinase inhibitor approaches—such as antibody-drug conjugates and bispecific antibodies—could further diversify treatment options in the evolving non–small cell lung cancer (NSCLC)landscape.

Videos

Panelists discuss how novel agents and emerging strategies may further optimize sequencing and outcomes for EGFR PACC-mutated NSCLC.

Data From the FURTHER Trial in NSCLC With EGFR PACC Mutations

Panelists discuss how the phase 3 FURTHER trial evaluated firmonertinib in 

 PACC-mutated non–small cell lung cancer (NSCLC), showing encouraging efficacy across subgroups and manageable safety.

Panelists discuss how response rates were particularly strong in more frequent variants like G719X and S768I, as well as in compound mutations and patients with central nervous system involvement.

Panelists discuss how these findings suggest a meaningful improvement over existing standards of care, highlighting firmonertinib’s potential as a preferred option pending broader regulatory approval.

Panelists discuss how the FURTHER trial demonstrated firmonertinib’s efficacy and safety in patients with PACC mutations.

Emerging Data on Firmonertinib for PACC Mutations in NSCLC

Panelists discuss how firmonertinib, a fourth-generation EGFR tyrosine kinase inhibitor, has demonstrated promising properties such as strong central nervous system penetration and broad activity against classical and uncommon EGFR mutations.

Panelists discuss how it is already approved in China for 

-mutated non–small cell lung cancer (NSCLC) and is under global investigation in multiple settings, including first line, second line, and adjuvant therapy.

Panelists discuss how these studies may redefine the treatment landscape by offering a potentially more effective and better-tolerated option for patients with PACC-driven NSCLC.

Panelists discuss how firmonertinib shows promise as a next-generation TKI with broad EGFR activity and favorable tolerability.

Current Treatment Approaches in NSCLC With PACC Mutations

Panelists discuss how existing tyrosine kinase inhibitors (TKIs)—first through third generation—demonstrate limited and variable activity against PACC mutations, reflecting the structural challenges these variants pose.

Panelists discuss how real-world treatment strategies often involve empiric use of later-generation TKIs or chemotherapy, with modest response rates compared to those seen in classical 

 mutations.

Panelists discuss how clinicians must balance efficacy and tolerability while awaiting results from newer agents, emphasizing individualized decisions and the integration of clinical trial opportunities for eligible patients.

Panelists discuss how current TKI therapies offer limited efficacy for PACC mutations, necessitating individualized and trial-based approaches.

EGFR PACC Mutation Identification Strategies in NSCLC

Panelists discuss how comprehensive genomic profiling, including next-generation sequencing (NGS), remains critical for accurately identifying PACC mutations. They note that these variants can be underrecognized due to their rarity and structural complexity, making advanced molecular platforms essential.

Panelists discuss how RNA-based or hybrid-capture sequencing may enhance detection of compound or uncommon mutations, ensuring a complete molecular picture before treatment.

Panelists discuss how consistent communication between oncologists, pathologists, and molecular laboratories improves testing quality and facilitates timely identification, enabling patients to benefit from the most appropriate targeted therapies.

Panelists discuss how advanced genomic profiling techniques are vital for accurate detection of PACC mutations.

EGFR PACC Mutations in NSCLC

Panelists discuss how understanding the classification of 

 mutations—classical-like, T790M-like, P-loop and αC-helix compressing (PACC), and exon20—has reshaped diagnostic and therapeutic strategies in non–small cell lung cancer (NSCLC).They emphasize that PACC mutations represent a distinct molecular group with unique structural effects on the kinase domain, altering tyrosine kinase inhibitor binding and resistance mechanisms.

Panelists discuss how PACC mutations, though relatively uncommon, include variants like G719X, S768I, E709X, and V774M. They note the growing recognition of these alterations in molecular profiling, highlighting their nuanced impact on drug sensitivity and disease progression.

Panelists discuss how this classification framework enables more precise patient stratification, guiding therapy selection and the interpretation of emerging trial data. This approach is seen as a cornerstone for personalized oncology in NSCLC management.

We expand abbreviations in each segment summary because they stand alone once the video segment is clicked on and goes to the separate page.

Panelists discuss how classifying EGFR mutations into molecular subgroups, including PACC, refines diagnosis and informs targeted treatment decisions.

 Patients with cancers driven by BRAF Class II (C II) or C III alterations and/or NRAS mutations are unlikely to benefit from approved BRAF-targeted therapies and have few other treatment options. Exarafenib is a potentially best in class orally available pan-RAF inhibitor optimized for potency & high selectivity. It has differentiated dose-dependent activity across a broad range of cell lines & models driven by BRAF C I (inc. those with acquired resistance to 1st gen RAFi), C II, C III or NRAS alterations.

 KN-8701 (NCT04913285) is an ongoing Phase 1 dose escalation & dose expansion study at 35 sites in 7 countries evaluating exarafenib monotherapy in participants (pts) with advanced solid tumors harboring oncogenic BRAF or NRAS alterations.

Preliminary results as of 13 Dec 2022 are reported for 52 pts (median age 63, 51.9% male) with a median of 3 prior therapies treated in 6 dose levels. Treated pts included those with solid tumors driven by BRAF C I (38.5%), C II (19.2%), C III (28.8%) alterations or melanoma pts with NRAS mutations (13.5%). Steady state exarafenib exposure (Cmax and AUC) increased dose proportionally. Pathway inhibition & decreases in ctDNA were observed across BRAF classes & tumor types. Dose limiting toxicities observed at the highest dose level were Grade 3 (Gr3) acneiform rash & Gr3 macular rash. The maximum tolerated dose (MTD) was determined to be 300 mg bid. Treatment-related adverse events (TRAEs) (any grade) occurred in 69.2% of pts with 13.5% of pts having Gr ≥3 events. Skin AEs (any grade) were the most common TRAEs observed in 48.1% of pts with 7.7% of pts having Gr ≥ 3 skin events. GI TRAEs occurred in 19.2% pts (Gr 1-2 only), including diarrhea (1 pt, Gr 1). Reversible, asymptomatic Gr 3 increased ALT and/or increased AST AEs in 3 pts were the only non-skin Gr ≥ 3 TRAEs reported in ≥ 2 pts. At therapeutically relevant exposures, there was no cutaneous evidence of paradoxical activation. Of the 34 pts across all dose levels with at least 1 post-baseline tumor assessment, 6 pts (17.6%) had a partial response (5 confirmed at submission date) & 16 pts (47.1%) had stable disease including 8 pts (23.5%) with objective tumor shrinkage (up to 20%). The 6 responders all continue exarafenib therapy (treatment duration up to 12 months) and include 3 pts with BRAF C I alteration-driven cancers (inc. 1 RAFi + MEKi pre-treated melanoma pt) and 1 pt each with BRAF C II, BRAF C III-driven & NRAS-mutation driven cancers. For pts who achieved or confirmed their best response at MTD, the response rate was 33% (4/12) & included responses in pts with BRAF C I, C II, C III, and NRAS mutant tumors.

 Exarafenib achieves therapeutically meaningful drug exposures and demonstrates promising tolerability & clinical activity in BRAF or NRAS alteration-driven solid tumors. Pt enrollment & exarafenib treatment at 300 mg bid continues.

Alexander I. Spira, MD, PhD, shares new dose escalation data from the first-in-human Phase 1 KIN-2787 study of the pan-RAF inhibitor exarafenib in patients with BRAF-altered solid tumors or NRAS-mutant melanoma.

A Phase 1 Clinical Trial Evaluating Monotherapy With Exarafenib (KIN-2787), a Highly Selective Pan-RAF Inhibitor, in BRAF‑Altered Solid Tumors and NRAS-Mutant Melanoma

Alexander I. Spira, MD, PhD