A New Era in Lung Cancer: Targeting the Protein’s Shape, Not the EGFR Mutation
In this article
A Response That Reaches the Brain: What Firmonertinib Offers Patients with Rare PACC Mutations
For many years, EGFR mutations in lung cancer were classified by a single question: "Which exon?" Yet mutations in the same gene can change the three-dimensional shape of the protein in very different ways, and that shape determines how well drugs work. We have previously discussed why the location of a mutation and its effect on the protein matter. Now a concrete clinical example of this approach was published in Cancer Cell on October 16, 2026: in the FURTHER study, firmonertinib produced encouraging responses in rare EGFR mutations known as "PACC," including in disease that had spread to the brain.
- What was found: In a 60-patient study of advanced non-small cell lung cancer (NSCLC) with PACC mutations, first-line firmonertinib at 240 mg daily achieved an objective response rate of 68% and a median progression-free survival (PFS) of 16.0 months. At 160 mg daily, these figures were 43% and 11.1 months.
- Brain metastases: Among 17 patients with brain metastases at baseline, brain tumors shrank in 47% and disappeared completely in 41%.
- Caution: This is a small Phase 1b study without a control group. In October 2026, the same drug failed to meet its primary endpoint in the Phase 3 FURVENT trial in patients with EGFR exon 20 insertions. Firmonertinib is not approved in the US or in Turkey.
- In practice: The options currently used for PACC-mutant disease are afatinib and osimertinib. Until results arrive from the Phase 3 ALPACCA trial, which compares firmonertinib with these drugs, firmonertinib should be considered only within a clinical trial.
Why does this matter?
EGFR mutations are among the most important treatment targets in non-small cell lung cancer. They are found in about 15% of patients in Western countries and 30–40% in Asia, and they are more common in people who have never smoked. In recent years, a large share of the approvals that have changed lung cancer treatment have come in this area. Most of these patients carry one of two so-called "classical" mutations (exon 19 deletion and L858R), and drugs developed against them have substantially extended survival.
However, about one third of patients with EGFR-mutant disease have other mutations, described as "atypical" or "uncommon," and these patients do not benefit as much from the classical drugs. The difficulty is that these uncommon mutations do not form a single group: each affects the protein differently. A study published in Nature in 2021 sorted EGFR mutations into four groups based not on their location but on their effect on the protein's structure, and showed that this classification predicts drug sensitivity better than classification by exon. PACC is one of these groups and accounts for about 12% of EGFR-mutant lung cancers. Detecting these mutations requires a comprehensive next-generation sequencing (NGS) test; tests that look only for classical mutations can miss them.
No. But it is one of the first large studies designed specifically for the PACC group:
- Afatinib (2018): In the US, its label was expanded to include uncommon EGFR mutations such as G719X, S768I and L861Q. This approval was based on pooled data from several studies.
- Osimertinib: Supported in uncommon mutations by small, single-arm Phase 2 studies, and frequently chosen because of its good brain penetration.
- Firmonertinib (2026): A Phase 1b study directly targeting the PACC group and comparing two doses, followed now by the Phase 3 ALPACCA trial comparing it with afatinib or osimertinib. It is not yet approved for this indication in any country. Similarly, targeted options are also expanding rapidly in rare HER2-mutant lung cancer.
What is an EGFR PACC mutation?
PACC (P-loop and αC-helix compressing) refers to a group of uncommon mutations that change the shape of the EGFR protein by compressing regions called the "P-loop" and the "αC-helix." The most common examples are G719X, S768I and E709X. They account for about 12% of EGFR-mutant lung cancers, have a high tendency to spread to the brain, and respond less well to classical EGFR drugs.
Four structure-based EGFR groups
| Group | Examples | Effect on the protein | Drugs with greatest sensitivity in the lab |
|---|---|---|---|
| Classical-like | Exon 19 deletion, L858R | Minimal change to the drug-binding pocket | All EGFR drugs, especially third-generation (osimertinib) |
| T790M-like | Mutations including T790M | Change within the drug-binding pocket | Third-generation drugs (some) |
| Exon 20 insertion | Short sequences inserted into exon 20 | Lengthens the loop following the αC-helix | Variable; specific drugs such as amivantamab |
| PACC | G719X, S768I, E709X, G724S | Compresses the P-loop and αC-helix | Second-generation drugs (afatinib); firmonertinib under investigation |
This table is a general framework based on laboratory and retrospective patient data. A single patient may have more than one mutation; in about half of the PACC patients in the FURTHER study, the PACC mutation occurred together with another EGFR mutation (a compound mutation).
What did the FURTHER study find?
| Feature | Details |
|---|---|
| Design | International, open-label Phase 1b study (FURMO-002); 40 centers in 10 countries. In the PACC cohort, patients were randomized 1:1 to two doses. |
| Patients | 60 patients with PACC-mutant advanced non-small cell lung cancer who had not previously received an EGFR drug (160 mg: 31, 240 mg: 29); about three quarters had received no prior treatment for advanced disease |
| Drug | Firmonertinib, taken orally once daily, 160 mg or 240 mg |
| Assessment | Responses by blinded independent central review; median follow-up 16.5 months |
| Publication | Le X et al., Cancer Cell, October 16, 2026; funded by ArriVent, the company developing the drug |
In patients with no prior treatment for advanced disease, the 240 mg dose was clearly more effective: an objective response rate of 68% versus 43%, a median duration of response of 14.6 months, and a median progression-free survival of 16.0 versus 11.1 months. The average maximum tumor shrinkage was 55% with 240 mg and 38% with 160 mg. For these reasons, the 240 mg dose was selected for the Phase 3 trial. However, the study was not powered to compare the two doses statistically.
First-line objective response rates in uncommon EGFR mutations
Percent. Colored bars: firmonertinib (FURTHER, PACC); gray bars: broader uncommon-mutation groups in other studies.
Afatinib data are from a pooled analysis of LUX-Lung 2, 3 and 6 (38 patients); osimertinib data are from the KCSG-LU15-09 Phase 2 study (36 patients). These groups also include non-PACC mutations. Comparisons across different studies are indirect; patient populations, prior treatments and follow-up differ.
Median progression-free survival in uncommon EGFR mutations
Months. Colored bars: firmonertinib (FURTHER, PACC); gray bars: other studies.
In FURTHER, median duration of response with 240 mg was 14.6 months. Overall survival data are not yet available. Comparisons across different studies are indirect; patient populations, prior treatments and follow-up differ.
Response in brain metastases
Brain metastases are common in PACC-mutant lung cancer and are among the problems that most affect quality of life. Firmonertinib can cross the blood-brain barrier. Among 17 patients with brain metastases at baseline, brain tumors shrank in 8 (47%) and disappeared completely in 7 (41%); this is the intracranial response. In this group, median first-line progression-free survival was 14.2 months with 240 mg and 8.4 months with 160 mg. Given complications such as brain edema and spread to the lining of the brain, this is an important finding. Although the numbers are small, a drug that could reduce the need for radiation therapy or corticosteroids for brain metastases matters to these patients.
Tumor DNA in the blood: an early signal of response
Among 25 patients whose PACC mutation was detected in the blood at baseline and could be measured again at week 6, the mutation cleared completely from the blood in 80%. In these patients, the response rate and the duration of response were clearly better. Monitoring circulating tumor DNA (ctDNA) could in the future be used to assess treatment response early and to change treatment if needed; however, this is still at the research stage. The use of liquid biopsy in other cancers is moving in a similar direction.
Clearance of tumor DNA from the blood at week 6 predicts response
Percent, confirmed objective response rate. 25 patients with a PACC mutation detected in the blood at baseline and measurable at week 6.
Median progression-free survival from week 6 onward was 15.1 months with clearance versus 3.0 months without. Numbers are small; this finding is exploratory.
Side effects
| Side effect in the PACC cohort | 160 mg | 240 mg |
|---|---|---|
| Treatment-related side effects of any grade | 90% | 97% |
| Grade 3 or higher treatment-related side effects | 26% | 21% |
| Diarrhea (any grade / grade 3 or higher) | 42% / 6% | 72% / 10% |
| Elevated liver enzymes | 29% | 52% |
| Dose reduction | 19% | 24% |
| Discontinuation due to side effects | 3% | 0% |
The most common side effects were diarrhea, elevated liver enzymes, rash, mouth sores and dry skin. These were the types of side effects expected with EGFR drugs; most were mild and could be managed with dose adjustments. No lung inflammation (pneumonitis) was seen in the PACC cohort. Because diarrhea is common at the 240 mg dose, it is important to keep an antidiarrheal medicine on hand from the start of treatment and to pay attention to fluid intake.
Firmonertinib had also shown encouraging results in Phase 1b studies in patients with EGFR exon 20 insertions. However, in the 398-patient Phase 3 FURVENT trial comparing it with chemotherapy in this group, results announced in October 2026 showed that the primary endpoint, progression-free survival by independent review, was not significantly prolonged (11.0 versus 9.5 months with 240 mg; HR 0.75, p=0.065). This is a reminder that impressive response rates in early-phase studies do not always translate into a clear benefit in Phase 3. The result in the PACC group also needs to be confirmed by the ALPACCA trial. This example also illustrates well why the drug approval process is so long and proceeds in stages.
How is treatment chosen today in EGFR-mutant lung cancer?
Figure 1 · First-line treatment by mutation type in advanced EGFR-mutant lung cancer
Simplified; as of October 2026. The four boxes are separate mutation groups, not sequential lines of treatment.
How should the results be interpreted?
Strengths
- One of the first large prospective studies based on structural classification and designed specifically for the PACC group.
- Two doses were randomized, and responses were measured by blinded independent central review.
- High and durable responses at 240 mg; meaningful responses in brain metastases.
- The strong association between early clearance of tumor DNA from the blood and response is promising for personalizing treatment in the future.
Points of caution
- No control group: A Phase 1b study; there was no direct comparison with afatinib or osimertinib. The comparisons in the charts are indirect and involve different patient groups.
- Small numbers: About 30 patients per dose group, and only 17 patients with brain metastases.
- No overall survival data: Response rate and progression-free survival do not by themselves mean that survival is extended.
- Industry funding: The study was funded by the company developing the drug.
- Side effect burden: Diarrhea and elevated liver enzymes are quite common at the 240 mg dose.
Practical information for patients and physicians
- Comprehensive testing is essential: In advanced non-small cell lung cancer, a comprehensive NGS panel on tissue or blood should be performed whenever possible, rather than tests that look only for classical EGFR mutations. Which structural group the mutation named in the report (for example, G719A, S768I, E709K) belongs to should be reviewed with the oncologist; if needed, a second opinion can be obtained from an experienced center.
- Current options: Afatinib and osimertinib are used for PACC mutations. In patients with brain metastases, choosing a drug with good brain penetration is especially important. Chemotherapy and other options come into play depending on the course of the disease.
- Clinical trials: Today, firmonertinib is available only in clinical trials. The ALPACCA trial is comparing firmonertinib with afatinib or osimertinib in about 480 patients.
- Watch for symptoms: Diarrhea, rash and mouth sores are common with EGFR drugs; new shortness of breath or cough, however, may signal lung inflammation and should be reported to the oncology team right away.
Firmonertinib is not licensed in Turkey, and it has no FDA approval in the US. The drug is approved in China for lung cancer with classical EGFR mutations, but it is not approved for PACC mutations in any country. For this reason, using it for this indication in Turkey through the named-patient import route (via TEB) does not currently appear realistic; the most suitable route is enrollment in an appropriate clinical trial. We were unable to find verified information on whether the ALPACCA trial has sites in Turkey. Afatinib and osimertinib are licensed in Turkey; reimbursement conditions for uncommon mutations should be checked against the current SUT provisions together with the oncologist. You can find other recent developments in lung cancer in our WCLC 2026 summary. You can follow the access status of new drugs in Turkey on our access map.
Frequently asked questions
- What is an EGFR PACC mutation?
- PACC is a group of uncommon mutations that change the shape of the EGFR protein by compressing its P-loop and αC-helix regions. G719X, S768I and E709X are the most common examples. They account for about 12% of EGFR-mutant lung cancers and respond less well to classical EGFR drugs.
- How effective is firmonertinib for PACC mutations?
- In the Phase 1b FURTHER study, first-line firmonertinib at 240 mg daily achieved an objective response rate of 68% and a median progression-free survival of 16 months. Among 17 patients with brain metastases, brain tumors shrank in 47%. However, there was no control group, and the results need to be confirmed in Phase 3.
- Is firmonertinib available in Turkey?
- No. Firmonertinib is not licensed in Turkey, and it has no FDA approval in the US. For patients with PACC mutations, the most suitable route to access today is enrollment in a clinical trial such as ALPACCA, which compares the drug with afatinib or osimertinib.
- Which drugs are used for PACC mutations today?
- Afatinib and osimertinib are the most commonly used today. Afatinib is approved in the US for uncommon mutations such as G719X and S768I. In patients with brain metastases, drugs with good brain penetration may be preferred. The choice should be made together with the oncologist based on the mutation type and the patient's condition.
Glossary
- EGFR
- A protein on the cell surface that transmits growth signals; when mutated, it can drive uncontrolled growth of cancer cells.
- Tyrosine kinase inhibitor (TKI)
- A class of oral targeted drugs that block signaling by proteins such as EGFR.
- PACC mutation
- A group of uncommon mutations that compress the P-loop and αC-helix regions of EGFR, changing the shape of the protein.
- Compound mutation
- The presence of more than one EGFR mutation in the same tumor.
- Intracranial response
- Shrinkage or disappearance of brain metastases with treatment.
- ctDNA
- Fragments of DNA shed from tumor cells into the bloodstream that carry the tumor's mutations.
DROZDOGAN Academy Commentary
FURTHER shows precision oncology moving a step forward: treatment may now be guided not only by "which gene, which exon?" but also by "how does the mutation change the protein?"
⚡ Why it matters
Patients with uncommon EGFR mutations have less effective options than those with classical mutations, and they are at high risk of brain metastases. A study designed specifically for this group on the basis of structural classification represents both scientific and practical progress for these patients.
✅ Strengths
Two randomized doses, blinded independent central review, high and durable responses, meaningful responses in brain metastases, and ctDNA as an early marker of response. It was published in a peer-reviewed journal and has led directly to a Phase 3 trial.
⚠️ Limitations
A small Phase 1b study without a control group; no overall survival data; industry funded. The failure of the same drug to meet its primary endpoint in the Phase 3 trial in exon 20 insertions calls for caution in interpreting early-phase results. The response rate for afatinib in pooled data is also close to that of firmonertinib.
🩺 In practice
Every patient with advanced non-small cell lung cancer should undergo comprehensive molecular testing, and uncommon EGFR mutations should be reported together with their structural group. Patients with PACC mutations can start treatment today with afatinib or osimertinib; eligible patients should be referred to clinical trials. As with all treatment decisions in lung cancer, the presence of brain metastases directly affects the choice. Exercise and rehabilitation also support quality of life during treatment.
❓ Open questions
Does firmonertinib truly extend progression-free survival and overall survival compared with afatinib and osimertinib? Which PACC subtypes and compound mutations benefit most? Can treatment be intensified or changed based on early ctDNA clearance?
Bottom line: Firmonertinib is a promising candidate in PACC-mutant lung cancer, including in brain metastases. The idea of choosing treatment by protein structure is compelling; however, the results of the Phase 3 ALPACCA trial are needed before current standards can change.
- This article was prepared in October 2026.
- Data from the FURTHER study were taken from the abstract of the Cancer Cell publication and from reports by MD Anderson and the oncology press; we were unable to access the full text of the article. Side effect rates refer to the PACC cohort.
- Afatinib and osimertinib data come from different and broader "uncommon mutation" groups and do not correspond exactly to the PACC group. FURVENT results are based on a company announcement and press reports.
- Comparisons between drugs in the charts are indirect. The diagram is derived from the text and contains no new data. The Academy commentary is our own.
References
- Le X, et al. Firmonertinib in advanced non-small cell lung cancer with epidermal growth factor receptor P-loop and αC-helix compressing mutations. Cancer Cell 2026. doi:10.1016/j.ccell.2026.09.011
- MD Anderson Cancer Center. Structurally guided therapy shows promise for patients with specific EGFR-mutated lung cancer in Phase 1b trial (October 16, 2026). mdanderson.org
- OncoDaily. FURTHER: firmonertinib shows promising activity in EGFR PACC-mutant advanced NSCLC (October 17, 2026). oncodaily.com
- OncLive. Firmonertinib demonstrates antitumor activity, CNS responses in EGFR PACC–mutated NSCLC. onclive.com
- CancerNetwork. Firmonertinib misses PFS end point in first-line EGFR exon 20 NSCLC (FURVENT, October 6, 2026). cancernetwork.com
- Robichaux JP, et al. Structure-based classification predicts drug response in EGFR-mutant NSCLC. Nature 2021;597:732–737. doi:10.1038/s41586-021-03898-1
- Yang JC, et al. Clinical activity of afatinib in patients with advanced non-small-cell lung cancer harbouring uncommon EGFR mutations: a combined post-hoc analysis of LUX-Lung 2, 3, and 6. Lancet Oncol 2015;16:830–838. PubMed
- Cho JH, et al. Osimertinib for patients with non-small-cell lung cancer harboring uncommon EGFR mutations: a multicenter, open-label, phase II trial (KCSG-LU15-09). J Clin Oncol 2020;38:488–495. PubMed
- ALPACCA (NCT07185997): Phase 3 trial comparing firmonertinib with afatinib or osimertinib. clinicaltrials.gov
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