RET Fusion Lung Cancer: Proactive Strategy -- Beyond Standard Treatment

If you are reading this, it means you have made it through the first few months. You have the diagnosis, you have the treatment, you understand the basics. Selpercatinib is working – the tumor has probably shrunk, you probably feel better than you expected.

And yet, the question that never goes away: how long will it last?

This guide is for you. Not to scare you, but to show you that there are options your oncologist does not always mention – not because they are irrelevant, but because they are new, specialized, and not (yet) part of standard protocols. Your oncologist remains the central piece of your treatment. This guide gives you the tools to have a more informed conversation with them.

If you are just starting out, first read the complete guide for newly diagnosed patients. This article picks up where that one ends.

If you are a physician: this article is designed as a complement to clinical practice – a structured inventory of emerging options for RET+ lung cancer, with references. The goal is to facilitate the physician-patient dialogue, not to replace it.

The problem with “wait and see”

The current standard of care for RET fusion lung cancer looks like this:

1. Diagnose the RET fusion through molecular testing (NGS)
2. Start Selpercatinib (RETSEVMO)
3. Monitor with CT every 2-3 months
4. When the tumor progresses, switch treatment

This protocol works. Selpercatinib offers an 84% response rate as first line, and the median progression-free survival is nearly 25 months. Compared to traditional chemotherapy, that is an enormous difference.

But “median” means half of patients progress before 25 months. Some resistance mechanisms appear early: solvent front mutations (G810) can be detected on ctDNA at just 3-4 months, and MET amplification – the most common bypass mechanism – appears on average at 8 months. Other patients remain stable well past 3 years. Every case is different.

But the strategy remains passive. You wait for the disease to return, then react.

What “standard of care” means and why it matters:

“Standard of care” is the treatment that hospitals and clinics routinely apply. For a new treatment to reach this level, it must go through rigorous clinical trials – Phase 1 (safety), Phase 2 (efficacy), Phase 3 (direct comparison with existing treatment). This process has traditionally taken many years, but the pace is accelerating. Selpercatinib, for example, received accelerated FDA approval just 3 years after the first patient was treated, and programs like “breakthrough therapy” and “expanded access” are constantly shortening the path from discovery to patient.

Nevertheless, many of the options described in this article have not yet gone through all stages – not because they do not work, but because the process, although increasingly faster, requires time and validation across hundreds or thousands of patients. Your oncologist follows validated protocols – and is right to do so. This guide does not contradict their protocol, but shows you what complementary options exist beyond it, with what level of evidence, and how you can discuss them in an informed way.

The fundamental problem remains: at stage IV, nearly every patient will develop resistance at some point. The question is not “if” but “when” – and “what have you prepared for that moment.”

The good news: technology has advanced enough that proactive action is now possible. We are not talking about baseless experimental treatments. We are talking about options with clinical trials, published data, and solid biological rationale – available now or within the next 1-3 years.

The window of opportunity is now, while treatment is working. Your immune system and treatment response are at their best. Once resistance sets in, options narrow.

Advanced molecular profiling – know your enemy

The NGS test that confirmed the RET fusion was just the beginning. There are much deeper layers of molecular information that directly influence what options you have.

Beyond NGS: complete sequencing

Whole Exome Sequencing (WES) analyzes all genes in your tumor, not just a panel of 50-500. Why it matters:

• Identifies co-mutations that influence prognosis (TP53, PIK3CA, KEAP1)
• Finds tumor neoantigens – protein fragments unique to your tumor that the immune system can recognize. They are the basis of personalized vaccines
• Detects DNA repair defects (FANCL, BRCA, ATM) that can open additional therapeutic options, such as PARP inhibitors

RNA-seq goes even further: it shows which genes are actually active in your tumor, not just present. It can confirm the RET fusion partner (KIF5B, CCDC6, etc.) with certainty and detect resistance mechanisms that do not appear at the DNA level.

Specific biomarkers that open trial options

Beyond general sequencing, a few specific biomarkers are worth explicitly testing because they gate access to emerging treatment classes:

• MTAP loss (methylthioadenosine phosphorylase) – A peer-reviewed 2026 study (Aldea et al., Annals of Oncology, March 2026) documented MTAP loss in 18-35% of RET fusion-positive NSCLC patients – a high prevalence that opens eligibility for PRMT5 inhibitors, a new class of targeted therapies currently in phase 2-3 trials. MTAP status is best confirmed by IHC on tumor tissue (not by liquid biopsy, which cannot reliably detect MTAP deletions). If you have a stored FFPE biopsy, MTAP IHC can be added at marginal additional cost.
• RB1 status (tumor suppressor gene) – Relevant for understanding lineage plasticity risk (see the “Resistance mechanisms” section below). Usually reported as part of a standard NGS panel; worth confirming is included.

Ask your oncologist whether these markers are part of the panel already run. If not, they can often be added to the existing tissue sample at marginal additional cost.

Genetic testing: not just the tumor, but also you

Three genetic tests that matter beyond the tumor:

1. Germline (hereditary) testing

The tumor has acquired mutations, but some may be inherited. For example, mutations in the FANCL or BRCA genes may indicate a vulnerability in DNA repair – which opens therapeutic options (PARP inhibitors) and has implications for blood relatives.

2. HLA typing

HLA genes determine which protein fragments your immune system can “see.” They are essential for:

• Eligibility for anti-cancer vaccines (some require specific HLA types)
• Design of personalized vaccines (neoantigens are filtered through your HLA type)
• Immunotherapy planning

A simple blood test, performed once.

3. Pharmacogenomics

How your body metabolizes medications. Selpercatinib is processed by the CYP3A4 and CYP2C8 enzymes. Genetic variants in these enzymes can explain why some patients have more side effects than others at the same dose.

ctDNA – real-time disease monitoring

Imaging (CT, PET-CT) shows what the tumor looked like weeks ago. Circulating tumor DNA (ctDNA) shows what the tumor is doing today.

What is ctDNA

Tumor cells release DNA fragments into the bloodstream. These can be detected through a simple blood draw – no biopsy, no anesthesia. It is called a liquid biopsy.

Why it matters

ctDNA can detect disease progression 3-6 months before it becomes visible on imaging. In practice, this means:

• You detect resistance early, when intervention options are at their maximum
• You can identify the mechanism of resistance (RET mutation, MET amplification, KRAS activation) directly from blood
• You can monitor treatment response without additional radiation
• After local treatment (radiotherapy, cryoablation), undetectable ctDNA is a strong indicator of complete response

Available platforms

There are multiple ctDNA monitoring platforms, with different levels of sensitivity:

Note: Sensitivity is measured in VAF (Variant Allele Frequency) – the minimum percentage of mutant DNA out of total circulating DNA that the test can detect. The smaller the number, the finer the traces of disease the test can pick up.

The difference between fixed panels and personalized monitoring is enormous. A fixed panel like Guardant360 detects known mutations at a relatively high level. A personalized platform (Signatera, NeXT Personal, Haystack) detects traces of disease 100-1000 times smaller – essential for confirming whether the disease has been completely eliminated.

A further distinction matters for patients already on treatment months in: most personalized platforms (Signatera, Haystack) track a fixed set of variants selected from your initial tumor biopsy. If new resistance mutations emerge during treatment, those fixed panels may not see them. NeXT Personal (Personalis) introduced in April 2026 a “Real-Time Variant Tracker” capability that uses hybrid-capture to detect new mutations as they appear during therapy – useful for early detection of emerging resistance. Ask your lab which approach they use and whether emergent-mutation tracking is available.

When to test

Practical access in Romania and the EU

FoundationOne Liquid CDx (Roche/Foundation Medicine) is the most widely used broad-panel liquid biopsy test (300+ genes) and is available in Romania through partner laboratories, including the Regina Maria network and other molecular oncology centers. The test requires only a blood draw and provides results in 2-3 weeks.

Guardant360 CDx is accessible in the EU through partner laboratories in Germany (TherapySelect) or the UK.

Signatera (Natera) – the personalized MRD (minimal residual disease) monitoring platform – has CE-IVD marking and is available in the EU through Oncompass Medicine (Hungary/Switzerland).

Haystack MRD (HPH Hamburg) – the most sensitive platform available in Europe – accepts samples from across the EU.

For personalized platforms (Signatera, Haystack), the first step is sending the tumor NGS result (from biopsy) to the laboratory, which creates a personalized monitoring profile. Afterward, each test requires only a blood draw.

Consolidative local therapy – treat what remains

If treatment is working and you have a small number of residual lesions (1-5 sites), you do not have to wait for progression. You can actively treat what remains, while Selpercatinib controls the rest of the disease.

This concept is called consolidative local therapy (CLT) and has solid evidence from randomized trials.

Why it works

The logic is simple: if 90% of the disease responds to Selpercatinib, but a few lesions have cells that could develop resistance, destroying them now eliminates the source of future problems.

The evidence is strong:

• SINDAS (randomized trial, Phase III): SBRT + TKI vs TKI alone – median survival +8 months (25.5 vs 17.4 months)
• SABR-COMET (8-year follow-up): 21% of patients progression-free at 8 years – a cure signal in 1 out of 5 oligometastatic patients
• LIBRETTO-001 (RET-specific data): Continuing selpercatinib + SBRT at oligoprogression adds +9.8 months of progression-free survival

The optimal window for CLT: months 4-6 from starting treatment, when response is maximal but residual lesions are still visible on imaging.

Local treatment options

SBRT (stereotactic body radiation therapy)

A focused radiation beam destroys the tumor with millimeter precision, in 1-5 sessions. It is the most studied form of CLT.

Advantages:

• Local control >95% at 1 year
• Outpatient, no anesthesia
• Low risk of pneumothorax
• Covered by insurance in many countries

Limitations:

• Cumulative doses limit repeatability
• At standard ablative doses, tumor antigens can be denatured by radiation – systemic immune activation is often modest

Two dosing philosophies:

SBRT can be delivered with two different intents, and the correct choice depends on the clinical objective:

The PEMBRO-RT trial used the immunogenic dose (8 Gy x 3) combined with pembrolizumab and achieved 41.7% abscopal response even in “cold” tumors. But local control of the irradiated lesion is lower than with ablative doses.

In practice, the radiation oncologist may choose an intermediate or ablative dose for the primary lesion (local control priority) and an immunogenic dose for a secondary lesion (immune activation priority). The decision belongs strictly to the radiation oncologist, depending on tumor location, the priority goal for each lesion, and the overall treatment strategy.

Cryoablation – the “in-situ vaccine”

Cryoablation destroys the tumor through repeated freeze/thaw cycles, using a CT-guided probe inserted percutaneously.

What makes it special: Unlike heat or radiation, cryoablation preserves tumor antigens intact – the tumor proteins remain recognizable to the immune system. The result:

• STING pathway activation (immune signaling pathway) without PD-L1 overexpression
• NK cell and CD8+ lymphocyte expansion
• Potential abscopal effect – untreated distant tumors shrink

Clinical evidence:

• BOOSTER (randomized trial): Cryo + immunotherapy vs immunotherapy alone – progression-free survival 26.7 vs 11.7 months (HR 0.213). The strongest clinical effect demonstrated for cryoablation
• ECLIPSE (Gustave Roussy, 5 years): Local control 79.2% at 5 years – the longest follow-up for pulmonary cryoablation in the world
• JVIR 2026 meta-analysis (786 patients): Local control at 1 year 90.5%. For tumors under 2 cm, 3-year control reaches 96-100%
• SOLSTICE (128 patients, 7 centers): Local control after re-cryoablation rises to 91.1% – cryoablation is repeatable without limit, with no cumulative dose

Robotic vs manual cryoablation:

Robotic platforms (Perfint MAXIO, Quantum Epione) offer precision of 1.7-6.1 mm, major complications of only 3%, and over 80% reduction in radiation exposure for the patient. They are available at a few reference centers in Europe, but do not yet have long-term data (the technology is 3-5 years old). Manual CT-guided cryoablation has two decades of experience and proven results.

Limitations:

• Risk of pneumothorax (15-25% for tumors under 2 cm; 75% resolve spontaneously)
• Does not produce tumor tissue for analysis – cryoablation destroys in-situ. If you need tissue for molecular testing or vaccines, a separate biopsy during the same session is required

Surgery

Rarely indicated at stage IV, but may be considered if:

• The residual lesion is solitary and completely resectable
• There is a need for fresh tumor tissue for functional testing or vaccines
• Other local options are not anatomically feasible

What to choose: SBRT, cryo, or surgery?

The optimal approach may combine methods: for example, cryoablation on the primary tumor (for immune activation) and SBRT on the bone metastasis (for maximum local control).

Anti-cancer vaccines – train your immune system

Therapeutic anti-cancer vaccines do not prevent cancer. They train the immune system to recognize and attack existing tumor cells. And RET fusion cancer has a unique advantage in this space.

Why the RET fusion is an ideal vaccine target

The RET fusion occurs when two genes (for example, KIF5B and RET) join abnormally. At the junction point, a protein sequence that does not exist anywhere in the normal body is formed – a perfect tumor neoantigen.

This means:

• Zero risk of autoimmunity – the vaccine targets something only the tumor has
• The tumor cannot escape without losing the mutation it depends on for survival
• A single design covers all patients with the same fusion type (e.g., KIF5B-RET)

Unlike other cancers where each patient must be sequenced individually, the RET fusion offers a shared, clonal, and specific target.

Types of vaccines

1. Peptide vaccines (protein-based)

The simplest concept: a synthetic protein fragment (peptide) from the fusion junction, injected with an adjuvant that stimulates the immune response.

FusionVAC (University of Tubingen, Germany):

• Proven platform on other cancers with genetic fusions – in the Phase 1 trial on the DNAJB1-PRKACA fusion (Nature Medicine 2025): 75% disease control (9 out of 12 patients), 3 patients with no detectable disease, one patient on compassionate use cancer-free for over 4 years. Note: these results are from a different cancer type (fibrolamellar carcinoma), not RET+ lung cancer. The platform is modular – it adapts to any fusion, but RET-specific clinical data do not exist yet
• The 22-amino acid peptide covers 93-96% of the European population, without requiring specific HLA typing
• The XS15 adjuvant is specifically designed for immunocompromised patients (relevant, since 52% of selpercatinib patients develop lymphopenia)
• Requires fresh frozen tumor tissue (-80C) for feasibility assessment and vaccine design. Paraffin blocks (FFPE) are not sufficient. This means biopsy planning is essential – at any future intervention (cryoablation, CT-guided biopsy), explicitly request that tissue cores be preserved in cryopreservation at -80C for Tubingen
• Estimated production time of a few weeks at the GMP facility in Tubingen (peptide synthesis, not cell culture)
• Access: Through the German “individual use” procedure (Individueller Heilversuch)

Validated KIF5B-RET neopeptides:

• NNDVKEDPK – strongest HLA-C*07:02 binder, immune response experimentally confirmed (Gunaratne, Frontiers in Immunology 2025)
• KEDPKWEFP – second immunogenic hit
• 15 TCR clonotypes identified, 5 with high activation markers
• The FusionNeoAntigen database (Oxford) maps KIF5B-RET to 92 HLA-I alleles, covering approximately 94% of the global population

2. mRNA vaccines

The same technology from the COVID vaccines, adapted for oncology. A messenger RNA encodes the tumor antigens, and the body’s cells produce and present them to the immune system.

BNT116 (BioNTech) + Cemiplimab:

• Encodes 6 common tumor antigens (not RET fusion-specific)
• Phase 1/2 ongoing: 45% response rate, 80% disease control in NSCLC
• Active clinical trial at multiple European centers (including Turkey)
• Limitation: Most protocols exclude patients with driver mutations (EGFR, ALK, RET) – eligibility verification is essential

V940/mRNA-4157 (Moderna + Merck):

• Personalized vaccine: encodes up to 34 unique neoantigens from your tumor
• Combined with pembrolizumab (Keytruda)
• Results in melanoma: 44% reduction in recurrence
• Phase 3 for NSCLC (INTerpath-002) – actively recruiting, estimated results ~2030+

mRNA-4359 (Moderna, Mobilize Trial):

• Explicitly accepts patients with driver mutations (including post-TKI)
• Personalized vaccine with up to 34 neoantigens
• Combined with pembrolizumab

3. Dendritic cell vaccines

Dendritic cells are the “teachers” of the immune system – they present tumor antigens directly to T lymphocytes, activating a targeted immune response.

IOZK (Cologne, Germany) – IO-VAC:

• Autologous dendritic cells (from the patient’s blood), loaded with tumor antigens
• Combined with oncolytic Newcastle Disease Virus (NDV) and hyperthermia
• 350+ patients treated annually
• No restrictions related to standard immune markers (PD-L1, TMB – tumor mutational burden) or driver mutations
• Important limitation: Requires fresh or frozen tumor tissue (FFPE does not work). Also has limited data in lung cancer, with zero RET+-specific data

PDC*lung01:

• Allogeneic dendritic cells (pre-manufactured, standardized) – does not require the patient’s own tumor tissue
• Phase 1/2: 51-55% response rate in combination with immunotherapy
• Limitation: Requires HLA-A*02:01 (present in approximately 40% of Europeans)

CeGaT CancerNeo (Tubingen, Germany):

• Complete pipeline: tumor sequencing, AI neoantigen prediction, GMP synthesis, administration
• 90% immune response rate (87 out of 97 patients)
• Median survival of 53 months in responders, compared to 27 without response
• Accepts FFPE (important advantage if you already have a stored biopsy)
• Production time: approximately 2 months

4. Personalized neoantigen vaccines

The most advanced concept: complete sequencing of your tumor, identification of all unique neoantigens, and creation of a vaccine targeting all of them.

Advantages: Broad coverage (the tumor cannot escape by losing a single antigen). Disadvantages: Higher cost, longer production time (2-5 months).

Active companies and programs:

• CeGaT CancerNeo (Tubingen, Germany) – described above, complete pipeline from sequencing to administration. Accepts FFPE
• Jaime Leandro Foundation (USA) – personalized neoantigen peptide vaccine. Explicitly accepts lung cancer. 48 patients treated (August 2025). Access through FDA Expanded Access (Form 3926, approval rate >99%). Production: 4-5 months
• BioNTech Individualized Neoantigen Therapy (iNeST/BNT122) – personalized mRNA platform (autogene cevumeran). Phase 2 in pancreatic cancer and melanoma, with significant reduction in recurrence. Extension to NSCLC is anticipated
• Moderna mRNA-4157/V940 – described above under mRNA vaccines. Up to 34 personalized neoantigens per patient
• Gritstone Bio (GRANITE/SLATE) – combined platform: adenoviral vector (prime) + self-amplifying mRNA (boost). Phase 2 in MSI-stable solid tumors (direct relevance for RET+, which is MSI-stable)

Most of these programs are accessible through clinical trials or compassionate use. CeGaT is the only one with direct commercial access in Europe.

Vaccines: what is available now vs what is coming

The combination that amplifies efficacy

Vaccines work best when combined with other treatments that amplify the immune response. The optimal evidence-based sequence:

1. Immune activation (ANKTIVA/IL-15 – see next section) – restores lymphocytes before vaccination
2. Vaccination (FusionVAC or another platform) – trains the immune system
3. Cryoablation – releases tumor antigens in-situ, amplifying the vaccine’s effect
4. Vaccine booster at 6-12 weeks after cryoablation – within the window of maximum immune activation
5. Continuing Selpercatinib throughout – tyrosine kinase inhibitors (TKIs, the class to which Selpercatinib belongs) upregulate HLA class I on tumors, making them more visible to vaccine-trained T cells

Immune system activation

RET fusion cancer has an unfortunate characteristic: the tumor is immunologically “cold” – few lymphocytes infiltrate it, PD-L1 expression is low. That is why classical immunotherapy (pembrolizumab, nivolumab) works poorly.

But that does not mean the immune system cannot be activated. It just requires different tools.

ANKTIVA (N-803) – IL-15 superagonist

ANKTIVA is a biologic drug that activates NK cells (natural killers) and CD8+ T lymphocytes without expanding regulatory T cells (which would suppress the immune response).

Why it matters for RET+:

• Works independently of PD-L1 – it does not matter that your tumor is “cold”
• Reverses lymphopenia (low lymphocyte counts) – 80% of patients in trials achieved lymphocytes >1200/uL
• In the QUILT-3.055 trial (86 refractory NSCLC patients), PD-L1 negative patients had superior median survival compared to PD-L1 positive (15.4 vs 13.8 months) – cold tumors benefited more

Status:

• FDA approved (2024) and EC approved (February 2026) for bladder cancer
• Approved in Saudi Arabia (January 2026) for metastatic NSCLC – the first global approval for lung cancer
• Phase 3 trial ResQ201A actively recruiting – the first Phase 3 trial that explicitly includes RET+ patients

Access in the EU:

• Off-label (EC-approved drug, use outside indication)
• Named patient programs (Everyone.org or Accord Healthcare, EU distributor)
• Clinical trial (ResQ201A – requires progression after immunotherapy)

Pembrolizumab (Keytruda) – limited role, but not zero

The LIBRETTO-431 trial clearly demonstrated: Selpercatinib alone is superior to chemotherapy + pembrolizumab as first line (84% vs 56% response rate). Pembrolizumab alone has a response rate of only 6-10% in RET+.

When it could still help:

• After cryoablation: Tissue destruction + immune activation + systemic pembrolizumab – the abscopal effect (PEMBRO-RT: 41.7% abscopal response even in cold tumors, with SBRT 8 Gy x 3 + pembrolizumab within 7 days)
• Combined with vaccines: Vaccines + checkpoint inhibitors > vaccine alone
• With ANKTIVA: IL-15 activates T lymphocytes, pembrolizumab “unblocks” them

The abscopal effect – treat one lesion, benefit all

When you destroy a tumor (through cryoablation, SBRT, or even a vaccine), it releases antigens and danger signals. If the immune system is already activated (through ANKTIVA, vaccine, or checkpoint inhibitor), it can attack distant tumors you did not directly treat.

The combination that maximizes the abscopal effect: cryoablation (intact antigen release) + vaccine (specific training) + ANKTIVA (immune amplification).

On the horizon: cellular cancer therapies

Beyond activating existing NK and T cells in the body, research is advancing toward adoptive cell therapies – immune cells harvested, genetically modified in the laboratory, and reinfused into the patient.

• CAR-NK (chimeric antigen receptor NK cells): “Off-the-shelf” NK cells (from donors, not the patient) modified to recognize tumor markers. Advantage: does not require HLA matching, low risk of graft-versus-host disease. Multiple active clinical trials in NSCLC, but none specifically for RET+
• TCR-T anti-RET: The only program in the world developing T cells genetically modified to specifically recognize peptides derived from the RET protein. Led by Dr. Alexandre Reuben at MD Anderson (Houston). Preclinical stage – estimated 3-5 years until clinical trial

These therapies are not available now, but represent an important direction for patients who exhaust current options. ANKTIVA remains the nearest available NK activation option today.

Drug repurposing – existing medications with anti-cancer potential

Some medications approved for decades for other conditions have demonstrated anti-cancer properties in clinical or preclinical studies. They are inexpensive, available, and have well-known safety profiles.

The basic principle: As long as Selpercatinib is working, you do not want to add significant toxicity. Drug repurposing focuses on options with low risk and potential supplementary benefit.

Candidates with evidence

Aspirin (in studies, the dose of 100 mg/day with enteric coating was used)

Mechanism: Inhibits TXA2, which forms a “platelet shield” around circulating tumor cells, protecting them from the immune system. Aspirin removes this shield.

Evidence: Retrospective study in NSCLC (Chen, Lung Cancer 2020): 21% reduction in death risk. Nature 2025: TXA2/Treg mechanism confirmed.

Propranolol (in studies, 10-20 mg twice daily was used)

Mechanism: Non-selective beta-blocker that reduces adrenergic signaling – chronic stress stimulates metastasis through beta-adrenergic receptors.

Evidence: 2025 meta-analysis in lung cancer: distant metastasis-free survival HR 0.67, overall survival HR 0.78.

Precaution: Requires prior cardiology evaluation, especially in patients with low resting heart rate.

Rosuvastatin (in studies, doses of 10-20 mg/day were used)

Mechanism: HMG-CoA inhibitor – blocks the mevalonate pathway, with anti-angiogenic effects and suppression of mutant p53 function. Important: not atorvastatin, simvastatin, or lovastatin, which are processed by CYP3A4 (the same enzyme as selpercatinib – risk of toxic interaction).

Evidence: 41% mortality reduction in combination with immunotherapy (JCI Insight 2022).

Vitamin D3 (in studies, doses of 4000-5000 IU/day were used)

Evidence: DKFZ 2025 meta-analysis (14 randomized trials, >100,000 patients): -12% all-cause cancer mortality. Target in studies: 60-80 ng/mL in blood. Optimal dose should be determined by your physician based on your current level.

Metformin (if indicated for diabetes or pre-diabetes)

The strongest level of evidence among all: a randomized trial (JAMA Oncology Japan) shows progression-free survival 13.1 vs 9.9 months and overall survival 31.7 vs 17.5 months in patients with driver mutations (EGFR+). The benefit is dependent on body mass index – stronger in overweight patients. It is not prescribed off-label solely for the anti-cancer effect without a metabolic indication.

What to avoid

Next-gen RET inhibitors and ADCs – your backup plan

If Selpercatinib is working, why do you need a Plan B? Because resistance will appear at some point – and when it does, you want to act fast, not search for options.

Why resistance occurs

Two main mechanisms:

1. On-target RET mutations (14%): The tumor modifies the RET protein itself, so selpercatinib can no longer bind. Most common: G810R/S/C (solvent front mutations).

2. Bypass (off-target, 86%): The tumor activates another survival pathway, completely bypassing RET. Most common:

• MET amplification (18.2% – most frequent and most aggressive, appears on average at 8.4 months)
• KRAS activation (7.1%)
• YAP/HER3/EGFR bypass (adaptive, appears early)
• MAPK reactivation (30% of cases)

3. Lineage plasticity – the tumor changes identity

A third, less-known mechanism: under sustained targeted therapy, some adenocarcinomas can transition toward a neuroendocrine phenotype – the tumor changes what it is, not just how it responds. This was a major theme at AACR 2026 (MSK opening plenary by Charles Sawyers), documented across EGFR, ALK, and other targeted therapy classes. It is driver-agnostic, including RET.

RB1 gene loss is the strongest predisposing biomarker. Patients with RB1 loss at baseline – or acquired during treatment – face a higher risk of this transition. Preclinical data (mostly from prostate cancer, cross-domain) suggests FGFR and JAK inhibitors may reverse lineage plasticity in RB1-deficient tumors, but this is not yet validated in NSCLC.

Clinical implication: If RB1 loss is detected on your NGS or ctDNA (now or later), a rebiopsy at progression becomes essential – not just switching to a next-generation TKI. Neuroendocrine-phenotype disease responds to different drugs (platinum/etoposide-based regimens, not RET TKIs). Acting on imaging progression without re-confirming tumor biology risks choosing the wrong next treatment.

Next-generation RET inhibitors

These agents are designed to work where selpercatinib fails – including solvent front mutations.

EP0031 (Lunbotinib) is currently the most clinically advanced, with an active trial at European centers (VHIO Barcelona, Gemelli Rome, Christie Manchester, Sarah Cannon London).

ADCs (Antibody-Drug Conjugates)

A new class of drugs: antibodies that deliver a chemotherapy payload directly to tumor cells, reducing systemic toxicity.

Relevant for RET+ at progression:

• Telisotuzumab Vedotin (Emrelis) – targets MET (the most common bypass mechanism). FDA approved 2025. Response rate 35% as monotherapy, 50% in combination. Available in Turkey
• Datopotamab Deruxtecan (Dato-DXd) – targets TROP2. FDA approved 2025. Response rate 35.8% in driver-mutated cancers
• HER3-DXd (Patritumab Deruxtecan) – targets HER3. Phase 2. Excellent results in brain and leptomeningeal metastases

PROTACs – the future of protein destruction

PROTACs do not block the RET protein – they completely destroy it through the cell’s recycling system (the proteasome). If the protein no longer exists, resistance mutations at the binding site become irrelevant.

• QZ2135 (Peking University): active on G810 variants
• RD-23: independent validation
• Estimate: 2028+ for clinical trial entry

Combinations at progression

If resistance appears, drug combination based on the identified mechanism is critical:

The golden rule: At progression, never stop selpercatinib without an alternative. Continue + add.

The path to NED – eradication strategy

NED means No Evidence of Disease – no evidence of disease. Not a cure (we cannot guarantee that), but the absence of any detectable sign of cancer.

What NED means in practice

Both criteria must be met simultaneously and sustained (minimum 6 months):

1. Negative PET-CT at all known sites
2. Undetectable ctDNA (<1 copy/mL) on an ultrasensitive platform

Is it realistic?

Yes. It is not guaranteed, but the data support it:

• SABR-COMET (8 years): 21% progression-free at 8 years – a cure signal in 1 out of 5 oligometastatic patients
• LIBRETTO-432: Selpercatinib has curative potential in early stages
• CML (chronic myeloid leukemia) analogy: 40-60% of patients on imatinib (another TKI) achieve treatment-free remission – they stop the medication and remain disease-free. RET fusion cancer is not CML, but the model is relevant

Realistic probability for an integrated strategy (TKI + CLT + vaccines + immunomodulation):

• 10-20%: Sustained functional NED (>5 years with no detectable disease)
• 40-50%: Long-term control (3-4+ years with minimal disease)
• 30-50%: Treatment does not generate detectable immune response
• <5%: Net risk (the safety profile of vaccines is excellent)

The 4 phases of the eradication strategy

Phase 1: Response and optimization (months 1-3)

• Selpercatinib as main line
• Complete molecular profiling (WES + RNA-seq + ctDNA baseline)
• Low-risk drug repurposing (aspirin, rosuvastatin, vitamin D)
• ctDNA monitoring at 8-12 weeks

Phase 2: Consolidation + local therapy (months 4-6)

• PET-CT for re-evaluation
• Cryoablation/SBRT on residual lesions
• Biopsy for fresh tumor tissue (vaccines, functional testing)
• ctDNA pre and post intervention

Phase 3: Immune activation (months 7-12)

• Immune activation (ANKTIVA – lymphocyte recovery)
• Vaccination (FusionVAC or alternative) with booster at 6-12 weeks
• Cryoablation provides an immune amplification window
• ctDNA every 3 months
• Assessment of specific immune response (ELISpot anti-fusion T cells)

Phase 4: TFR evaluation (from month 24)

• If sustained negative ctDNA + negative PET-CT >12 months
• Discussion with oncologist about reducing or stopping TKI
• Intensive monitoring protocol: ctDNA every 3 months
• If disease returns: resume Selpercatinib (in CML, 96% re-response rate)
• The “Stay Paranoid” principle: Even at NED, never stop monitoring

Real-world example: Sid Sijbrandij

Sid Sijbrandij, co-founder of GitLab, publicly documented his strategy against cancer (osteosarcoma). When doctors told him he had exhausted the standard of care and there were no clinical trials for his situation, he went into “Founder Mode” – he assembled a team of physicians and researchers, used AI to analyze medical data, and systematically explored every diagnostic and treatment option beyond standard protocols. The full story is on his blog and at sytse.com/cancer. It is not RET cancer, but it demonstrates that a proactive, informationally aggressive strategy is possible and can generate results beyond average statistics.

Biobanking – protect your future options

At every biopsy or surgical intervention, explicitly request that a portion of tissue be properly preserved. This simple step can open options that do not exist today.

Why it matters

• Personalized vaccines require tumor tissue (either fresh or frozen)
• Functional testing (organoids, drug sensitivity) requires living tissue
• Complete molecular profiling works best on fresh frozen tissue (not just FFPE)
• If the tumor changes under treatment (and it will change), tissue from each biopsy is a “snapshot” of disease evolution

What to request

At every biopsy or intervention:

1. FFPE (formaldehyde + paraffin) – standard, sufficient for most molecular tests. This is done routinely anyway
2. Cryopreservation at -80C – essential for organoids, dendritic cell vaccines, and high-quality RNA sequencing. Must be explicitly requested
3. Sufficient samples – not a single fragment. Request 4-8 biopsy cores if possible, distributed between:
   • Pathology (diagnosis, mandatory)
   • Molecular sequencing (WES + RNA-seq)
   • Biobank (-80C, for the future)
   • Vaccine/functional testing (if already planned)

ROSE evaluation

ROSE (Rapid On-Site Evaluation) means that a pathologist verifies during the procedure whether the biopsy fragments contain viable tumor cells. Without ROSE, you risk freezing tissue that does not contain tumor.

Not all centers offer ROSE. Ask specifically whether it is available.

How to access these options

Many of the options described in this article are not available through the standard pathway (oncologist prescription, pharmacy). But that does not mean they are inaccessible. Specific legal mechanisms exist.

Clinical trials

The most direct access to new treatments. Treatment is free, monitoring is intensive, and you contribute to advancing knowledge.

Where to search:

• ClinicalTrials.gov – search “RET fusion NSCLC”
• EU Clinical Trials Register
• LUNGevity Foundation – LungMATCH navigator
• RETpositive.org – RET-specific database

Practical tip: You can be pre-screened for a trial without being eligible today. The relationship with the research center is established before you need it.

Compassionate use / expanded access

New medications that are not yet approved can be accessed for individual patients:

• Expanded Access (USA): FDA Form 3926, approval rate >99%, processing in 48h
• Heilversuch (Germany): Individual compassionate use procedure, legal basis Sec. 34 StGB. Covers vaccines, experimental drugs, and off-label combinations
• Named Patient Programs (EU): Through platforms like everyone.org (11,000+ patients served, 100% confirmed delivery)

S2 form (EU Cross-Border Healthcare Directive)

If you are insured in the EU, you can receive medical treatment in another member state with health insurance authorization. The S2 form (or E112) covers:

• Consultations and second opinions
• Procedures (cryoablation, biopsy) at specialized centers
• Treatment that is not available or has excessive waiting times in your country

The process: Your oncologist completes the medical justification -> the health insurance body approves -> the external center bills the insurance body, not the patient.

Off-label (outside indication)

Medications approved for another indication, used based on scientific evidence for your situation. Examples: ANKTIVA (EC approved for bladder cancer, used off-label for NSCLC).

Requires a prescription from the oncologist + documented medical justification.

Timeline: what is available and when

Resources

RET-specific communities

• RETpositive.org – patient community, clinical trials, registries
• The Happy Lungs Project – research updates, webinars
• RET Renegades (Facebook) – support group
• LUNGevity Foundation – LungMATCH navigator, communities
• Cancer GRACE – forum for RET+ patients

Clinical trial databases

• ClinicalTrials.gov – global database
• EU Clinical Trials Register – European trials

Reference centers for RET+ NSCLC

• Memorial Sloan Kettering (New York) – Dr. Alexander Drilon, the world’s largest RET registry
• Gustave Roussy (Paris) – the largest oncology center in Europe, active RET research programs
• MD Anderson (Houston) – Dr. Vivek Subbiah, RET combination research
• IEO Milan – real-world experience with RET+ in a European context