Targeted Therapy

What is targeted therapy?

Targeted therapy is a type of cancer treatment that identifies and attacks specific parts of cancer cells and the signals that proteins send to cancer cells that cause them to grow and divide uncontrollably.¹ Targeted therapies are precise; they prevent the growth and spread of the cancer cells only. They do no harm to the body's normal, healthy cells.

Because each targeted therapy works to control a specific driver mutation, a patient may be treated with that targeted therapy only if they have the driver mutation for which the targeted therapy is intended.

Targeted therapies are approved primarily for patients whose lung cancer is metastaticCharacterized by metastasis, which is the spread of cancer from the primary site, or place where it started, to other places in the body; that is, the cancer has spread from its original site to other places in the body.

Targeted therapies work differently from the other three types of lung cancer drug treatments. To summarize the differences:¹

• Targeted therapy: Blocks the cancer cells' growth and division; leaves healthy cells alone
• Standard chemotherapy: Attacks the cancer cells directly, but also attacks healthy cells
• Immunotherapy: Stimulates the body's immune system to attack the cancer cells
• Angiogenesis inhibitor: Stops the formation of new blood vessels to cut off the tumor's blood supply

In addition, except for one medication given intravenously (an infusion through a vein), targeted therapies are administered orally (typically by pill once or twice daily). Other drug treatments (such as chemotherapy and immunotherapy) are most likely to be administered intravenously.

A targeted therapy is given to a patient until disease progressionThe continuation in the growth or spread of cancer—the lung cancer continues to grow and spread—or the side effects of the drug become intolerable.

Types of targeted therapies

Kinase inhibitors

Kinases are specific proteins that act as enzymesSpecial proteins that the body produces to control its cells and carry out chemical reactions quickly to control cell functions, including cell signalingThe procss by which a cell responds to substances outside the the cell, growth, and division. There are different types of kinases. The proteins encoded by the ALK, EGFR, MET, NTRK, RET, and ROS1 genes are all examples of a type of kinase called a tyrosine kinase. The BRAF gene encodes a different type of kinase, serine/threonine. If a gene has a driver mutation, the kinases can signal the cancer cell to grow and divide.¹

The targeted therapy drugs that have been approved so far by the FDA for the treatment of driver mutations in lung cancer are all kinase inhibitors, which block the cell functions and keep the cancer from growing and dividing. Except for the BRAF V600E combination treatment, all of the inhibitors are tyrosine kinase inhibitors (TKIs). Kinase inhibitors are all administered orally.

Bispecific antibodies

An antigen is any substance that causes the body to have an immune response against it. Cancer cells have antigens on them that can cause an immune response by antibodies, which are specific to the antigen. While in nature an antibody can only bind to one antigen, bispecific antibodies developed by researchers are able to target two antigens and block signaling functions that allow cancer cells to flourish.¹ One such bispecific antibody has been developed for a specific variation of the EGFR gene. This drug is given as an infusion through the vein.

RAS GTPase family inhibitors

In normal cells, the KRAS protein acts like an on/off switch to control signaling pathways that manage cell growth. The KRAS gene controls the production of the KRAS protein. A mutation in the KRAS gene leads to the production of a faulty protein that is always on, or active, resulting in the continuous, out-of-control proliferation of cells and leading to the formation of cancerous tumors. Different KRAS mutations are found in lung cancer. All these mutations lead to an “on” KRAS protein. One inhibitor has been developed to target the most common mutation of the KRAS gene in NSCLC. This drug, a RAS GTPase family inhibitor, is administered orally.⁴⁴

Topoisomerase inhibitor antibody-drug conjugates

Antibody-drug conjugates (ADCs) are composed of a monoclonal antibody that is chemically linked to a drug. The antibody binds to specific proteins or receptors found on certain types of cells, including cancer cells. Once bound, the linked drug enters these cells and kills them without harming other cells. Some ADCs are used to treat cancer.¹

Topoisomerases are enzymes that break and rejoin DNA strands that are needed for cell division and growth. Blocking these enzymes can lead to death of cancer cells. When a topoisomerase inhibitor is delivered by nonspecific targeting, higher doses are required to eradicate tumors, which can cause adverse side effects.⁴⁸

Administering a topoisomerase inhibitor with an ADC allows for the drug to be delivered only to tumor cells with specific receptors that bind to the antibody contained in the ADC. This means that there is a more efficient drug delivery to tumor cells while minimizing toxicity to healthy cells.⁴⁸

Where do targeted therapies fit into a treatment plan?

Sometimes, treatment with a targeted therapy will be the only treatment a patient receives. However, a targeted therapy may also be used before, together with, or after other treatments; treatment will depend on when the driver mutation was discovered, the patient's response to treatment, and other individual factors that the doctors consider. The other treatments are most likely to include another targeted therapy, chemotherapy, chemotherapy-immunotherapy, an angiogenesis inhibitor, and/or radiation therapy. In addition, in those cases where a targeted therapy is appropriate and there is more than one approved therapy for a particular driver mutation, doctors again consider factors specific to the patient before prescribing a particular treatment.²

Driver mutations with FDA-approved targeted therapies

Genes with driver mutations for which there are FDA-approved targeted therapies for the treatment of lung cancer are:

• ALK
• BRAF V600E 
• EGFR (including mutations not sensitive to TKIs)
• KRAS
• MET exon 14 skipping
• NTRK
• RET
• ROS1

All current FDA-approved targeted therapies treat non-small cell lung cancer (NSCLC). There are as yet no approved targeted therapies for small cell lung cancer.

Clinical trials are currently studying promising drugs to target these and other driver mutations; read more about them later in this section.

ALK

An anaplastic lymphoma kinase (ALK) rearrangement is a fusionA gene made by joining parts of two different genes between two genes: ALK and, most commonly, echinoderm microtubule-associated protein-like 4 (EML4). (In fact, the ALK gene rarely fuses to other genes.) The fusion of these two genes produces an abnormal ALK protein that causes cancer cells to grow and spread.

About 5% of patients with NSCLC in Western populations have tumors with an ALK fusion. The fusion between ALK and EML4 is more common among younger patients (median age at diagnosis is 52 years); nonsmokers or light smokers; and those with lung adenocarcinoma. It has rarely been found in patients with squamous cell lung cancer.³

What are the Approved ALK TKIs?

There are currently six FDA-approved ALK TKIs:

• Alectinib (Alecensa®):⁴ Approved for patients with metastatic ALK-positive NSCLC, as detected by an FDA-approved test. It is also approved for adjuvant treatment in adult patients following tumor resection of ALK-positive NSCLC (tumors ≥ 4 cm or node positive) as detected by an FDA-approved test.
• Brigatinib (Alunbrig®):⁵ Approved for adult patients with metastatic ALK-positive NSCLC, as detected by an FDA-approved test
• Ceritinib (Zykadia®):⁶ Approved for patients with metastatic ALK-positive NSCLC, as detected by an FDA-approved test
• Crizotinib (Xalkori®):⁷ Approved for patients with metastatic ALK-positive NSCLC, as detected by an FDA-approved test
• Ensartinib (Ensacove^TM)⁵⁶: Approved for treatment of adult patients with ALK-positive locally advanced or metastatic NSCLC who have not previously received an ALK inhibitor
• Lorlatinib (Lorbrena^®):⁸Approved for adult patients with metastatic ALK-positive NSCLC, as detected by an FDA-approved test

WHAT ARE THE SIDE EFFECTS OF THE ALK TKIs?

Side effects of the ALK TKIs differ by drug and by patient.^4,5,6,7,8

Some common side effects of ALK TKIs as a group include:

• Nausea
• Vomiting
• Diarrhea
• Constipation
• Fatigue
• Swelling of the hands or feet

Among the more serious but less common side effects of ALK TKIs as a group are:^4,5,6,7,8

• Liver problems
• PneumonitisInflammation of the lungs that may be caused by disease, infection, radiation therapy, allergy, or irritation of lung tissue by inhaled substance
• Abnormal heartbeats

In addition, crizotinib (Xalkori®) and ensartinib (Ensacove^TM) have unique vision-specific side effects. These include:^7,56

• Trouble looking at light
• Blurred vision
• Double vision
• Seeing flashes of light
• New or increased floatersA bit of optical debris (as a dead cell or cell fragment) in the vitreous body or lens that may be perceived as a spot before the eye 

Ensartinib (Ensacove^TM) can cause dermatologic adverse reactions, including:⁵⁶

• Drug reaction with eosinophilia and systemic symptoms (DRESS)
• Rash
• Itching
• Photosensitivity

Low testosterone is one source of fatigue in patients being treated with crizotinib (Xalkori®). This can also lead to sexual dysfunction and depression.⁹

Get tips on managing treatment-related side effects.

If you have an ALK mutation, the LUNGevity ALK Patient Gateway has more information about all available treatments, finding a specialist, clinical trials, online patient groups, and more.

BRAF V600E

Mutations in the BRAF V600E gene occur in 1%-3% of lung adenocarcinoma patients. Most of these patients are current or former smokers.¹⁰

What are the APPROVED BRAF V600E treatments?

There are currently two FDA-approved treatments for patients with a BRAF V600E mutation, as detected by an FDA-approved test. Both are combination treatments of a BRAF kinase inhibitor with a MEK kinase inhibitor.

• Dabrafenib (Tafinlar®) in combination with trametinib (Mekinist®) for treatment of patients with metastatic NSCLC with BRAF V600E mutation.¹¹
• Encorafenib (Braftovi®) in combination with binimetinib (Mektovi®), for the treatment of adult patients with metastatic non-small cell lung cancer (NSCLC) with a BRAF V600E mutation^{50, 51}

WHAT ARE THE SIDE EFFECTS OF THE approved BRAF V600E treatments?

Side effects vary by drug and by patient.^{11, 50, 51}

Some common side effects of the BRAF V600E combination inhibitors include:

• Fatigue
• Nausea
• Vomiting
• Diarrhea
• Dry skin
• Decreased appetite
• Fever
• Swelling of the hands or feet
• Rash
• Bleeding
• Cough
• Difficulty breathing
• Chills

Among the more serious but less common side effects of the BRAF V600E combination inhibitors are:^11,50,51

• Vision toxicities
• Pneumonitis
• Cardiomyopathy
• Hyperglycemia
• Anemia

Get more tips on managing treatment-related side effects.

If you have a BRAF mutation, the LUNGevity Rare Mutations Patient Gateway has more information about all available treatments, finding a specialist, clinical trials, online patient groups, and more.

EGFR

Approximately 15% of patients with NSCLC in the US and 35% of patients from East Asia have tumors with an EGFR (epidermal growth factor receptor) driver mutation. Regardless of the patient's ethnicity, EGFR driver mutations are more often found in tumors of females and nonsmokers. Most commonly, these patients have lung adenocarcinoma.^12,13

What are the approved EGFR drugs?

There are currently seven FDA-approved EGFR TKIs. All except mobocertinib (Exkivity^TM), which is approved for EGFR exon 20 insertion mutations, are approved for EGFR exon 19 deletion and exon 21 (L858R) substitution mutations. Afatinib (Gilotrif^®) and osimertinib (Tagrisso^®) have additional indications as well:

• Afatinib (Gilotrif^®):¹⁴  Approved for first-line treatmentThe first therapy given for a disesase of patients with metastatic NSCLC whose tumors have EGFR non-resistant mutations, as detected by an FDA-approved test. (The most common of these are the exon 19 deletion and the exon 21 (L858R) substitution mutations. The rarer mutations are S768L, L861Q, and G719X.)
• Dacomitinib (Vizimpro®):¹⁵ Approved for first-line treatment of patients with metastatic NSCLC whose tumors have EGFR exon 19 deletions or exon 21 (L858R) substitution mutations, as detected by an FDA-approved test
• Erlotinib (Tarceva^®):^16,17 Approved for the treatment of patients with EGFR-positive metastatic NSCLC. This includes patients whose tumors have EGFR exon 19 deletions or exon 21 (L858R) substitution mutations, as detected by an FDA-approved test, who are receiving first-line or maintenance treatmentTreatment that is given to help keep cancer from coming back after it has disappeared following the initial therapy. It may include treatment with drugs, vaccines, or antibodies that kill cancer cells, and it may be given for a long time, or second- or subsequent-line treatment after progression following at least one prior chemotherapy regimen. Erlotinib (Tarceva®) is also approved in combination with ramucirumab (Cyramza®), an angiogenesis inhibitor, for the first-line treatment of metastatic NSCLC with EGFR exon 19 deletions or exon 21 (L858R) substitution mutations
• Gefitinib (Iressa^®):¹⁸ Approved for the first-line treatment of patients with metastatic NSCLC whose tumors have EGFR exon 19 deletions or exon 21 (L858R) substitution mutations, as detected by an FDA-approved test
• Lazertinib (Lazcluze^TM):⁵³ Approved in combination with amivantamab for the first-line treatment of adult patients with locally advanced or metastatic NSCLC with EGFR exon 19 deletions or exon 21 L858R substitution mutations, as detected by an FDA-approved test.
• Mobocertinib (Exkivity^TM):⁴⁵ Approved for the treatment of adult patients with locally advanced or metastatic EGFR exon 20 insertion-mutant NSCLC, as detected by an FDA-approved test, and who have received prior platinum-based chemotherapy
  Following discussions with the US Food and Drug Administration, EXKIVITY will be officially withdrawn from the market in the United States no later than March 2024.  EXKIVITY remains available to prescribe until the official withdrawal; moreover, after withdrawal patients will be able to maintain access through an established compassionate use program. All current patients on the drug whom Takeda has contact information for will have received an official communication. For more information, please visit www.exkivity-update.com
• Osimertinib (Tagrisso®):¹⁹
  • Approved for first-line treatment of patients with metastatic NSCLC whose tumors have EGFR exon 19 deletions or exon 21 (L858R) substitution mutations, as detected by an FDA-approved test.
  • Approved for second-line treatment of patients with metastatic NSCLC whose tumors are EGFR T790M-positive, as detected by an FDA-approved test, and whose disease has progressed on or after EGFR TKI therapy.
  • Approved for the treatment of adult patients with locally advanced, unresectable (stage III) NSCLC whose disease has not progressed during or following concurrent or sequential platinum-based chemoradiation therapy and whose tumors have EGFR exon 19 deletions or exon 21 L858R mutations, as detected by an FDA-approved test.

Note: The US FDA granted approval for the use of osimertinib (Tagrisso®) as adjuvant therapyThe additional cancer treatment given after the primary treatment to lower the risk that the cancer will come back after surgical removal of a tumor in adult patients with stagesThe extent of a cancer in the body 1B to IIIA NSCLC whose tumors are mostly nonsquamous and have EGFR exon 19 deletions or exon 21 (L858R) substitution mutations, as detected by an FDA-approved test.²⁰

Osimertinib (Tagrisso®) is also approved in combination with pemetrexed and platinum-based chemotherapy for the first-line treatment of adult patients with locally advanced or metastatic NSCLC whose tumors have EGFR exon 19 deletions or exon 21 L858R mutations, as detected by an FDA-approved test.¹⁹

There currently is also one FDA-approved treatment that is not a TKI for the treatment of EGFR driver mutations: this treatment is an EGFR bispecific antibody.⁴⁰

• Amivantamab-vmjw (Rybrevant^TM):⁴¹
  • Approved for the treatment of adult patients with locally advanced or metastatic NSCLC with EGFR exon 20 insertion mutations, as detected by an FDA-approved test, whose disease has progressed on or after platinum-based chemotherapy.
  • Approved in combination with carboplatin and pemetrexed for the first-line treatment of adult patients with locally advanced or metastatic NSCLC with epidermal growth factor receptor (EGFR) exon 20 insertion mutations, as detected by an FDA-approved test.
  • Approved in combination with lazertinib for the first-line treatment of adult patients with locally advanced or metastatic NSCLC with EGFR exon 19 deletions or exon 21 L858R substitution mutations, as detected by an FDA-approved test.
  • Approved in combination with carboplatin and pemetrexed for the treatment of adult patients with locally advanced or metastatic NSCLC with EGFR exon 19 deletions or exon 21 L858R substitution mutations, whose disease has progressed on or after treatment with an EGFR tyrosine kinase inhibitor.

What are the side effects of EGFR Drugs?

Side effects of the EGFR drugs vary by drug and by patient.^{14,15,16,18,19,41}

Some common side effects of EGFR drugs as a group include:

• Rash
• Itching
• Diarrhea
• Mouth sores
• Loss of appetite
• Inflammation around nails
• Weakness
• Cough

Among the more serious but less common side effects of EGFR TKIs as a group are:^{14,15,16,18,19}

• Interstitial lung diseaseA group of disorders that cause scarring of the lungs, which eventually affects the body's ability to get enough oxygen into the bloodstream and to breathe
• Vision toxicities
• Severe skin lesions
• Cardiomyopathy
• Cough

Get more tips on managing treatment-related side effects.

If you have an EGFR mutation, the LUNGevity EGFR Patient Gateway has more information about all available treatments, finding a specialist, clinical trials, online patient groups, and more.

HER2 (ERBB2)

Mutations in the HER2 gene (also called ERBB2) are responsible for approximately 3% of nonsquamous NSCLCs. HER2 mutations are more commonly associated with younger women without a history of smoking. Those with these mutations have a higher incidence of brain metastases than those without HER2 mutations or with other mutations.⁴⁶

What is the approved HER2 (ERBB2) drug?

There is currently one FDA-approved targeted drug to treat HER2-positive NSCLC:

Trastuzumab deruxtecan (Enhertu^®): Approved for adult patients with unresectable or metastatic NSCLC whose tumors have activating HER2 (ERBB2) mutations, as detected by an FDA-approved test, and who have received a prior systemic therapy.⁴⁷

This treatment is a topoisomerase inhibitor antibody-drug conjugate.

What are the side effects of the HER2 (ERBB2) drug?

Side effects of trastuzumab deruxtecan vary by patient.

Some common side effects of trastuzumab deruxtecan include: ⁴⁷

• Nausea
• Fatigue
• Vomiting
• Alopecia
• Constipation
• Musculoskeletal pain
• Decreased appetite
• Diarrhea
• Anemia

Among the more serious but less common side effects of trastuzumab deruxtecan are: ⁴⁷

• Interstitial lung disease/pneumonitis
• Neutropenia
• Left ventricular dysfunction

Get more tips on managing treatment-related side effects.

If you have an HER2 mutation, the LUNGevity Rare Mutations Patient Gateway has more information about all available treatments, finding a specialist, clinical trials, online patient groups, and more.

KRAS

Approximately 30% of patients with NSCLC in the US have tumors with KRAS (Kirsten Rat Sarcoma) driver mutation. KRAS mutations are most often found in tumors of smokers. Most commonly, these patients have lung adenocarcinoma.⁴²

What are the approved KRAS drugs?

There are currently two FDA-approved drugs specifically for the KRAS G12C mutation. This mutation accounts for approximately 13% of NSCLC cases.⁴⁴

• Adagrasib (Krazati™):⁴⁹ Approved for the treatment of adult patients with KRAS G12C–mutated locally advanced or metastatic non–small cell lung cancer, as determined by an FDA-approved test, who have received at least one prior systemic therapy.
• Sotorasib (Lumakras™):⁴³ Approved for the treatment of adult patients with KRAS G12C-mutated locally advanced or metastatic non-small cell lung cancer (NSCLC), as determined by an FDA-approved test, who have received at least one prior systemic therapy.

What are the side effects of KRAS drugs?

Side effects of KRAS drugs vary by drug and patient.^43,49

Some common side effects of KRAS drugs as a group include:

• Diarrhea
• Musculoskeletal pain
• Nausea
• Fatigue
• Liver issues
• Cough

Among the more serious but less common side effects of the KRAS drugs as a group are:^43,49

• Interstitial lung disease
• Severe gastrointestinal adverse reactions

Get more tips on managing treatment-related side effects.

If you have a KRAS mutation, the LUNGevity KRAS Patient Gateway has more information about all available treatments, finding a specialist, clinical trials, online patient groups, and more.

MET

Approximately 3%-4% of NSCLC patients have a mutation that leads to MET (mesenchymal-epithelial transition) exon 14 skipping. Patients with MET-positive lung cancers are most likely to have a smoking history; a minority are never-smokers.^21,22

What are the APPROVED MET TKIs?

There are currently two FDA-approved MET TKIs:

• Capmatinib (Tabrecta^TM):²³ Approved for the treatment of adult patients with metastatic NSCLC whose tumors have a mutation that leads to MET exon 14 skipping, as detected by an FDA-approved test
• Tepotinib (Tepmetko®):²⁴ Approved for the treatment of adult patients with metastatic NSCLC whose tumors have a mutation that leads to MET exon 14 skipping

WHAT ARE THE SIDE EFFECTS OF THE MET TKIs?

Side effects of the MET TKIs vary by drug and by patient.^23,24

Some common side effects of the MET TKIs as a group include:

• Swelling of the hands or feet
• Nausea
• Vomiting
• Fatigue and weakness
• Musculoskeletal pain
• Shortness of breath
• Loss of appetite

Among the more serious but less common side effects of the MET TKIs as a group are:^23,24

• Pneumonitis
• Liver damage

Get more tips on managing treatment-related side effects.

If you have a MET mutation, the LUNGevity Rare Mutations Patient Gateway has more information about all available treatments, finding a specialist, clinical trials, online patient groups, and more.

NRG1

The NRG1 gene encodes a protein (neuregulin-1) that plays a role in organ development. FusionsGenes made by joining parts of two different genes in NRG1 cause abnormal signaling that can lead to tumor growth. NRG1 fusions have been found in NSCLC, pancreatic cancer, and other cancer types. These fusions are rare, accounting for only about 0.2% of solid tumors, and current evidence points to poor outcomes with chemotherapy and immunotherapy.⁵⁴

What is the approved NRG1 drug?

There is currently one FDA-approved targeted drug to treat NSCLC caused by a NRG1 gene fusion:

• Zenocutuzumab-zbco (Bizengri®): Approved in adults with advanced, unresectable or metastatic non-small cell lung cancer (NSCLC) harboring a neuregulin 1 (NRG1) gene fusion with disease progression on or after prior systemic therapy.⁵⁵ It is a bispecific antibody that binds HER2 and prevents binding of NRG1 to HER3. This disrupts the signaling pathway responsible for cell growth and proliferation.

What are the side effects of the NRG1 drug?

Side effects of zenocutuzumab-zbco vary by patient. Some common side effects of zenocutuzumab-zbco include:⁵⁵

• Diarrhea
• Nausea
• Musculoskeletal pain
• Cough
• Dyspnea (trouble breathing)
• Fatigue
• Rash
• Infusion-related reactions
• Vomiting
• Abdominal pain
• Edema

Among the more serious but less common side effects of zenocutuzumab-zbco are:⁵⁵

• Pneumonia
• Acute kidney injury
• Dysphagia (trouble swallowing)
• Bradycardia

Get more tips on managing treatment-related side effects.

If you have an NRG1 mutation, the LUNGevity Rare Mutations and Fusions Patient Gateway has more information about all available treatments, finding a specialist, clinical trials, online patient groups, and more.

NTRK

About 3%-4% of NSCLC patients have an NTRK (neurotrophic receptor kinase) gene fusion. NTRK fusions are more likely to be seen in patients who are light or never-smokers.^25,26 

What are the approved NTRK TKIs?

There are currently three FDA-approved NTRK TKIs:

• Entrectinib (Rozlytrek®):²⁷ Approved for the treatment of adult and pediatric patients 12 years of age and older with solid tumorsAn abnormal mass of tissue that usually does not contain cysts or liquid areas. Solid tumors may be benign or malignant that:
  • have an NTRK gene fusion with a known acquired resistanceDisease progression after a complete or partial response to treatment, or disease progression after six months or more of stable disease, after treatment with a targeted therapy mutation,
  • are metastatic or where surgical resection is likely to result in severe morbidityMedical problems caused by a treatment, and
  • have progressed following treatment or have no satisfactory alternative treatment
• Larotrectinib (Vitrakvi®):²⁸ Approved for the treatment of patients with NTRK solid tumors that:
  • have an NTRK gene fusion without a known acquired resistance mutation
  • are metastatic or where surgical resection is likely to result in severe morbidity, and
  • have progressed following treatment or have no satisfactory alternative therapy
• Repotrectinib (Augtyro^TM)⁵²: Approved for the treatment of adult and pediatric patients 12 years of age and older with solid tumors that:
  • have a neurotrophic tyrosine receptor kinase (NTRK) gene fusion and
  • are locally advanced or metastatic or where surgical resection is likely to result in severe morbidity
  • have progressed following treatment or have no satisfactory alternative therapy

what are the side effects of ntrk TKIs?

Side effects of the NTRK TKIs vary by drug and by patient.^27,28

Some common side effects of NTRK inhibitors as a group include:

• Fatigue
• Nausea
• Vomiting
• Dizziness
• Constipation
• Diarrhea
• Cough
• High AST (aspartate aminotransferase) levels, indicating liver issues
• High ALT (alanine aminotransferase) levels, indicating liver issues

Among the more serious but less common side effects of the NTRK TKIs as a group are:^27,28

• Congestive heart failure
• Skeletal fractures
• Central nervous system effects
• Vision disorders

Get more tips on managing treatment-related side effects.

If you have an NTRK mutation, the LUNGevity Rare Mutations Patient Gateway has more information about all available treatments, finding a specialist, clinical trials, online patient groups, and more.

RET

Approximately 1% of NSCLC patients have a RET (rearranged during transfection) fusion.  RET patients have been seen to have lung adenocarcinoma and be never-smokers.^29,30

What are the approved RET TKIs?

There are currently two FDA-approved RET TKIs:

• Selpercatinib (RetevmoTM):³¹ Approved for the treatment of adult patients with metastatic RET fusion-positive NSCLC, as detected by an FDA-approved test
• Pralsetinib (Gavreto^TM):³² Approved for the treatment of adult patients with metastatic RET fusion-positive NSCLC

WHAT ARE THE SIDE EFFECTS OF THE RET TKIs?

Side effects of RET TKIs vary by drug and by patient.^31,32

Some common side effects of RET TKIs as a group include:

• High blood pressure
• Dry mouth
• Diarrhea
• Musculoskeletal pain
• Fatigue
• Swelling of the hands or feet
• Rash
• Constipation
• High AST, indicating liver issues
• High ALT, indicating liver issues
• Other laboratory test abnormalities (eg., increased glucose and decreased calcium)

Among the more serious but less common side effects of RET TKIs as a group are:^31,32

• Bleeding
• Pneumonitis

Get more tips on managing treatment-related side effects.

If you have a RET mutation, the LUNGevity Rare Mutations Patient Gateway has more information about all available treatments, finding a specialist, clinical trials, online patient groups, and more.

ROS1

A ROS1 (receptor tyrosine kinase) rearrangement is a fusion between two genes, ROS1 and another gene. As with ALK, the fusion of the two genes produces an abnormal protein that causes cancer cells to grow and spread.

About 1%-2% of patients with NSCLC in the US and 2%-3% in East Asia have tumors with a ROS1 mutation. ROS1 tumors are more commonly found among younger patients (median age at diagnosis is 50 years), females, never-smokers, and patients with lung adenocarcinoma.^12,33

What are the APPROVED ROS1 TKIs?

There are currently three FDA-approved ROS1 TKIs:

• Crizotinib (Xalkori®):⁷ Approved for patients with metastatic NSCLC whose tumors are ROS1-positive, as detected by an FDA-approved test
• Entrectinib (Rozlytrek®):⁸ Approved for adult patients with metastatic NSCLC whose tumors are ROS1-positive
• Repotrectinib (Augtyro^TM):⁵²  Approved for the treatment of adult patients with locally advanced or metastatic ROS1-positive NSCLC

WHAT ARE THE SIDE EFFECTS OF ROS1 TKIs?

Side effects of ROS1 TKIs vary by drug and by patient.^7,27

Some common side effects of ROS1 TKIs as a group include:

• Nausea
• Vomiting
• Diarrhea
• Constipation
• Fatigue
• Muscle aches

Among the more serious but less common side effects of the ROS1 TKIs as a group are:

• Vision disorders
• Low testosterone
• Skeletal fractures
• Central nervous system effects

Crizotinib (Xalkori®) is also approved for the treatment of metastatic ALK-positive NSCLC; see the earlier section about ALK TKIs for more detail on the rarer eye and testosterone side effects of this drug.

Get more tips on managing treatment-related side effects.

If you have a ROS1 mutation, the LUNGevity Rare Mutations Patient Gateway has more information about all available treatments, finding a specialist, clinical trials, online patient groups, and more.

Management of targeted therapy side effects

As seen above, targeted therapies can cause side effects. However, just because a side effect is possible does not mean that a patient will experience it. Before beginning treatment with a targeted therapy, the patient should discuss with the healthcare team what side effects, both common and rare, might be expected and how to prevent or ease them. The patient should speak with the healthcare team if and when new side effects begin, as treating them early on is often more effective than trying to treat them once they have already become severe. In addition, it needs to be determined whether the side effects are related to treatment or not. What side effects are being experienced may impact future treatment plans. Although most side effects go away when treatment is over, some can last a long time.

Resistance to tyrosine kinase inhibitors (TKIs)

The biggest challenge of TKI targeted therapies is that a majority of patients with lung cancer who initially benefit from them eventually develop resistance. Acquired resistance can be defined as disease progression in a patient after initial benefit from a TKI.34

Cancer cells are adept enough to bypass roadblocks to their survival and often further mutate to overcome the effects of TKIs. Another way a tumor can become resistant to TKIs is by activating a different signaling pathway in the cell to bypass the pathway that the TKI uses to kill the cells. In a small number of cases among EGFR patients, the lung adenocarcinoma may even transform into other histologies, such as SCLC. ^34,35,36

Research is underway to overcome resistance in tumors and to keep the TKIs effective against cancer for longer periods of time. Approaches include:^37,38

• Simultaneously prescribing multiple TKIs, in case a different mutation in the cell has been activated
• Developing the next generation of inhibitors that will inhibit not only the activity of the mutated gene, but also the mutant form it could change into
• Prescribing other combination treatments (e.g., a TKI in combination with chemotherapy, immunotherapy, or radiation therapy)

In the meantime, if a patient's cancer has progressed after treatment with a TKI, a decision needs to be made about the next treatment option. A patient's doctor may recommend that a biopsy be done on one of the tumors that is growing to determine whether there is a new mutation, but will consider all of the treatment options mentioned earlier and make a determination based on the patient's particular situation.

Which driver mutations identified in lung cancer are being studied in clinical trials?

Currently, clinical trials are open for many drugs that inhibit the effect of mutations seen in NSCLC and SCLC. The targeted treatments are being studied alone, as well as in combination with other targeted agents, immunotherapy, chemotherapy, and radiation therapy. As the number of known driver mutations in lung cancer tumors increases, so do the number of drugs being developed to target them. Patients should discuss with their doctors whether participating in a clinical trial might be a good option. Read more about resources to help locate clinical trials later in this section.

Targeted therapies drugs that are currently being studied are intended to act against the following driver mutations:³⁹

Finding a clinical trial that might be right for you

If you are considering participating in a clinical trial, start by asking your healthcare team whether there is one that might be a good match for you in your geographic area. In addition, there are several resources to help you find one that may be a good match.

People are often surprised that a clinical trial is not the last option one turns to when standard treatments have failed. Today, clinical trials may present the FIRST line of treatment.

Resources to help you navigate your clinical trials search:

• EmergingMed: www.emergingmed.com/lcctal/home
  • LUNGevity partners with this free clinical trials matching service to help you with the decision of whether to participate in a clinical trial.
  • EmergingMed helps you identify lung cancer clinical trials for which you may be eligible
  • Clinical trial navigators are available Monday through Friday from 9:00am to 5:00pm ET at 877-769-4834
• National Cancer Institute (NCI):  www.cancer.gov/clinicaltrials/search
• My Cancer Genome:  www.mycancergenome.org
  • My Cancer Genome gives up-to-date information on what mutations make cancers grow and related treatment options, including available clinical trials
• Lung Cancer Master Protocol (Lung-MAP):  www.lung-map.org
  • For patients with advanced non-small cell lung cancer
  • LUNG-MAP is a collaboration of many research sites across the country. They use a unique approach to match patients to one of several drugs being developed

In addition, if you are interested in a specific drug or other treatment that is being developed, you can often find information about studies for that drug on the website of the company developing it.

Learn more about clinical trials here.