What Are the Most Common Side Effects of Small Molecule Inhibitors?

Lung cancer is one of the most commonly diagnosed type of cancer and so it is fitting that we start the first of our disease-specific oncology series with this diagnosis. This week, we continue our discussion on metastatic non-small cell lung cancer, focusing on NSCLC with driver mutations.

* The approach to treatment of a patient with widespread metastatic NSCLC (mNSCLC) is very different than a patient without distant disease, which highlights why we do what we do:

- Important to complete staging (discussed in prior episodes) to determine the extent of disease

- Important to check molecular testing (looking for mutations in the cancer cells) and IHC for tumor proportion score (TPS) helps determine treatment options

- If your molecular testing is identified in a driver mutation gene, there are targeted options for this!

*Driver mutations are predictive of response to an oral therapy and a LACK of response to immune therapy (particularly in EGFR and ALK mutated patients)

* EGFR Mutation:

- Pay attention to the types of mutation in EGFR (not all are the same):

-- Exon 19 deletion

-- Exon 19 L858R

-- Exon 21 T790M

-- Exon 20 Insertion (Osimertinib [see below] cannot be used for this mutation)

- Osimertinib is first-line standard of care for patients with EGFR

-- Used to be a second-line agent. Many patients with EGFR mutations receiving earlier generation TKIs would develop resistance and when these tumors were sequenced, they would have Exon 21 T790M mutations. Osimertinib was effective even with this mutation and had superior overall survival data compared to chemotherapy (AURA3 Trial)

--Now it is used in first-line setting for patients with EGFR mutation based on the FLAURA trial

--- In this study, patients received osimertinib as first line vs. older generation EGFR-targeting TKIs (erlotinib or gefitib) and Osimertinib had better outcomes:

---- Showed that the median OS was 38.6 months with Osi vs. 31.8 months; also improved brain penetration! 

---- Also effective in patients with metastatic disease to the brain:

----- Only 6% of patients had CNS progression with Osi vs. 15% with others

- What if a patient is on Osi and later develops new brain mets?

-- If there is progression within just the brain (and good control in other sites of the body) you can refer patient to Radiation Oncology for SRS

-- Remember, based on discussion with Dr. Osmundson in our RadOnc lectures (Episode 028), it is important to HOLD Osimertinib if patient is going to get radiation to minimize the side effects

- What is patient had progression of disease in several sites throughout the body?

-- Management is less straightforward.

-- In many of these cases, you can consider:

--- Consolidative radiation - If small amounts of disease

--- Changing therapy - If there has been widespread progression; likely would change to chemotherapy (without IO, since lower predictive response to IO with EGFR mutation)

---- No clear guidelines if you should continue the TKI

---- Remember that IO + TKIs can cause increased risk of side effects, such as pneumonitis and hepatitis. DO NOT DO THIS!

* ALK Mutation:

- There are many options for ALK mutations

-- The first generation drug is crizotinib

--- Lots of side effects —> “It is crazy to start with crizotinib”

--- Studies for later generation TKIs were compared to crizotinib

-- Many people today will use third generation ALK-inhibitor alectinib (Important trials: ALEX Trial and J-ALEX Trial)

--- With alectinib, PFS 34.8 months, RR 83%, less CNS progression (12% vs 45%)

--- 5 year OS rate 62.5%

- What to do with disease progression while on ALK inhibitor?

-- In ALK, you can actually switch to another ALK inhibitor and many will respond well

--- Of course, with each change, you may expect not as great of a response

* Lots of other mutations!

- TFOC recommends just looking these up!

-- Link to NCCN Guidelines on NSCLC; Page 41 has full list!

- Another way to think about this, when do we NOT do TKIs as first line:

-- KRAS G12C

-- EGFR Exon 20 Insertion

-- HER2

- How do you counsel a patient when considering/starting a TKI?

-- Patients with highest chance of having a targeted mutation are younger non-smokers with adenocarcinoma

-- Set expectations: great outcomes overall, but still not a cure.

-- Remembering the drugs: All TKIs usually end in “-nib”

-- In general, the way we recommend remembering this: “Fatigue, GI, Derm (skin/nail changes)”; rarely pneumonitis

References:

* AURA3 Trial - https://www.nejm.org/doi/full/10.1056/NEJMoa1612674

Established osimertinib was better than chemo for patients with EGFR mutation and acquired Exon 21 T790M resistance mutation

* FLAURA Trial - https://www.nejm.org/doi/full/10.1056/nejmoa1713137

Established osimertinib as first-line agent for patients with EGFR mutation

* ALEX Trial - https://www.nejm.org/doi/full/10.1056/nejmoa1704795

Helped establish alectinib as superior for ALK mutations compared to crizotinib

* J-ALEX Trial - https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(17)30565-2/fulltext

Helped establish alectinib as superior for ALK mutations compared to crizotinib

* NCCN Guidelines on NSCLC - https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1450

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