Targeted drugs are the first choice for patients with advanced lung cancer who have ALK mutations. The “scientific name” for these drugs is “Tyrosine Kinase Inhibitor (TKI),” and they are now in their third generation and are all oral drugs. The following table lists the five ALK-targeted drugs that are currently available in the United States, of which crizotinib, ceritinib, and alectinib are also available in China.
| Generic name | Trade name | Manufacturing Company | Category |
| Crizotinib | Cecrolimus | Pfizer | First generation |
| Ceretinib | Zenda | Novartis | Second generation |
| Aletinib | Ansamax | Roche | |
| Brigatinib | Alunbrig | Ariadh | |
| Lorlatinib | Lorbrena | Pfizer | Third generation |
Patients taking targeted drugs face two scenarios. One is that the tumor remains uncontrolled since the start of the drug; the other is that the disease is controlled for a period of time, but then begins to worsen or even metastasize. This is called “drug resistance” in medical terms.
What should we do at this point? Let’s look at the “root” of drug resistance.
Why does resistance occur?
Why does resistance occur?
The emergence of new targets that were previously “untargeted” by drugs
There are many resistance mutations in ALK-targeted drugs, including the L1196M, G1269A, C1156Y, and G1202R sites, and there is no significant difference in their incidence, and multiple mutations can occur at the same time.
Target sites have acquired the ability to “transform”
.
Another scenario is the presence of ALK variants, particularly the G1202R locus in variants 1 and 3, which are associated with resistance to ALK-targeted drugs.
Tumors bypass ALK and “find another way” to continue to amplify
For example, EGFR mutations, c-KIT amplification, KRAS mutations, etc.
Tumor transformation to other pathological types and “escalation” of invasive metastatic ability
Changes in tumor cell type and morphology increase the ability to invade and metastasize, making targeted drugs less effective.
What happens after drug resistance?
At present, the most commonly used clinical first-line ALK-targeted drugs in China are crizotinib or aletinib, and foreign guidelines also recommend ceritinib, but it is rare in China because this drug is only reimbursed by health insurance as second-line therapy. In the following, we will talk about the “response” to resistance to each of these first-line drugs.
Crizotinib
Crizotinib → second-generation ALK-targeted drug → Lorlatinib
After crizotinib resistance, doctors usually recommend another genetic test, and if a resistance mutation is found, a second-generation ALK-targeted drug – ceritinib, alectinib, or brigatinib – can be chosen. As seen in the table below:
- Brigatinib has the best efficacy and fewer adverse effects, but it is not yet available in China and patients can only use it in clinical trials; aletinib is slightly less effective but significantly better than ceritinib.
- If brain metastases occur, the order of merit of the three drugs is also Brigatinib > aletinib > ceritinib.
Table Comparison of the efficacy and adverse effects of 3 second-generation targeted drugs after crizotinib resistance
| Drugs |
Ceretinib |
Aletinib |
Brigatinib |
| 56% | 50% | 54% | |
| remission of central nervous system lesions (e.g., brain metastases) |
36% |
57% | 67% |
| Median progression-free survival | 6.9 months | 8.9 months | 12.9 months |
| Adverse reactions | Interstitial pneumonia and prolonged Q-T interval may occur in a very small number of patients. |
Adverse effects are mild and largely tolerated. |
Gastrointestinal reactions are common and mostly tolerated. |
(Note: Prolonged Q-T interval is an arrhythmia that can be life-threatening in severe cases)
What if I become resistant again after a drug change?
But second-generation drugs don’t really “stick” for long, and are even more prone to resistance mutations than crizotinib, and often the more problematic compound resistance mutations. The current guidelines recommend a third-generation targeted agent, Lorlatinib, which covers nine resistance mutations, and as a third-line treatment, can put 39% of patients into remission and half of them will have progression-free survival of nearly six months.
Overall, the longest progression-free survival time for patients with treatment regimens of one generation of resistance for two generations and two generations of resistance for three generations is up to 28.9 months.
So, what happens when the “ultimate” Lorlatinib is also resistant?
There is no fourth-generation drug, so what happens when Lorlatinib is also resistant? Let’s look at this patient’s story.
In 2016, a case of “cycling through ALK resistance” was published in the New England Journal of Medicine, a leading medical journal: after the patient was resistant to crizotinib, he switched to Lorlatinib, but soon became resistant to it as well. The doctor then retested the patient and found that he had a new mutation that was sensitive to crizotinib, and after reintroduction of crizotinib, he was in remission again. As you can see, it is still possible to revert to a first- or second-generation drug after Lorlatinib resistance.
Alectinib (ceritinib) → Lorlatinib
After resistance to first-line treatment with either aletinib or ceritinib, genetic testing is also done for Lorlatinib if there is a resistance mutation.
Patients who are resistant to alectinib can achieve remission with Lorlatinib in 31% of patients, and half have progression-free survival of more than 9 months, with the longest progression-free survival of 43.8 months. If Lorlatinib is also resistant, genetic testing will also need to be redone. If there is a new mutation that is sensitive to a first- or second-generation drug, it can be cycled.
So, regardless of the genetic test, what happens if there is no longer a “target” that can be targeted?
Don’t forget the chemotherapy combination regimen
.
Chemo±bevacizumab, which can put patients back into remission and possibly back on target
Some patients who are crizotinib-resistant can achieve remission again and may even be sensitive to crizotinib again with platinum-containing two-drug chemotherapy. Chemotherapy combined with bevacizumab may be more effective.
Chemotherapy + Atezolizumab ± bevacizumab, preferable for patients with lung adenocarcinoma
For patients with lung adenocarcinoma, chemotherapy combined with the immune drug Atezolizumab was better than chemotherapy alone, with or without the addition of bevacizumab. Patients had a median progression-free survival time of 8.3 months (6.8 months with chemotherapy alone).
Summary
- Patients with ALK-positive lung cancer, regardless of which targeted agent is used for first-line therapy, will have to undergo additional genetic testing after resistance occurs.
- After resistance to first-line therapy with crizotinib, second-generation drugs are available, with Brigatinib being the best; after resistance to second-line therapy, genetic testing is done again, and if the appropriate “target” is found, the third-generation target, Lorlatinib, can be used.
- First-line therapy with either ceritinib or aletinib can be followed by Lorlatinib after resistance.
- After resistance to a targeted agent, if there is no longer a “target”, chemotherapy can be used. In the case of adenocarcinoma, chemotherapy + Atezolizumab ± bevacizumab is the treatment of choice.
- The above recommendations are for reference only and patients should follow their doctor’s advice.