Strategizing Effective Ways to Overcome TKI Resistance in ALK+ NSCLC

February 8, 2021
Hayley Virgil
Hayley Virgil

Senior Editor, OncLive®
Hayley Virgil heads OncLive's feature article efforts and specializes in social issues and equality in oncology. Prior to joining the company in early 2020, she worked as an editor in numerous industries, including media, marketing, hospitality, and computer science, and freelanced in subjects such as history, culture, and the natural sciences.

Vincent Lam, MD, describes frontline indications for patients with advanced, ALK-positive non–small cell lung cancer, as well as strategies that can be utilized to overcome TKI resistance in later lines of therapy.

ALK TKIs have proven efficacy in the frontline treatment of patients with advanced, ALK-positive non–small cell lung cancer (NSCLC), but several factors must be taken into consideration when determining later-line approaches to combat the complex resistance mechanisms that develop, Vincent Lam, MD, said in a presentation during the 18th Annual Winter Lung Cancer Conference, a program hosted by the Physicians Education Resource®, LCC.1

“The acquired resistance landscape upon progression with a second-generation ALK TKI is quite diverse and we’re still learning about new bypass mechanisms and second drivers,” Lam, an assistant professor of the Upper Aerodigestive Group at John Hopkins Sydney Kimmel Cancer Center, said during the presentation. “The overall [theory] right now is to stay on the current TKI as long as possible, [implement] local ablative therapy for oligoprogression or dose escalation for alectinib [Alecensa] in central nervous system [CNS]–only progression, and, if available, utilize repeat molecular profiling to help inform our next treatment option.”

In his talk, Lam went into further described frontline indications for this patient population, as well as strategies that can be utilized to overcome TKI resistance in later lines of therapy.

Exploring the Frontline Treatment Landscape

Updated results from the phase 3 ALEX study (NCT02075840), which examined the use of alectinib versus crizotinib (Xalkori) in patients with previously untreated, ALK-positive NSCLC, indicated that those who received alectinib experienced a 5-year survival rate of 62.5%. The median progression-free survival (PFS) was 34.8 months in the alectinib arm compared with 10.9 months in the crizotinib arm.2 

Based on findings from ALEX, in November 2017, alectinib was approved by the FDA for the frontline treatment of patients with ALK-mutated NSCLC.3 Although other agents have also been approved for use in the first-line setting, such as brigatinib (Alunbrig), which was approved by the FDA in May 2020 and ceritinib (Zykadia), which was approved in May 2017,4,5 alectinib is the most commonly used option, according to Lam.

Another agent that has emerged in the frontline setting is lorlatinib (Lorbrena). Results from the phase 3 CROWN study (NCT03052608), which examined the use of lorlatinib versus crizotinib in patients with advanced ALK-positive NSCLC, showed a significant improvement in PFS with lorlatinib. The median PFS had not been reached (NR) in those who received lorlatinib (95% CI NR-NR) versus 9.3 months (95% CI, 7.6-11.1) in the crizotinib arm (HR, 0.28; 95% CI, 0.19-0.41; P <.001). Additionally, lorlatinib demonstrated improved survival without CNS progression over crizotinib (HR, 0.07; 95% CI, 0.03-0.17). 

However, Lam noted that toxicity is an important consideration when determining whether a patient should receive lorlatinib. Adverse effects such as hypercholesterolemia (70%), hypertriglyceridemia (64%), weight increase (38%), peripheral neuropathy (34%), and cognitive effects (21%), have all been associated with lorlatinib.6

“Lorlatinib is undoubtedly coming to the first-line landscape in the future and we’ll have to see what acquired resistance looks like in this new context,” Lam said.

Forming Effective Strategies to Combat TKI Resistance

f possible, it’s ideal to keep patients on their current TKI for as long as possible, according to Lam. In cases of oligoprogression, local ablative therapy, such as radiation and/or surgery, has been shown to yield an additional 6 months of disease control in a retrospective analysis. Also, for patients on alectinib with CNS-only progression, escalating treatment with alectinib to 900 mg twice daily may be useful.7

When selecting therapies for the second-line of treatment and beyond, options include starting with the third-generation TKI lorlatinib if it has not been used already. Treatment with a second-generation TKI such as brigatinib could also represent an effective strategy for some patients, according to Lam. Other options in the second line of treatment and beyond include targeted agents that bypass resistance pathways, such as MET, EGFR, or BRAF, and chemotherapy-based regimens.

According to Lam, several factors need to be considered when choosing among these regimens.

“It’s helpful to review the general paradigm of required resistance and ALK,” Lam said. “About 50% of resistance to ALK TKIs is due to acquired mutations in the ALK gene that impair the efficacy of the current ALK TKI,” explained Lam “There is a broad spectrum of these mutations, the most common being the solvent front mutation [ALK] G1202R; this is considered to be an ALK-dependent acquired resistance since the tumor is primarily still signaling through the ALK receptor tyrosine kinase; next-generation TKIs should be effective.”

Other acquired resistance is ALK-independent and involve 2nd driver alterations, histologic transformation (such as small cell transformation), or other bypass mechanisms that mediate tumor proliferation despite adequate ALK inhibition. Just switching to a more potent ALK TKI likely won’t overcome this resistance.

The Importance of Repeat Molecular Profiling

Moreover, the use of molecular profiling should be employed to inform decisions in later lines of treatment; this can be done both through standard tumor tissue biopsies, as well as plasma-based assays, although Lam noted that some limitations exist with liquid biopsies. 

“If genetic testing reveals a G1202R mutation, it’s best to pursue treatment with lorlatinib, while someone with a L1196M mutation should be treated with brigatinib," Lam explained. Additionally, patients with MET amplifications and fusions should be treated with crizotinib or capmatinib (Tabrecta), while those with EGFR and BRAF V600E mutations and NRG1 and RET fusions should be approached with a targeted agent for second driver mutations, Lam added.

Repeat molecular profiling may be able to help inform options following disease progression. The National Cancer Institute is supporting a large clinical trial effort, the ALK Master Protocol (NCT03737994), to determine how effective a combination of different biomarker/ALK inhibitors are in improving clinical outcomes for patients with stage IV ALK-positive NSCLC.

The ALK Master Protocol is open across the United States and it is enrolling patients with ALK-positive, stage IV NSCLC who have progressed on a second-generation TKI. To be eligible for enrollment, patients had to have measurable disease and an ECOG performance status of 0-2. Patients were able to receive prior crizotinib, but they could not have received lorlatinib. Notably, patients with stable, untreated brain metastases are permitted to enroll.

Examining Efficacy of Second-Line Agents

Although lorlatinib has demonstrated benefit in patients with ALK resistance mutations, the agent has been shown to elicit less efficacy in patients without an ALK mutation. Following treatment with a second-generation TKI, patients with no mutations had an overall response rate (ORR) of 27% (95% CI, 18%-38%) with the agent compared with an ORR of 69% (95% CI, 49%-85%) in patients with at least 1 mutation. Additionally, the median PFS achieved with lorlatinib is essentially cut in half in patients without ALK mutations, going from 11.0 months to 5.4 months (HR, 0.47).8

“Notably, only about half of the patients in this study had a fresh biopsy specimen obtained for tissue biopsy profiling prior to starting lorlatinib,” said Lam. “The actual number of responders who actually had no ALK resistance mutation may actually be lower than what was detected in the study.” 

Available data also support the use of brigatinib following treatment with a second-generation TKI. Preliminary results from the phase 2 ATOMIC study (NCT02706626) showed that brigatinib elicited an ORR of 40% and a median PFS of 7.0 months in patients who were primarily previously treated with alectinib; the median overall survival (OS) had not yet been reached.9 Moreover, data from the BRIGALK expanded access study (NCT02784158), which primarily enrolled patients who were previously treated with ceritinib, brigatinib elicited an ORR of 50%, a median PFS of 6.6 months, and a median OS of 17.2 months.10

The ALK Master Protocol (NCT03737994) is open across the United States and it is enrolling patients with ALK-positive, stage IV NSCLC who have progressed on a second-generation TKI. To be eligible for enrollment, patients had to have measurable disease and an ECOG performance status of 0-2. Patients were able to receive prior crizotinib, but they could not have received lorlatinib. Notably, patients with stable, untreated brain metastases are permitted to enroll.

For the research, patients will be stratified based on their ALK mutation to 1 of several different TKIs or chemotherapy. The primary objectives of the study include ORR to ALK TKI based on ALK mutations, ORR to chemotherapy based for patients with non–ALK-mutant disease, and ORR to crizotinib based on ALK L1198F or MET amplifications. Secondary end points include PFS, duration of response, OS, CNS ORR, as well as safety and tolerability.

Lastly, when examining chemotherapy-based options in this patient population, platinum-based chemotherapy and pemetrexed are the most commonly used therapies, noted Lam. Patients with ALK-positive disease are known to demonstrate increased sensitivity to pemetrexed.

“That being said, the IMpower150 chemotherapy and immunotherapy regimen with carboplatin, paclitaxel, bevacizumab [Avastin], and atezolizumab [Tecentriq] is another approved chemotherapy-based option,” concluded Lam, “as that study did show PFS benefit compared with chemotherapy and bevacizumab alone for the EGFR/ALK [patient] subgroup[s].”

Dr. Lam cautions that EGFR patients may be largely driving the clinical benefit seen there though, as ALK patients were only a small percentage of that combined subgroup.


  1. Lam V. Overcoming resistance to ALK TKIs. Presented at: 18th Annual Winter Lung Cancer Conference; February 5-7, 2021; Virtual.
  2. Peters S, Mok TSK, Gadgeel SM, et al. Updated overall survival (OS) and safety data from the randomized, phase III ALEX study of alectinib (ALC) versus crizotinib (CRZ) in untreated advanced ALK+ NSCLC. J Clin Oncol. 2020;38(suppl 15):9518. doi:10.1200/JCO.2020.38.15_suppl.9518
  3. FDA approves Genentech’s Alecensa (alectinib) as first-line treatment for people with specific type of lung cancer. News release. Genetech. November 6, 2017. Accessed February 8, 2021.
  4. U.S. FDA approves Takeda’s ALUNBRIG (brigatinib) as a first-line treatment option for patients diagnosed with rare and serious form of lung cancer. News release. Takeda. May 22, 2020. Accessed February 8, 2021. 
  5. FDA broadens ceritinib indication to previously untreated ALK-positive metastatic NSCLC. News release. FDA. May 26, 2017. Accessed February 8, 2021.
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  9. Stinchcombe T, Doebele RC, Wang XF, et al. Preliminary results of single arm phase 2 trial of brigatinib in patients (pts) with progression disease (PD) after next-generation (NG) anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKIs) in ALK+ non-small cell lung cancer (NSCLC). J Clin Oncol. 2019;37(suppl 15):9027. doi:10.1200/JCO.2019.37.15_suppl.9027
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