Dr Lin Shares Systemic Therapies to Overcome Resistance in ALK+ Lung Cancer

Jessica J. Lin, MD, Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts, presented systemic therapies used to overcome anaplastic lymphoma kinase (ALK) resistance and the importance of local therapies to prevent disease progression.

There are various ALK-tyrosine kinase inhibitors (TKIs) developed over the past decade approved by the FDA to treat advanced ALK+ lung cancer. The first-generation (1G) ALK-TKI was crizotinib, second-generation (2G) inhibitors include ceritinib, alectinib, brigatinib, and ensartinib, and the third-generation (3G) inhibitor which is lorlatinib.

Each generation is characterized by increased potency, improved central nervous system (CNS) activity, and broader activity against ALK resistant mutations.

Currently, newly diagnosed patients with advanced ALK+ non-small cell lung cancer (NSCLC) receive standard-of care next-generation ALK-TKIs. Most commonly, alectinib is used to treat patients on the first-line setting. Secondary options are lorlatinib, chemotherapy, or clinical trials.

“In 50 to 60 percent of cases that are resistant to 2G ALK-inhibitors, the resistance is caused by a secondary ALK mutation. The most common mutations are G1202R and I1171N, which are both highly resistant to ALK-inhibitors,” said Dr Lin.

Notably, there is not a single predominant compound mutation that emerges from lorlatinib-resistance. However, many compounds contain either a G1202R or I1171 mutation, which are the most common to arise after alectinib resistance prior to a 3G treatment.

2G inhibitors such as certinib and brigatinib show potential after disease progression due to differential potency levels against various ALK-mutations. During the ASCEND-9 trial, ceritinib showed modest activity with response rates ranging from 16% to 25% with a median progression-free survival (PFS) rate of 4.4 months.

Dr Lin clarified that ceritinib should primarily be used after disease progression with alectinib.

Data of brigatinib show greater appeal, wherein the ATOMIC trial demonstrated the response rate was 40% with a median PFS of 6.4 months.

There are other options available when resistance develops against a 2G ALK-inhibitor. In a phase 2 study, lorlatinib, with high potency, CNS penetration, and an FDA approval for those with disease progression after 2G resistance, patients had a response rate of 40% with a median PFS of approximately 7 months.

“With lorlatinib, both PFS and overall response rates (ORR) were similar and significantly longer for patients with tumors were known to have baseline ALK-mutations as opposed to those who did not. These results suggest that lorlatinib has higher efficacy in patients with ALK-mutations after progression following 2G ALK-TKIs,” continued Dr Lin.

However, Dr Lin noted that patients with ALK-mutated negative tumors can still respond to lorlatinib and they should not be entirely excluded from receiving this treatment option.

Dr Lin highlighted that many compound ALK-mutations, both 2G and 3G, may be refractory or insensitive to all current ALK inhibitors. Data suggests that structurally distinct TKIs may ultimately be required to overcome diverse ALK-mutations after lorlatinib.

Emerging data from show gliteritnib, an FLT3/AXL/ALK inhibitor, had preclinical potency against an array of single ALK-mutations. However, gliteritnib was not potent against both G1202R and D1203N base mutations. This indicates that one ALK-inhibitor may not be able to overcome double mutations following lorlatinib.

“NVL-655 is another novel ALK-TKI that is highly selective and brain-penetrant. Preclinical data was presented at the 2021 AACR to demonstrate potency against G1202R double-base mutations. This treatment will enter phase 1 trials next year,” said Dr Lin.

Current phase 1 testing is ongoing for TPX-0131 as a next-generation macrocyclic ALK-TKI that demonstrated efficacy against various mutations, including G1202R, but lacks potency against an I1171 base mutation.

“An important aspect of overcoming lorlatinib resistance is switching to another inhibitor, that may be potent on specific mutations. Additionally, going beyond inhibitors in monotherapy will be important. As patients receive increased potency, a significant percentage experience disease progression with or without an ALK mutation or compound,” continued Dr Lin.

This suggests that tumors are becoming more ALK-independent which can be linked to resistance or histologic transformation.

Dr Lin emphasized the critical importance of biopsies in genotyping to detect gene alterations and identifying phenotypic changes such as small cell or squamous cell transformations. Small cell transformation is significantly resistant to ALK-TKIs. Histologic transformations are important to identify for prognoses and treatment selection.

“Resistance is an inevitable challenge that limits clinical benefit from ALK-TKIs in most patients with advanced ALK+ lung cancer. The prevalence of ALK-independent resistance mechanisms increases with the use of more potent ALK inhibitors, like lorlatinib, highlighting the urgency to develop combination strategies that can overcome ALK independent resistance,” concluded Dr Lin. – Alexa Stoia