First Things First: Navigating ALK-Positive Metastatic Non-Small Cell Lung Cancer Treatment Options—A Podcast

00:00:00: You are listening to an ADIS Journal podcast.

00:00:06: Hello and welcome to the podcast.

00:00:08: My name is Dr.

00:00:09: Eric Singhi and I'm a thoracic and head and neck medical oncologist and assistant professor at the University of Texas, MD Anderson Cancer Center.

00:00:17: Hello, my name is Eric Navarbe and I'm the medical director of health outcomes at Bellar University Medical Center and a head and neck and lung cancer doctor there as well.

00:00:27: In today's podcast, which is being hosted in the journal Targeted Oncology, we discuss the use of first-line treatments in patients with anaplastic lymphoma kinase positive or ALC-positive metastatic non-small cell lung cancer.

00:00:44: We will provide an overview of the guidelines for first-line treatment and discuss the clinical trials and evidence of efficacy and safety supporting these first-line treatment options, sequencing strategies, patient attrition from the first line to the second line, and the appropriate treatment based on the available data.

00:01:04: Eric, can you provide us with an overview of ALK-positive non-small cell lung cancer?

00:01:11: Sure, so MS-CLC, it accounts for approximately eighty-five percent of all lung cancers and is the leading cause of cancer deaths worldwide.

00:01:19: ALK-positive non-small cell lung cancer represents three to five percent of all non-small cell lung cancer cases, and is more common in younger patients and patients with no smoking history.

00:01:28: ALK-positive NSLC is characterized by a genetic rearrangement of the ALK gene, leading to the expression of fusion proteins that function as potent oncogenic drivers.

00:01:37: These gene arrangements also confer sensitivity to treatment with ALK tyrosine kinase inhibitors or TKIs.

00:01:44: Brain metastases in patients with ALK-positive NSLC remain a key clinical challenge, with the baseline and cumulative incidences higher than with most other oncogenes.

00:01:54: So in clinical studies, twenty-six to forty-two percent of patients had brain metastases diagnosed at baseline.

00:02:00: Furthermore, brain metastases can develop after the initial diagnosis of ALK-positive non-swall cell lung cancer, with more than half of patients developing brain metastases over the course of their disease, and varying intracranial outcomes reported in clinical trials over different follow-up periods.

00:02:15: Brain metastases are associated with a poorer prognosis, therefore treatments to control intracranial disease and delay the onset of new brain metastases are important, and central nervous system or CNS response can influence treatment choices.

00:02:29: A real-world study published this year showed that brain metastases continue to impact Medicare patients with incident brain metastases associated with a higher risk of mortality.

00:02:39: Patients without positive NSCLC often need multiple lines of therapy due to development of resistance, disease progression, brain metastases, or adverse events.

00:02:49: Various options are available for the treatment of ALK-positive NSCLC.

00:02:53: Therefore, it is important to make an informed decision on which treatment to use in the first line.

00:02:58: Eric, can you provide us with an overview of the current guidelines for first-line treatment in patients with ALK-positive metastatic non-small cell lung cancer?

00:03:06: Yes.

00:03:07: Currently, six ALK-TKI's are available for patients with ALK-positive metastatic non-small cell lung cancer.

00:03:14: According to the NCCN Clinical Practice Guidelines in Oncology, second-generation ALK-TKI, such as Electinib, Purgatinib, and Insartinib, and the third-generation ALK-TKI, Borlotinib, are recommended as preferred first-line treatments for patients with ALK-positive metastatic non-small cell lung cancer.

00:03:35: The third-generation ALK-TKI, LOR-Latinib, was designed with improved ability to cross the blood-brain barrier and to overcome ALK resistance mutations.

00:03:46: These next-generation ALK-TKIs have demonstrated superior systemic and intracranial efficacy, including improved progression-free survival or PFS, compared to Crisotnib, a first-generation ALK-TKI in randomized clinical trials.

00:04:02: These results are summarized in supplemental figure one that accompanies this podcast.

00:04:09: Other ALK-TKIs can be useful in certain circumstances.

00:04:13: When deciding upon a treatment, clinicians select an ALK-TKI based on the balance of its clinical efficacy profile, including CNS activity, as well as its adverse event profile.

00:04:26: Eric, can you tell us about the trials and the results that position the second-generation ALC-TKIs as preferred agents in the current guidelines?

00:04:35: Absolutely.

00:04:36: So several Phase III studies have compared the second-generation ALC-TKIs to first-generation Krasotnib, and these include Electinid in the ALC study, Brigatinid in the Alto-IL study, and Insartinid in the Exalt III study.

00:04:49: These studies led to the U.S.

00:04:51: Food and Drug Administration, or FDA, approval of these ALP-TKI's in the first line setting.

00:04:57: The primary analysis from the ALEKS trial showed significantly improved investigator-assessed PFS with Electinib compared with Chrysotinib with a hazard ratio of zero point four seven.

00:05:07: Time to CNS progression was significantly longer with Electinib than with Chrysotinib with a hazard ratio of zero point one six.

00:05:14: The twelve month cumulative incidence rate was nine point four percent with Electinib versus forty one point four percent with Chrysotinib.

00:05:21: In a follow-up analysis, At thirty-seven point eight months of median follow-up, median PFS was thirty-four point eight months with electinib with a four-year PFS rate of forty-four percent.

00:05:30: In the final analysis of the ALEC study, after a median follow-up of fifty-three point five months with electinib and twenty-three point three months with chrysotinib, median overall survival was eighty-one point one months with electinib compared with fifty-four point two months with chrysotinib.

00:05:45: The seven-year overall survival rate was forty-eight point six percent with electinib compared with thirty-eight point two percent with chrysotinib.

00:05:52: However, the study was not powered to demonstrate any statistically significant difference in overall survival.

00:05:57: Eric, can you review the key efficacy results from the other second-generation ALK TKI's?

00:06:03: Of course.

00:06:04: Let's start with the first interim analysis from the Alto-I-L trial, which showed superior PFS with Brigatinib compared with Chrysotinib, and a hazard ratio of zero point four.

00:06:15: nine by blinded independent Santro review.

00:06:18: In the follow-up analysis, at forty point four months of median follow-up, the median PFS was twenty-four months with Pregatinib, with a four-year PFS rate of thirty-six percent.

00:06:30: The four-year overall survival rate was sixty-six percent with Pregatinib, and the four-year intracranial PFS rate was forty-six percent in the intention to treat population.

00:06:41: In the Exalt-III trial, with a median follow-up of twenty-three point eight months, a median PFS was twenty-five point eight months with insardinib in the intention to treat population.

00:06:53: At the time of the final analysis of overall survival, no statistical significant difference was observed between insardinib and chrysodinib.

00:07:02: Eric,

00:07:03: can you talk through the key efficacy results for the third generation ALP-TKI, lorladinib?

00:07:09: Certainly.

00:07:10: The interim analysis from the Crown study demonstrated significantly longer PFS or latinib than chrysotinib with a hazard ratio of zero point two eight.

00:07:19: In subsequent three- and five-year follow-up analyses, or latinib continued to show superior efficacy in patients with ALK-positive metastatic NSCLC.

00:07:28: As presented at ASCO twenty-twenty-four by Dr.

00:07:31: Ben Sullivan, at a median follow-up of sixty point two months, median PFS was not reached with or latinib with a five-year PFS rate of sixty percent.

00:07:40: which is unprecedented in the treatment of stage IV nonspecial lung cancer.

00:07:44: The time to intracranial progression was longer with urlatinib than with chrysotinib, with a hazard ratio of zero point zero

00:07:50: six.

00:07:51: The probability of being free of intracranial progression was ninety-two percent with urlatinib and twenty-one percent with chrysotinib at five years.

00:07:59: Brain scans were done every eight weeks.

00:08:02: Overall survival follow-up is still ongoing.

00:08:04: The results were immature at the time of the five-year analysis.

00:08:08: Now that we've discussed efficacy, let's talk about some of the safety data that have come from these clinical trials.

00:08:15: With electinib, the most common adverse events were constipation in thirty-seven percent of patients, anemia in twenty-six percent, and fatigue in twenty-two percent.

00:08:26: Great three to five adverse events occurred in fifty-two percent of the patients treated with electinib.

00:08:32: Adverse events led to doethic interruptions in twenty-six percent of patients, dose reductions in twenty percent of patients, and treatment discontinuation in fourteen percent of patients.

00:08:43: With reasons for discontinuation, including increased alanine immunotransferase, increased aspartate immunotransferase, and pneumonitis.

00:08:53: With progadneb, the most common adverse events for diarrhea in fifty-eight percent of patients increased blood creatine, phosphokinase in fifty percent, and cough in thirty-six percent.

00:09:05: Myalgia was reported in ten percent of patients treated with brigatinib versus eight percent in patients treated with crasatinib.

00:09:13: Grade three or four adverse events occurred in seventy percent of patients treated with brigatinib.

00:09:18: Brigatinib was associated with the unique side effect of interstitial lung disease or pneumonitis which occurred in six percent of patients and led to dose reductions in one percent.

00:09:29: Adverse events led to dose interruptions in seventy-two percent of patients, dose reductions in forty-four percent of patients, and treatment discontinuation in thirteen percent.

00:09:41: Within Sardinib, the most common treatment emergent adverse event were ration seventy-one percent of patients, increased alanine immunotransferase in fifty percent, and increased aspartate transaminase in thirty-eight percent.

00:09:56: Grade three or four adverse events occurred in fifty percent of patients.

00:10:00: Treatment-related adverse events led to dose reduction in twenty-four percent of patients and treatment discontinuation in nine percent.

00:10:09: With Orladnib, the most common adverse events were hypercholesterolemia in seventy-two percent of patients, hypertriglycerideemia in sixty-six percent, and edema in fifty-seven percent.

00:10:20: Grade three or four adverse events occurred in seventy-seven percent of patients.

00:10:24: Adverse events led to dose interruption in sixty-two percent of patients, dose reduction in twenty-three percent, and permanent discontinuation in eleven percent.

00:10:33: With LRLATNIB, CNS adverse events, unique but important adverse events to be aware of, were reported in forty-two percent of patients.

00:10:42: The majority, or eighty-six percent of these, events were grade one or two.

00:10:47: CNS adverse events were further broken down into cognitive effects that occurred in twenty-eight percent of patients.

00:10:52: mood effects in twenty-one percent, speech effects in six percent, and psychotic effects in five percent.

00:10:59: Among the hundred and forty-nine patients treated with relatinate in the crown study, cognitive effects led to permanent discontinuation in two patients, and psychotic effects led to permanent discontinuation in one patient, indicating that most of the CNS adverse events can be managed.

00:11:15: Overall, sixty percent of CNS adverse events result.

00:11:18: A post hoc analysis showed that Warlatnib dose reduction in the first sixteen weeks of treatment did not impact median progression pre-survival or time to intracranial progression, indicating that dose reduction may be a strategy to mitigate toxicity without compromising efficacy.

00:11:35: Another crowned post hoc analysis presented recently at ASCO- Twenty-Twenty-Five showed us that dose reductions enabled patients to continue treatment on Warlatnib.

00:11:43: The median duration of treatment after a reduction was forty-two point two months for the duration on a seventy-five milligram dose, one dose reduction, and twenty point seven months for the duration on a fifty milligram dose, two dose reductions.

00:11:57: Eric, given the treatment options, what are the common sequencing patterns observed in clinical practice?

00:12:04: The current NCCN guidelines indicate that following progression on second or third generation ALK-TKI, a different second or third generation ALK-TKI, can be used as subsequent therapy.

00:12:16: However, no prospective trials have compared these drugs sequentially, so data from clinical trials are limited.

00:12:23: Nutrition rates are high from first line to second line therapy, and many patients do not receive the second line

00:12:29: therapy.

00:12:31: A real-world study showed that among patients who discontinued first line therapy, forty-four percent did not receive the second line therapy.

00:12:39: In addition, clinical trials have shown that treatment efficacy declines with each additional line of therapy, suggesting that efficacy in the first line does not translate to the second line.

00:12:51: Therefore, patients may be most likely to derive the greatest clinical benefit from the most effective ALP-TKIs in the first line setting.

00:13:00: After five years of follow-up in the Crown study, in a small cohort of thirty-eight patients treated with Thorlatonib, who had at least one subsequent systemic anti-cancer therapy, The most common subsequent systemic therapy was electinib or chemotherapy.

00:13:16: In a U.S.

00:13:17: real-world evidence study that looked at sequencing patterns in patients treated with second-generation ALK-TKI's prior to lorlatinib's FDA approval, the most frequent treatment sequence was electinib followed by lorlatinib.

00:13:32: The FDA approved lorlatinib for ALK-positive non-small cell lung cancer in the first line in March of.

00:13:40: It is important to note that patients may eventually develop resistance to elk TKIs.

00:13:46: Depending on the specific elk TKI, resistance may be due to on-target alterations in elk, for example, mutations or gene amplification, elk independent resistance mechanisms, for example, the activation of a bypass signaling

00:14:01: pathway,

00:14:03: or progression in the CNS due to inadequate CNS penetration.

00:14:09: Therapy sequencing should thus consider the efficacy and safety outcomes with each drug, the possibility of drug resistance, and the health of the patient.

00:14:20: Decision should be made based on shared decision-making by the patient and the physician.

00:14:26: Eric, what are some considerations when selecting the appropriate first line treatment?

00:14:33: When considering treatment options for our patients without positive NSLC, we must remember that these patients are typically younger, and active, often caring for young families, and are working.

00:14:43: Therefore, delaying development of brain metastases and controlling active metastases is significant for them.

00:14:50: An oncology using the best treatment first should be prioritized because second-line treatment is not guaranteed.

00:14:56: If the patient does not tolerate the first-line treatment, then other options can be considered.

00:15:01: Given that the clinical trial is compared a second or third generation ALT-TKI against chrysotinib, Head-to-head clinical comparative data for these next generation of TKI's are lacking, resulting in difficulty comparing the efficacy and safety of these drugs and making a selection.

00:15:17: Comparisons between these trials should be made with caution as the methods and patient populations differ.

00:15:23: Notably, diagnostic methods varied with fluorescence and situ hybridization used in Alta-one-L and Exalt-three, and immunohistochemical assays in Alta-one-L,

00:15:32: Alex,

00:15:33: and Crown.

00:15:34: Full disease characterization is important when selecting first-line treatment, as the EML-IV ALC variant or presence of commutation may impact treatment response.

00:15:44: In a five-year matching adjusted indirect comparison, despite the small sample sizes, Lurlatnib demonstrated a numerical benefit over Lactinib in patients with baseline brain metastases.

00:15:54: The safety profile was similar between Lurlatnib and Lactinib in terms of adverse events leading to treatment changes.

00:15:59: However, rates of grade three and higher adverse events were higher with RELATED.

00:16:05: Selecting the optimal treatment requires an analysis of the available evidence with attention to systemic and intracranial efficacy, as well as patient factors and preferences.

00:16:14: Each of the ALT-TKI's has their own reported adverse event profile that needs to be considered.

00:16:20: However, the studies show that some of these events can be managed with dose reduction or interruption.

00:16:25: We mentioned earlier that brain metastases are highly prevalent among patients with ALT-positive NSDLC at baseline.

00:16:32: Some LTKIs have shown intracranial activity, as discussed earlier, and should be considered as options to delay development of brain metastases or for patients with baseline brain metastases.

00:16:43: Ultimately, the risk-benefit profile of each treatment option should be assessed and discussed with patients, taking into consideration disease and patient-related factors.

00:16:54: For example, extent of disease or tumor burden, performance status, and comorbidities.

00:17:00: As we conclude our discussion, we should mention some of the future directions in treating patients with ALK-positive metastatic non-small cell lung cancer.

00:17:08: Therapies in development for ALK-positive non-small cell lung cancer include fourth generation ALK-TKIs, fourth generation or double mutant active ALK-TKIs such as TPX-Zero-One-Three-One and NVL-Six-Five-Five are being developed to overcome the emergence of double ALK mutations.

00:17:31: with sequential use of single mutant-active second and third-generation ALK-TKIs.

00:17:39: The Phase I-II-ALCOV-I study is assessing NVL-SX-V-Vs in patients with previously treated metastatic ALK-positive non-small cell lung cancer and other solid tumors.

00:17:53: If approved, this may provide a treatment option after progression on second and third-generation ALK-TKIs.

00:18:00: Another study, the Phase III Alkazar study, is assessing NVL-SX-V-V compared with Electinib and treat naive patients with ALK-positive non-small cell lung cancer.

00:18:13: We also look forward to the continued crown data on Lroladnib and to wait the eventual time at which median PFS and overall survival are reached, as this will provide a more complete understanding of the long-term benefit of this ALK-TKI.

00:18:29: Thank you for listening to both Eric

00:18:49: and Eric.