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Spotlight

The ALTA-1 trial showed benefit of brigatinib over crizotinib in all patients with ALK-positive lung cancer and those with brain metastases.

Real-world data demonstrated most patients received another ALK-TKI after brigatinib if they experienced disease progression.

The BRIGHTSTAR study showed efficacy of adding local consolidative therapy to brigatinib and a randomized trial is underway.

Targeted Oncology: Could you discuss the outcomes of the ALTA-1 trial (NCT02737501) in patients with 

-positive non–small cell lung cancer (NSCLC)?

Brigatinib [Alunbrig] is a second-generation ALK inhibitor. We give a 90-mg daily dose for 7 days as a lead-in followed by 180 mg once a day if that 7-day, 90-mg dose is well tolerated. In the ALTA-1 trial, brigatinib was compared with crizotinib [Xalkori] in a randomized fashion. A few things to notice in the trial was that 1 line of prior systemic therapy was allowed for patients with locally advanced or metastatic NSCLC, so a patient could have gotten a dose or few cycles of chemotherapy before enrollment in the trial, and crossover was permitted at the time of progression if the patient was assigned to crizotinib. The primary end point was the blinded independent review committee [BICR]–assessed progression-free survival [PFS].

The objective response rate was better numerically, 74% with brigatinib and 62% with crizotinib.

 That didn’t change much based on presence or absence of brain metastases and so this is certainly an active drug in this space.

In the intent-to-treat [ITT] population, the investigator-assessed PFS was a median of 30.8 months [for brigatinib] vs 9.2 months with crizotinib with a HR of 0.43 [95% CI, 0.31-0.58; log-rank 

 < .0001]. Then the BICR-assessed PFS was 24 months with brigatinib vs 11 months with crizotinib [HR, 0.48; 95% CI, 0.35-0.66; 

Looking at those patients with baseline brain metastasis, intracranial PFS in the ITT population, there was more CNS [central nervous system] activity with brigatinib compared with crizotinib and more CNS progression in those patients who were assigned to crizotinib [HR, 0.44; 95% CI, 0.30-0.65; 

 < .0001], and then in patients who had baseline metastasis, the benefit was greater in favor in brigatinib [HR, 0.29; 95% CI, 0.17-0.51; 

 < .0001]. Crizotinib doesn't have a lot of CNS activity and that is being reflected in the Kaplan-Meier curves.

For overall survival [OS], there was a crossover from crizotinib to brigatinib so in the ITT population, there was no difference in OS with an HR of 0.81 [95% CI, 0.53-1.22; 

 = .305]. There may be a little bit more difference in OS in those with baseline brain metastases [HR, 0.43; 95% CI, 0.21-0.89; 

 = .020], but overall in the ITT population, there was no OS difference.

What real-world data are there for post-brigatinib treatment?

They looked at treatment patterns and outcomes after brigatinib therapy for 

Thirty patients received second-line ALK-TKI [tyrosine kinase inhibitor], and then 16 out of the 30 received second-line lorlatinib [Lorbrena]. If you look at the time to treatment discontinuation, patients were able to stay on the second-line ALK-TKI a total of 34.7 months, but in the patients who received lorlatinib it was 37.2 months so a little better.

What is the safety profile of brigatinib?

There are adverse events that we need to monitor with brigatinib.

 The first is the creatine phosphokinase elevation, and then hypertension. Brigatinib has some VEGF inhibition, and then also EGFR [inhibition]. In this case, there was rash that happened. Blood pressure is something we need to monitor. We also talk about the early onset pulmonary events, where patients can develop early onset but usually transient pulmonary events such as shortness of breath. Rarely, some patients require oxygen, but this can be treated with dose interruption, and some people can stay on the treatment with supportive care; that is seen in about probably 3% to 5% of patients.

What additional research is being done with brigatinib in this setting?

This brings us to another study. This is the BRIGHTSTAR study [NCT03707938], and this is a clinical trial of brigatinib plus local consolidative therapy [LCT] in stage IV or recurrent ALK fusion–positive NSCLC. This was not a randomized trial. Patients received brigatinib for 8 weeks, then had a scan. If there was no progressive disease, then they received brigatinib until progression, but also got local consolidative therapy, so if they had less than 3 active sites, then they got LCT to all sites. For more than 3 active sites, they [received] LCT to sites at the discretion of the treating physician.

If you look at the PFS rate across the 1-year, 2-year, or 3-year marks, although we shouldn’t do cross-trial comparison, numerically, there's a better PFS rate with the incorporation of LCT on top of brigatinib first-line treatment.

 There is an ongoing randomized trial that compares brigatinib alone and then intensification on top of brigatinib, adding LCT or chemotherapy; that is BRIGHTSTAR-2 [NCT06522360]. It was overall safe, and then showed us some promising results. BRIGHTSTAR-2 is a randomized trial that compares between those treatment intensification strategies on top of brigatinib.

1. Camidge DR, Kim HR, Ahn MJ, et al. Brigatinib versus crizotinib in advanced alk inhibitor-naive ALK-positive non-small cell lung cancer: second interim analysis of the phase III ALTA-1L trial. 

. 2020;38(31):3592-3603. doi:10.1200/JCO.20.00505

2. Camidge DR, Kim HR, Ahn MJ, et al. Brigatinib versus crizotinib in ALK inhibitor-naive advanced ALK-positive NSCLC: final results of phase 3 ALTA-1L trial. 

. 2021;16(12):2091-2108. doi:10.1016/j.jtho.2021.07.035

3. Delmonte A, Ahn M, Ghosh S, et al. Real-world treatment patterns and effectiveness of subsequent treatments following first-line (1L) brigatinib for patients with anaplastic lymphoma kinase positive (ALK+) non-small cell lung cancer (NSCLC) from ALTA-1L. 

. 2024;9(suppl 3):1-53. doi:10.1016/esmoop/esmoop102569

4. Elamin Y, Gandhi S, Saad M, et al. BRIGHTSTAR local consolidative therapy with brigatinib in tyrosine kinase inhibitor-naïve ALK-rearranged metastatic NSCLC. 

. 2023;18(suppl 11):S96. doi:10.1016/j.jtho.2023.09.109

During a Case-Based Roundtable® event, Chul Kim, MD, discussed the ALTA-1 trial and BRIGHTSTAR trials of brigatinib in ALK+ lung cancer in the first article of a 2-part series.

Brigatinib Plus Local Consolidative Therapy Shows Promise in ALK+ NSCLC

Targeted Oncology: Please discuss the long-term data from the KEYNOTE-407 trial (NCT02775435) evaluating chemotherapy plus pembrolizumab.

Data from the KEYNOTE-407 study led to FDA approval of the combination of chemotherapy plus pembrolizumab [Keytruda] for patients who were treatment naive with non–small cell lung cancer [NSCLC] and squamous histology.

 In this trial, patients who had stage IV disease and had no symptomatic brain metastases were included.

Patients were a randomly assigned 1:1 to receive pembrolizumab plus chemotherapy with the backbone of carboplatin plus paclitaxel followed by pembrolizumab maintenance for up to 31 cycles vs placebo plus chemotherapy and followed by placebo maintenance. In this study, they did allow optional crossover of pembrolizumab for up to 35 cycles. The primary end points were progression-free survival [PFS] and overall survival [OS].

The 5-year OS and PFS data from the KEYNOTE-407 trial showed sustained benefit in the squamous cell population with an OS of 18.4% with pembrolizumab vs 9.7% with placebo and an HR of 0.71.

 The PFS was also improved in the treatment arm at 10.8% months vs 3.5%, respectively.

How does PD-L1 expression affect the efficacy for patients with NSCLC?

When evaluating the breakdown by PD-L1 expression, what has been demonstrated across the KEYNOTE trials is that the higher the PD-L1 expression, the greater the magnitude of benefit from the combination.

In the population with a PD-L1 expression of 50% or greater, the 5-year updated OS rate is 23% [in the experimental arm] vs 8.3%. In the population with a PD-L1 of 1% to 49%, the OS update is 20.6% vs 7.5%. In the population with a PD-L1 negative expression, the OS rates are 10.7% vs 13%, and the median was 15 months of follow-up. For the PD-L1 negative subgroup, especially in frontline, monotherapy is not recommended.

Regarding the PFS, the greater the PD-L1 expression, the greater the magnitude in terms of PFS benefit. For patients with a PD-L1 expression of greater than 50%, the PFS is 15% vs not reached [NR]. For those with a PD-L1 expression of 1% to 49%, the PFS was 11.8% [vs NR], and then for the patients with a negative PD-L1 expression the PFS was 7.1% [vs 6.7%]. For patients with a PD-L1 less than 1% the median is 7.1 months vs 6.7 months.

What were the adverse events (AEs) seen on KEYNOTE-407?

In terms of AEs, we have all been accustomed to using this regimen. The majority of the AEs are from the chemotherapy backbone [occurring in 20% of patients in the experimental vs control arms]. These AEs include anemia [53.2% vs 51.8%], alopecia [46.0% vs 36.4%], neutropenia [38.7% vs 32.9%], nausea [35.6% vs 32.1%], and thrombocytopenia [30.6% vs 23.2%; in each arm respectively].

For the immune mediated AEs, the grade 3 to 5 AEs were lower [than the grade 1 and 2 AEs]. Pneumonitis was 2.1% with chemotherapy alone and 6.5% with pembrolizumab plus chemotherapy. [Other most common immune-mediated AEs included hypothyroidism (1.8% vs 7.9%, respectively) and hyperthyroidism (0.7% vs 7.2%)].

What were the long-term data from the phase 3 POSEIDON trial (NCT03164616) evaluating durvalumab with or without tremelimumab plus chemotherapy?

The phase 3 POSEIDON trial is an open-label, global, randomized study evaluating patients with metastatic NSCLC in the front line.

 Patients were also stratified by PD-L1 expression, disease stage, and histology.

In this trial, the study design is a little bit different, because patients were randomly assigned 1:1:1. In the first arm, patients received tremelimumab [Imjudo], the CTLA-4 inhibitor, plus durvalumab [Imfinzi], the PD-L1 inhibitor, plus chemotherapy for 4 cycles. This was followed with tremelimumab for only 1 additional dose on cycle 5, and then continued with durvalumab monotherapy maintenance. In the second arm, patients received durvalumab plus chemotherapy for 4 cycles, followed by durvalumab maintenance. In the control arm, patients received platinum-based chemotherapy for up to 5 or 6 cycles. The end points for the durvalumab/chemotherapy vs chemotherapy arm were PFS and OS as well as for the quadruplet, tremelimumab/durvalumab/chemotherapy vs chemotherapy.

In terms of PFS and OS, the durvalumab/tremelimumab plus or minus chemotherapy 4-year update showed durable benefit for PFS and OS for the quadruplet. For the triplet, which was durvalumab/chemotherapy vs chemotherapy, the PFS rate was improved but did not meet OS. Thus, we do not have approval for this combination, but we do have approval for the quadruplet.

At the 4-year update, the HR was 0.77 and the 24-month OS was 32.9 months in the quadruplet vs 22.1 in the triplet.

What did the 5-year update of POSEIDON show?

For the updated OS rate at 5 years, at the 60-month landmark analysis, the probability of OS with tremelimumab/durvalumab/chemotherapy vs chemotherapy was 15.7 months vs 6.8 in all comers.

Although numerically improved, the durvalumab/chemotherapy vs chemotherapy did not meet statistical significance in terms of OS by histology. At the 60-month update for the non–squamous population, the OS rate was 20.5% in the quadruplet vs 9.1% chemotherapy alone. In the squamous population at the 60-month analysis, the OS rate was 7.6% vs 2.9%, respectively. The OS was 10.4 months for the squamous population with the quadruplet vs 10.5 months with chemotherapy alone. It is important to note that the greater benefit was in the non–squamous population here, with an OS rate of 20% vs 9%.

In terms of the 5-year OS for the PD-L1 negative population receiving tremelimumab/durvalumab/chemotherapy the OS rate was 6.1% vs 4% in the chemotherapy-alone arm.

In terms of subsequent anti-cancer therapy, data showed that for the patients receiving the tremelimumab/durvalumab/chemotherapy vs chemotherapy alone, approximately 19 patients were still receiving chemotherapy in the tremelimumab/durvalumab/chemotherapy arm at the data cutoff vs 0 patients in the chemotherapy-alone arm. There were approximately 10 patients who were still ongoing with maintenance pemetrexed, and approximately 35% of patients received subsequent therapies, including a small number of patients that received subsequent immunotherapy.

There were higher rates of patients receiving immunotherapy in the chemotherapy arm, which are quite low. This was a global study, and even though you might expect more patients would have received immune therapy, this was not the case.

In terms of safety, overall, when adding the CTLA-4 inhibitor and comparing with chemotherapy, the treatment-related AEs leading to death were comparable to the chemotherapy-alone arm. In the longer-term follow-up, there was no additional signal of increased toxicity with this combination strategy.

1. Paz-Ares L, Luft A, Vicente D, et al. Pembrolizumab plus chemotherapy for squamous non-small-cell lung cancer. 

. 2018;379(21):2040-2051. doi:10.1056/NEJMoa1810865

2. Novello S, Kowalski DM, Luft A, et al. Pembrolizumab plus chemotherapy in squamous non-small-cell lung cancer: 5-year update of the phase III KEYNOTE-407 study. 

. 2023;41(11):1999-2006. doi:10.1200/JCO.22.01990

3. Johnson ML, Cho BC, Luft A, et al. Durvalumab with or without tremelimumab in combination with chemotherapy as first-line therapy for metastatic non-small-cell lung cancer: the phase III POSEIDON study. 

. 2023;41(6):1213-1227. doi:10.1200/JCO.22.00975

4. Peters S, Cho BC, Luft AV, et al. Durvalumab with or without tremelimumab in combination with chemotherapy in first-line metastatic NSCLC: five-year overall survival outcomes from the phase 3 POSEIDON trial. 

. Published online September 5, 2024. doi:10.1016/j.jtho.2024.09.1381

During a Case-Based Roundtable® event, Ticiana Leal, MD, discusses phase 3 trials of combinations in the non–small cell lung cancer setting in the second article of a 2-part series.

Pembrolizumab/Chemo Continues to Impress in NSCLC With 5-Year Updates

Targeted Oncology: Please discuss the long-term data for nivolumab [Opdivo] plus ipilimumab [Yervoy] in non–small cell lung cancer (NSCLC).

We now have 5-year updates from the CheckMate 9LA trial [NCT03215706], which included patients with stage IV NSCLC with no prior systemic therapy, [and] no actionable driver mutation for performance status.

Patients were stratified by PD-L1 [expression of] less than1% and 1% or greater. About 32% of the patients had a PD-L1 of 15% to 49% and then 24% of the patients had a PD-L1 of 50% or greater. There was 32% of the patients who were squamous histology and 68% that were non-squamous. More than one third of the enrolled participants in this study had PD-L1 expression of less than 1%.

These patients were randomly assigned 1:1 to [receive] nivolumab plus ipilimumab. The dose for ipilimumab is a low dose, 1 mg/kg every 6 weeks with only 2 cycles of chemotherapy vs chemotherapy for 4 cycles with optional maintenance in the pemetrexed group of patients with non-squamous histology.

It is important to note that adding the short course of chemotherapy was to help patients through a challenging phase for when they do not do well with immunotherapy alone in the first 3 months of treatment. You can synergize with immunotherapy to get a more rapid response, minimize toxicity of chemotherapy by reducing the number of cycles of chemotherapy, and then keep patients on maintenance immuno-oncology [IO].

The primary end point [for the trial] was overall survival [OS] and secondary end points were progression-free survival [PFS], overall response rate, efficacy by PD-L1 expression, and safety.

What was the efficacy with the combination in the CheckMate 9LA trial?

The results from CheckMate 9LA, which is [now] an approved regimen, led to improved OS for nivolumab/ipilimumab/chemotherapy vs chemotherapy [alone]. Now we have 5-year OS data that showed a median OS of 15.8 months vs 11.0 months for nivolumab/ipilimumab/chemotherapy vs chemotherapy, respectively, with an HR of 0.73. The 5-year OS rates are 18% vs 11% and this was in the all-comer population. 

When examining the data related to PD-L1 expression, what stands out is the excitement surrounding the PD-L1 negative group. Traditionally, this population has experienced shorter survival rates, but they do show positive responses to combinations of chemotherapy with immunotherapy or dual immune-oncology treatments. Comparatively, they are receiving benefit from this combination strategy. We saw a median OS of 9.8 months with chemotherapy vs 17.7 months with combination therapy, and with a HR of 0.63. Then we saw a median OS that is translating now into this durable benefit at the 5-year update: 22% vs 8%, respectively, with the PD-L1 positive group also deriving benefit. It was 18% vs 11% for the PD-L1 negative group, 18% for the all comers [group], 22% for PD-L1 negative [group], and 18% for the PD-L1 positive [group].

Regarding histology with this regimen, a subgroup of patients showed benefit in the squamous and in the non-squamous population with a median OS of 9.1 [months with chemotherapy] vs 14.5 [with the combination], and an HR of 0.63 [in the squamous group]. The 5-year OS rates were 18% vs 7% [in the squamous group], and in the non-squamous group 19% vs 12%, [respectively].

For all patients who were randomly assigned by PD-L1 expression, the overall response rate was also higher in the PD-L1 greater than 1% group of patients. Importantly, the duration of response [DOR] was higher, with a median DOR of 4.3 [months with chemotherapy] vs 17.5 [with the combination]. This was also seen in the DOR in the PD-L1 negative group. When you look at the survival curve at the 5-year update, there was a DOR of 25% for nivolumab/ipilimumab vs 0% for chemotherapy, and then in the PD-L1 positive it is 15% vs 10%, respectively.

Regarding the main end points, we saw improvement in OS across all subgroups, even subgroups who have been known to have worse outcomes, including the PD-L1 negative and the squamous subgroup.

We also see meaningful improvement in the median DOR, and importantly, as a 5-year update. This combination led to long-term, durable survival benefit compared with chemotherapy, and in patients with historically poor outcomes. The other end points were improved PFS and improved treatment-free interval.

How did this patient population do in terms of safety with the nivolumab/ipilimumab regimen?

For toxicities, we know that when you use combination immunotherapy with dual checkpoint inhibition, you see greater incidence of adverse events [AEs], which can have an earlier onset. However, in terms of the time of the toxicity, it is reassuring to see over time and [with] more exposure to ipilimumab, we are not seeing higher rates of [grade] 3 or 4 toxicities.

During a Case-Based Roundtable® event, Ticiana Leal, MD, discusses combination therapy with nivolumab plus ipilimumab and chemotherapy for patients with non–small cell lung cancer in the first article of a 2-part series.

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