Thomas E. Stinchcombe, MD, professor of medicine, Duke Cancer Institute, discusses the 2-year updated results of the randomized phase III ALTA-1L trial in 

At a median follow-up of 25 months, the investigator-assessed median progression-free survival (PFS) was 29.4 months (95% CI, 21.2—not estimated [NE]) with brigatinib (Alunbrig) versus 9.2 months (95% CI, 7.4-12.9) with crizotinib (Xalkori) in the intent-to-treat population of patients with 

-positive NSCLC who had not received prior treatment with an ALK inhibitor. Blinded independent review committee (BIRC)—assessed median PFS was 24.0 months (95% CI, 18.5-NE) and 11.0 months (95% CI, 9.2-12.9) with brigatinib and crizotinib, respectively.

Additionally, the intracranial objective response rate for patients with measurable brain metastases at baseline was 78% with brigatinib versus 26% with crizotinib.

The toxicities associated with brigatinib appear to be manageable, says Stinchcombe. Notably, health-related quality of life was improved for patients treated with brigatinib versus those treated with crizotinib.

In April 2017, the FDA granted an accelerated approval to brigatinib for the treatment of patients with 

-positive NSCLC who have progressed on or are intolerant of crizotinib.

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Thomas E. Stinchcombe, MD, discusses the results of the randomized phase III ALTA-1L trial in ALK-positive non–small cell lung cancer.

Dr. Stinchcombe on the ALTA-1L Trial in ALK+ NSCLC

Thomas E. Stinchcombe, MD, professor of medicine, Duke Cancer Institute, discusses the importance of molecular testing in ALK-positive non—small cell lung cancer (NSCLC).

Circulating tumor DNA can be used to detect 

 rearrangements. However, the sensitivity of the assay could lead to false negative results. As such, if there is a high clinical suspicion of an 

 rearrangement, a second biopsy may be warranted to eliminate the potential for false negative results, explains Stinchcombe.

All patients should receive molecular testing up front as the results may guide treatment selection, says Stinchcombe. The majority of patients with an 

 rearrangement will receive a TKI up front. If patients do not require immediate therapy, chemotherapy should be delayed until the results of the biopsy come back to ensure that the optimal therapy is given, concludes Stinchcombe.

Thomas E. Stinchcombe, MD, discusses the importance of molecular testing in ALK-positive non–small cell lung cancer.

Dr. Stinchcombe on Molecular Testing in ALK+ NSCLC

Thomas E. Stinchcombe, MD, professor of medicine, Duke Cancer Institute, discusses remaining challenges in 

-positive non&shy;—small cell lung cancer (NSCLC).

Though patients are responding well to upfront next-generation TKIs, the optimal treatment strategy for patients who experience disease progression is unclear, says Stinchcombe.

Chemotherapy or single-agent lorlatinib (Lorbrena) are potential regimens with response rates around 40% to 45% and a progression-free survival benefit of 6 to 8 months, explains Stinchcombe. Importantly, lorlatinib has a high rate of central nervous system activity that may benefit patients with brain metastases.

Remaining questions regarding repeat tumor biopsy, the utility of circulating tumor DNA, and how to further personalize treatment for patients need to be explored further, highlights Stinchcombe.

Additionally, up to 50% of patients will not have an 

 mutation either because insensitive testing did not catch a mutation, or because the patient has 

-independent mechanisms of resistance. Understanding the optimal treatment for these patients is critical going forward, Stinchcombe concludes. 

Thomas E. Stinchcombe, MD, discusses remaining challenges in ALK-positive non&shy;–small cell lung cancer.

Dr. Stinchcombe on Remaining Challenges in ALK+ NSCLC

Thomas E. Stinchcombe, MD, professor of medicine, Duke Cancer Institute, discusses the differences in toxicity profiles between brigatinib (Alunbrig) and alectinib (Alecensa) in 

-positive non—small cell lung cancer (NSCLC).

The toxicities with alectinib are fairly mild, although there may be subtle increases in liver function tests and creatine phosphokinase (CPK) levels, says Stinchcombe. Moreover, some patients may experience mild fatigue. With brigatinib, there can be some episodes of hypertension and early-onset pulmonary symptoms that physicians should be cautious of. Because of this, the drug is given 90 mg daily for the first week and then escalated up to 180 mg.

However, many of these events occur within the first 1 or 2 weeks of therapy, adds Stinchcombe. Patients can also experience an increase in CPK. Both agents have very similar toxicity profiles with the exception of pulmonary events, which are unique to brigatinib.

Thomas E. Stinchcombe, MD, professor of medicine, Duke Cancer Institute, discusses the differences in toxicity profiles between brigatinib (Alunbrig) and alectinib (Alecensa) in ALK-positive non–small cell lung cancer (NSCLC).

Dr. Stinchcombe Discusses Differences in Toxicity Profiles Among ALK Inhibitors in NSCLC

Thomas E. Stinchcombe, MD, professor of medicine, Duke Cancer Institute, discusses the benefit of alectinib (Alecensa) in the treatment of patients with 

Alectinib, a second-generation ALK TKI, has emerged as the frontline standard, although brigatinib (Alunbrig) is also making headway, Stinchcombe says. The benefit of alectinib is based on 2 phase III trials comparing the drug with crizotinib (Xalkori). Both trials demonstrated a significant improvement in progression-free survival (PFS) as well as a decrease in the risk of brain metastases with alectinib. The latter is important as patients with NSCLC in general are at risk of brain metastasis, particularly in patients treated with crizotinib, Stinchcombe adds.

In the phase III ALEX trial, long-term follow-up shows a median PFS of approximately 36 months with alectinib, setting a high bar for future developmental therapies, he concludes.

Thomas E. Stinchcombe, MD, professor of medicine, Duke Cancer Institute, discusses the benefit of alectinib in the treatment of patients with ALK-positive non–small cell lung cancer.

Dr. Stinchcombe on the Benefit of Alectinib in ALK+ NSCLC

Thomas E. Stinchcombe, MD, professor of medicine, Duke Cancer Institute, discusses pivotal trials that have reshaped the standard of care in non—small cell lung cancer (NSCLC).

The focus has been on targeted therapies because of the tremendous advances made last year. A phase III trial compared osimertinib (Tagrisso) with erlotinib (Tarceva) or gefitinib (Iressa) and revealed an improved progression-free survival (PFS), with a median PFS of about 18.9 months. This was in addition to a lower grade 3/4 toxicity. This was a practice-changing trial, notes Stinchcombe.

-rearranged NSCLC, there have been 2 important trials. Both trials compared alectinib (Alecensa) to the previous standard, crizotinib (Xalkori), and demonstrated a significant improvement in PFS, with a median PFS of 25 months. One of the trials prospectively assessed the development of brain metastases. It showed a dramatic reduction in the incidence of brain metastases, demonstrating the agent’s potency and blood-brain barrier penetration.

Thomas E. Stinchcombe, MD, professor of medicine, Duke Cancer Institute, discusses pivotal trials that have reshaped the standard of care in non–small cell lung cancer (NSCLC).

Dr. Stinchcombe on Advances in Targeted Therapies in NSCLC

Thomas E. Stinchcombe, MD, professor of medicine, Duke Cancer Institute, discusses the KEYNOTE-189 trial in patients with lung cancer.

The KEYNOTE-189 trial builds upon cohort G of the KEYNOTE-21 trial, which was a phase II trial that randomized patients to carboplatin/pemetrexed alone or carboplatin/pemetrexed with pembrolizumab (Keytruda). The phase II trial showed a robust response rate, progression-free survival (PFS), and a trend toward overall survival (OS). According to Stinchcombe, the phase III trial met the statistically significant improvement in PFS and OS. This serves as a confirmatory study to the promising results observed in the phase II trial.

In the experimental arm, patients received pembrolizumab at a 200 mg fixed dose every 3 weeks plus 500 mg/m

 of cisplatin or carboplatin on day 1 every 3 weeks for 4 cycles, followed by 200 mg of pembrolizumab plus 500 mg/m

 of pemetrexed every 3 weeks. The regimen administered to the control group was identical, except that pembrolizumab was replaced with placebo.

As for other combinations being developed with immunotherapy, the one that is furthest in development is the trial of carboplatin, paclitaxel, and bevacizumab (Avastin) alone or with atezolizumab (Tecentriq). This comparison was seen in a 3-arm trial showing promising improvement in response and a statistically significant improvement in PFS. The OS data are immature at this time.

Dr. Stinchcombe on the KEYNOTE-189 Trial in Lung Cancer

Thomas E. Stinchcombe, MD, professor of medicine, Duke Cancer Institute, discusses the PACIFIC trial for patients with non—small cell lung cancer (NSCLC).

The PACIFIC trial randomized patients with stage III NSCLC to durvalumab (Imfinzi) for 1 year or placebo. The trial showed a statistically significant improvement in response rate and progression-free survival (PFS), which showed an improvement of 11 months. These are promising results because the treatment landscape for this patient population has remained unchanged for 20 years, says Stinchcombe.

The median PFS was 16.8 months (95% CI, 13.0-18.1) with durvalumab compared with 5.6 months (95% CI, 4.6-7.8) for placebo (HR, 0.52; 95% CI, 0.42-0.65; 

 <.001). The objective response rates were 28.4% versus 16.0%, respectively (

The next steps are to build upon immunotherapy, identify which patients are most likely to benefit, and further investigate the overall survival which is still pending, explains Stinchcombe.

Thomas E. Stinchcombe, MD, professor of medicine, Duke Cancer Institute, discusses the PACIFIC trial for patients with non–small cell lung cancer (NSCLC).

Thomas E. Stinchcombe, MD

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