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Pfizer's Lorbrena Yields Impressive Responses in ALK-Positive NSCLC With Brain Metastases


NEW YORK – Advanced lung cancer patients with ALK rearrangements may soon have another ALK inhibitor to choose from as a front-line option according to interim Phase III study data presented at the European Society for Medical Oncology's Virtual Congress on Saturday.

Data from a planned interim analysis in the CROWN trial comparing Pfizer's third-generation ALK inhibitor lorlatinib (Lorbrena) against its first-generation drug crizotinib (Xalkori) showed that the newer agent shrunk tumors in 76 percent of patients compared to a 58 percent overall response rate with the older drug.

At the conference, oncologists reviewing the drug data were particularly impressed with the 82 percent response rate seen with lorlatinib in patients with measurable brain metastases compared to 23 percent for those on crizotinib. "The intracranial complete response rate was a remarkable 71 percent," highlighted Ben Solomon of the Peter MacCallum Cancer Center in Australia in a meeting presenting.

Christine Lovly, a lung cancer expert from Vanderbilt University Medical Center in Tennessee, reviewed the CROWN findings and agreed the data were impressive, but noted that oncologists will have to wait for the progression-free survival data to mature before they can decide whether lorlatinib will overtake the second-generation drug alectinib (Genentech's Alecensa), which is currently oncologists' favored first-line ALK inhibitor.

In the US, lorlatinib is approved for metastatic, ALK-positive NSCLC patients who have already received and progressed on first- and second-generation ALK inhibitors crizotinb, alectinib (Genentech's Alecensa), and ceritinib (Novartis' Zykadia).

The Phase III CROWN trial randomized 296 advanced, ALK-positive NSCLC patients to receive lorlatinib or crizotinib as a first-line treatment. Median progression-free survival was 9.1 months on crizotinib but had not been reached in the lorlatinib arm at 18.3 months follow up. However, the one-year progression-free survival rate was 80 percent on lorlatinib compared to 35 percent with crizotinib.

Ahead of the ESMO meeting, in August, Pfizer announced that the CROWN study had met its primary endpoint by demonstrating that lorlatinib improved progression-free survival compared to crizotinib in previously untreated, advanced NSCLC patients with ALK rearrangements. "Based on the positive outcome of the CROWN trial, we intend to share the results with the FDA and other health authorities to support conversion to full approval and to seek approval for an indication that includes previously untreated ALK-positive metastatic NSCLC," Pfizer said in a statement at the time. 

The first-line, advanced ALK-positive lung cancer market is competitive. Pfizer was first on the scene with crizotinib, which the US Food and Drug Administration approved for advanced, ALK-positive lung cancer in 2011. The agency approved second-generation drugs alectinib and ceritinib in 2017 in the first-line advanced disease setting. Earlier this year, Takeda's brigatinib (Alunbrig) was yet another second-generation ALK inhibitor approved by the FDA for first-line metastatic NSCLC. 

Pfizer's lorlatinib, meanwhile, is the first third-generation ALK inhibitor, which achieved accelerated approval in 2018 as a second- and third-line NSCLC treatment. However, the drug giant is keen on pushing this drug into the crowded first-line market based on the CROWN data, as its first-generation drug crizotinib loses market share to newer entrants.

In 2019, Genentech's alectinib netted global sales of CHF 876 million ($963 million), while crizotinib brought in $145 million in worldwide sales for Pfizer.

In a presentation for investors earlier this week, Pfizer's Oncology Chief Development Officer Chris Boshoff noted that the company specifically developed lorlatinib to inhibit the most common mutations that drive resistance to first- and second-generation drugs in this class, and to be more potent than other ALK inhibitors in treating brain metastases. Lorlatinib crosses the blood-brain barrier, which is important for the up to 40 percent of ALK-positive NSCLC patients whose disease will eventually spread to the brain.

In his presentation, Boshoff said that a 71 percent complete response rate, as seen in the CROWN study, was "unprecedented" in lung cancer patients with brain metastases. He highlighted the experience of one such complete responder, sharing a brain scan image that showed the patient's brain tumor had completely disappeared on lorlatinib. This patient is continuing to respond to the drug after 24 months.

Solomon during his ESMO presentation highlighted that the median time-to-progression for those with central nervous system metastases was 16.6 months on crizotinib but was not reached in the lorlatinib arm. "These data indicate the ability of lorlatinib not only to delay progression of existing brain metastases but also to prevent the development of new brain metastases in patients with ALK-positive NSCLC," he said.

Boshoff told Wall Street analysts last week that Pfizer believes the CROWN results will position lorlatinib "to be highly competitive with second-generation ALK inhibitors in the first-line setting, assuming regulatory approval."

However, Solomon and Lovly were careful not to position lorlatinib amongst the first-line options oncologists have in this regard based on this interim analysis. The overall responses and intracranial responses seen with lorlatinib are "wonderful news," said Lovly, but noted that deciding which drug to give first amongst the other first-line options, and how to sequence treatments or combine ALK inhibitors with other types of drugs once patients become resistant, is a complex task.

In terms of activity against brain metastases, alectinib and brigatinib have demonstrated response rates of 81 percent and 78 percent, respectively, compared to lorlatinib's 82 percent response rate in the CROWN study. Similarly, at the ESMO meeting, updated analysis from the ALTA-1L trial showed that the intracranial response rate with brigatinib was 78 percent compared to 26 percent with crizotinib.

But the metric that oncologists will want to focus on, Lovly noted, is progression-free survival. Alectinib is the one to beat in this regard, with a median progression-free survival of three years in the ALEX trial in those without brain metastases and two years in those with brain metastases. "We anxiously await additional data on lorlatinib to see how long the progression-free survival will be," she said.

Furthermore, in the absence of a head-to-head comparison between lorlatinib and second-generation drugs in the first-line NSCLC setting, oncologists will need to weigh efficacy advantages against safety considerations. "As we treat patients longer and longer with these drugs it's very important to consider the toxicity profile of these agents," Lovly said.

In this regard, there were more serious adverse events seen with lorlatinib than crizotinib in the CROWN study, but patients reported higher quality-of-life scores with the newer drug. Of particular note, patients experienced cognitive effects and hypercholesterolemia, which haven't been previously seen with other ALK inhibitors. Solomon noted that the neuro-cognitive effects, such as confusion, inattention, anxiety, and depression, associated with lorlatinib may be due to the fact that the drug was designed to be highly brain penetrant.

Although these side effects tend to go away with dose interruptions and reductions, Solomon said it will be important to educate patients about the possibility of these toxicities. Lovly added that if this drug is approved and marketed globally, oncologists will need to be educated on how to manage these toxicities, since ALK rearrangements occur in between 3 percent and 5 percent of patients, and oncologists may not have the opportunity to treat these patients often.

Although response rates to ALK inhibitors are initially high among ALK-positive lung cancer patients, most eventually develop resistance. Approximately 75 ALK mutations have been described as driving resistance to various ALK inhibitors. Earlier studies of lorlatinib suggest that patients tend to become resistant to it by acquiring compound mutations, though Lovly cautioned that not much is known about the biological mechanisms by which patients relapse on this newer drug.

Solomon noted that the field has a "good problem" on its hands with having to decide between multiple effective first-line options. However, he acknowledged that it would be helpful to have a better idea of whether specific mutations will lead to resistance with one ALK inhibitor or another.

Despite multiple treatment options, Lovly lamented that oncologists are "still not curing patients." In order to move the needle, she suggested researchers consider dynamic monitoring of ctDNA to assess recurrence early. The field might also consider studying the impact of earlier ALK targeted treatment, in the adjuvant setting, like the ADAURA trial has in EGFR mutated lung cancer, she proposed. 

Importantly, Lovly said the cancer community must do better in terms of molecularly testing all lung cancer patients to see if they harbor mutations in ALK rearrangements and other actionable tumor markers. "We can develop wonderful drugs … but if we're not actually testing for the markers then we cannot deploy the drugs in the best fashion," she said.

Lastly, she urged the community to improve the diversity of patients enrolled in cancer drug studies. In 2019, cancer drug trials enrolled 4 percent Black or African American patients and 5 percent Hispanic patients. The diversity problem is further exacerbated in precision oncology trials where drugs tend to be studied in rare, biomarker-defined subsets of patients. "This is an incredibly important issue in 2020 and beyond to make sure we have appropriate representation in all our studies, so we can understand effects across multiple different cohorts of patients," she said.