ASCO 2026 Updates: Seven Years & Median PFS Still Not Reached — What’s Next For Lorlatinib In NSCLC

The CROWN data confirmed what we already suspected about lorlatinib’s role in treating ALK-positive non-small-cell lung cancer (NSCLC), and then some. Phase 3 trial data show that, seven years in, more than half the patients on the experimental arm have still not progressed. Median PFS was not reached. The Kaplan-Meier curve plateaus after year two. Forty-four percent of patients are still on lorlatinib compared to 3% on crizotinib.

SurvivorNet was on the ground at ASCO 2026 and sat down exclusively with Dr. Alice Shaw, thoracic oncologist at Dana-Farber Cancer Institute and a co-investigator on the CROWN study, to discuss what these results mean.

“We’re not talking about months or even a few years,” Dr. Shaw stresses. “We’re talking about potentially over seven years, a decade of control of their disease — and control not just in the body, but also in the brain.”

That framing matters because metastatic ALK+ NSCLC once carried a median survival of 12 months or less. The conversation has shifted in ways that were hard to imagine even five years ago.

What The Numbers Actually Show

At 7 years, the PFS rate was 55% for lorlatinib versus 3% for crizotinib (hazard ratio 0.19). To be clear about what HR 0.19 means in plain terms: patients on lorlatinib had an 81% lower risk of progression or death at any given time point compared to crizotinib. That is one of the largest hazard ratios ever reported for a targeted therapy in solid tumors.

“The highest probability of progression is in the first two years. And then after that, the probability of progression starts to fall each subsequent year — the rate of progression starts to be about two to three percent per year,” Dr. Shaw explains. “What ends up happening is we have what we call a really sustained plateau in terms of progression-free survival. And that plateau settles out at about 50%.”

The intracranial data are, if anything, more striking. After 30 months on lorlatinib, there were zero new brain progression events. The hazard ratio for time to intracranial progression was 0.06, a 94% reduction in risk. For a disease where brain metastases are a leading driver of morbidity and mortality in ALK+ patients, this is arguably the most clinically consequential finding in the entire dataset.

For Dr. Shaw, this is the finding that carries the most weight for patients. “Lorlatinib not only can very effectively treat brain metastases but this long-term follow-up shows that lorlatinib likely can prevent brain metastases and protect the brain from dissemination of this disease,” she explains. “And that’s hugely important to patients, both in terms of symptoms that they could develop, quality of life, and of course overall survival.”

On tolerability: 34% of patients required a dose reduction, and only 5% discontinued due to treatment-related adverse events — lower than the 6% discontinuation rate seen with crizotinib. Crucially, all treatment-related discontinuations occurred within the first 26 months. None after.

The ‘Cure’ Question

In the interview, we asked Dr. Shaw directly: “Are we approaching cure territory?”

“I do think the seven-year data now does raise this really exciting possibility — could we be approaching a cure for patients who have advanced metastatic, what we used to previously call incurable disease?” she explains. “For most people, cure means no evidence of disease and also no active treatment. Many of our patients do not have signs of disease — that’s wonderful. But they do require ongoing treatment with lorlatinib. So, depending on how you define cure, this may not qualify. But for sure, this is long-term persistent control of cancer.”

That distinction matters clinically. These patients are doing well, but they are not off therapy. The question of what sustained, decades-long treatment with lorlatinib looks like (physically, cognitively, practically) is one that every treating oncologist now has to sit with.

The Sequencing Problem

The CROWN data creates an additional challenge with sequencing.

When lorlatinib was approved as first-line therapy, the assumption was that patients would eventually progress, and that post-lorlatinib options would matter enormously. The field spent considerable energy developing next-generation ALK inhibitors precisely because resistance to lorlatinib was considered inevitable, and the post-progression landscape would need to be robust.

Seven years of data complicate that picture in two directions.

First, for the 55% of patients who are still progression-free at year 7, the question of what comes next doesn’t yet apply. These patients are doing well on a single oral agent. The clinical imperative is to keep them there, manage side effects appropriately, and not disturb something that is working. For this group, the sequencing conversation is premature.

Next, for the 45% who did progress, the post-lorlatinib landscape remains genuinely difficult. Lorlatinib resistance mechanisms are complex: they include compound ALK mutations, bypass signaling through other pathways, and combinations thereof. There are no currently approved agents specifically designed for post-lorlatinib ALK+ NSCLC. Clinical trials exist, and fourth-generation ALK inhibitors are in development, but designing a trial large and long enough to outperform a more-than-7-year median PFS in the control arm is an extraordinary challenge in a population representing less than 4% of lung cancers.

CROWN has effectively made ALK+ NSCLC harder to study prospectively while simultaneously making it much better to have. That is an unusual position for a field to be in.

What This Means in Your Clinic, Right Now

For community oncologists managing ALK+ NSCLC patients, the CROWN update translates into three practical questions.

• Are you starting lorlatinib first-line? You should be, for the vast majority of patients. Alectinib was a reasonable first-line choice before the mature lorlatinib data arrived. With 7-year PFS rates now available, and a CNS protection profile that has no peer among ALK inhibitors, the argument for alectinib first-line has become harder to make. The exception may be patients with specific comorbidities where lorlatinib’s side effect profile (hyperlipidemia, weight gain, cognitive effects in some patients) is a particular concern. But for a typical ALK+ patient, lorlatinib as a first-line is now the standard that will be hardest to displace.
• How are you managing long-term tolerability? The CROWN data make an important point: dose reductions did not compromise outcomes. Thirty-four percent of patients required dose reductions, and those patients contributed to the same flat PFS tail as everyone else. This is clinically actionable. If a patient on lorlatinib is struggling with side effects (hyperlipidemia requiring multiple medications, significant cognitive changes, weight gain affecting quality of life), a dose reduction is not a concession: it’s appropriate management. Don’t sacrifice a patient’s long-term well-being on a dose that isn’t necessary.
• What do you tell patients who progress? Honestly, the post-lorlatinib space is unsettled. Platinum-based chemotherapy remains an option. Clinical trials should be the first conversation, not the last resort. Fourth-generation inhibitors targeting compound ALK mutations are moving through early-phase trials, but none have yet demonstrated the kind of efficacy data that would constitute a clear standard. The most promising agent in this space right now is neladalkib (NVL-655), currently in the phase 1/2 ALKOVE-1 trial.

The Bigger Picture

Dr. Shaw has been in thoracic oncology for over 20 years. She put what this data mean in a historical context into perspective.

“Initially, before the whole targeted therapy era, these patients had a pretty poor prognosis — average survival, probably 12 months or less in the metastatic setting,” she says. “And now with the Crown follow-up, we’re seeing an incredibly prolonged progression-free survival. The median has not been reached at seven years — it actually exceeds seven years.”

She sees lorlatinib not as an endpoint but as a proof of concept for what precision oncology can achieve. “I think this is pointing to the hope that a disease such as ALK-positive lung cancer could in fact become more like a chronic condition that does require treatment. This is a pill that you would take every day — but the disease is incredibly well managed.”

For the patients in your clinic today, that is the conversation worth having.