乌鸦传媒

"I feel the need, the need for speed." Tom Cruise uttered that iconic line as Pete "Maverick" Mitchell in 1986's blockbuster "Top Gun." Cruise himself has been known to race cars, and a study from the early aughts showed that experienced full-throttle similar to those of athletes who relied on their feet, rather than a flywheel, to compete. A revved-up Starbucks barista can make a drink in , while pizza once came with a side order of 30-minute delivery (at least until a on that).

The point is, , including fast-tracked FDA approvals for new treatments, especially in a challenging disease like small-cell lung cancer (SCLC). "Accelerated FDA approvals usher in new hope and excitement especially in areas of oncology such as SCLC, where there is a grave unmet need," noted Parth Desai, MD, MBBS, of Fox Chase Cancer Center/Temple University Hospital in Philadelphia, and Anish Thomas, MD, MBBS, of the National Cancer Institute in Bethesda, Maryland.

They noted in a review that current FDA-approved treatments for relapsed extensive-stage SCLC (ES-SCLC), such as topotecan and lurbinectedin, "offer only modest (15%-20%) and short-lived responses, resulting in a dismal overall survival rate of 5% at 2 years post-diagnosis."

Newer treatments, such as tarlatamab (Imdelltra) have pretty much blasted out of pole position, at least in terms of getting an FDA green light in ES-SCLC. The IV bispecific delta-like ligand 3 (DLL3)-directed CD3 T-cell engager (BiTE) got the FDA go-ahead in May 2024, based on the study.

But are data from a phase II study that has an estimated study completion date of enough to bring the agent into clinical practice so quickly? Sure, tarlatamab has shown significant early promise, Desai and Thomas conceded. They also cautioned that "it is imperative for the oncologists to ensure that their patients are aware of the early and cautionary nature of this approval," explaining that almost "22% of accelerated approvals in oncology get withdrawn, and 40% have failed to show benefit in confirmatory trials."

While hopes are high that tarlatamab will stay on track and meet its primary endpoints in the trial, and modify the landscape of current upfront ES/LS-SCLC management, Desai and Thomas said, lung cancer specialists are still going to have a rough road ahead of them with "obstacles in drug access, delivery, and toxicity management for solid oncology providers and healthcare settings aiming to integrate BiTEs like tarlatamab in routine practice."

In the meantime, other immunotherapy (IO) that has already done a few hot laps in ES/LS-SCLC are worth exploring, even if an agent is a bit of a . In a presentation at the 2024 (ASTRO) annual meeting, Kristin Higgins, MD, of City of Hope Cancer Center Atlanta, and colleagues shared findings from the NRG Oncology/Alliance LU005 trial.

The study of 500+ patients in the U.S. and Japan tested standard chemoradiotherapy (CRT) with or without atezolizumab (Tecentriq). All patients received radiotherapy either twice daily to a total dose of 45 Gy or once daily to a dose of 66 Gy, as well as four cycles of concurrent chemotherapy. Patients in the atezolizumab arm also received the agent every 3 weeks beginning at the start of radiotherapy, for a maximum of 1 year.

Prophylactic cranial RT was done at the discretion of the investigator for patients with a complete or near-complete response to CRT. Median follow-up for the second planned interim analysis was 21 months.

Higgins discussed the findings at an ASTRO press briefing, while Kenneth Rosenzweig, MD, of Icahn School of Medicine at Mount Sinai in New York City, offered an expert perspective.

What was the impetus for the NRG Oncology/Alliance LU005 trial?

Higgins: LS-SCLC has historically been a difficult disease to treat. We've relied on the concurrent CRT backbone, plus or minus prophylactic cranial irradiation, for the past 30 years. There has been recent successes in the ES lung cancer setting with the addition of IO to chemotherapy in improving survival. Stratification factors for the trial included the RT schedule -- also, cisplatin versus carboplatin, male versus female, and ECOG performance status 0/1 versus 2.

What are some of the main findings?

Higgins: The primary endpoint of our study was overall survival [OS]. There was no significant difference in survival for patients who received concurrent CRT with atezolizumab compared with the control arm [CRT only]. The median OS for the control arm was 39 months and 33 months for the atezolizumab arm.

Median progression-free survival was 11.5 months for the control arm and 12 months for the atezolizumab arm.

Interestingly, we wanted to look at the RT schedule. In the U.S., you can either deliver RT twice daily to 45 Gy or once daily, between 66 and 70 Gy. If we look at fractionation alone, the twice-daily patients did have improved survival compared with the once-daily patients, with a median OS of 35 months for twice-daily radiation versus 28 months for once-daily RT.

What are some take-home messages from the trial?

Higgins: Concurrent atezolizumab did not improve survival for patients with LS-SCLC compared with standard CRT. Twice-daily RT may be associated with improved survival compared with daily RT and, I think, should be considered the optimal RT choice for patients with LS-SCLC. I think giving patients the best shot with twice-daily RT is something that we as radiation oncologists can do to help our patients with SCLC.

Rosenzweig: This is a very ill patient population and getting treatment started immediately is crucial. I think there are two key findings. One is that the timing of IO is crucial. Ten years ago, when the first trials in IO in cancer were coming out, they were miraculous and routinely very positive -- it's very nuanced, how to combine RT with IO.

I think one major lesson from this trial is that RT that is being done to the major lymph nodes, and to a lot of the blood volume, might affect the effectiveness of the IO. I think the issue of twice-daily RT is something where we should strongly look at the toxicity, and can definitely be limited with modern techniques. Unfortunately, twice-daily RT is still just as inconvenient for patients, coming in twice a day to the same clinic, but maybe there are some ways to get around that, so that certainly brings that question back on the table.

Read the review by Desai and Thomas here.