TRIPLEX: Concurrent Thoracic Radiotherapy Should Not Be Used Routinely With Chemoimmunotherapy in ES-SCLC

The results of the TRIPLEX trial, presented by Professor Bjørn Henning Grønberg at ASCO, challenge the routine use of early thoracic radiotherapy on top of chemoimmunotherapy in patients with extensive-stage small cell lung cancer.

The message from Grønberg is clear.

“Early thoracic radiotherapy given concurrently with chemoimmunotherapy should not be used routinely outside clinical trials in extensive-stage small cell lung cancer,” Grønberg told HealthTalk.

TRIPLEX was presented as a Late-Breaking Abstract at ASCO. The trial investigated whether thoracic radiotherapy — radiation directed at disease in the chest — could enhance the effect of current standard first-line treatment for extensive-stage small cell lung cancer: carboplatin and etoposide combined with the PD-L1 inhibitor durvalumab.

The rationale was biologically plausible. Radiotherapy, given early and concurrently with immunotherapy, could potentially release tumour antigens and make the immune response more effective.

That is not what the trial showed.

No survival benefit

TRIPLEX randomised 228 patients at 23 hospitals in Norway, Sweden, Estonia, Iceland and the Netherlands. Patients received either chemoimmunotherapy alone or chemoimmunotherapy plus thoracic radiotherapy.

Radiotherapy was given early in the treatment course, between the second and third cycle, at a dose of 30 Gy in 10 fractions.

Median overall survival was 10.0 months in the chemoimmunotherapy-plus-radiotherapy arm, compared with 11.8 months in the control arm. The hazard ratio was 1.14, with a 95% confidence interval of 0.84 to 1.56 and a p value of 0.40.

This means the trial cannot exclude either a moderate benefit or substantial harm from radiotherapy. However, the point estimate moved in the negative direction, and the safety data pointed in the same direction.

Progression-free survival was also not improved: 5.1 months in the radiotherapy arm versus 5.0 months in the control arm. The overall response rate was numerically lower in the radiotherapy arm: 79.1% versus 84.1%.

“The control arm performed roughly as expected based on previous studies. But survival was actually numerically worse in the experimental arm,” Grønberg said.

Subgroup analyses did not indicate a survival benefit in any subgroup.

More adverse events and more deaths

The most important finding was the safety signal.

Overall, adverse events were more frequent in the radiotherapy arm than in the control arm: 87.8% versus 69.9%. The difference was statistically significant. Grade 3–4 adverse events were also more frequent in the radiotherapy arm, 40.9% versus 33.6%, although this difference was not statistically significant.

Most concerning was the number of deaths during study treatment. Fifteen patients died during the study treatment period in the radiotherapy arm, compared with two in the control arm.

Grønberg emphasised that the finding must be interpreted with caution.

“Six of the fifteen patients died before they received radiotherapy, which tells us that many of these patients are very ill and have substantial comorbidity,” he said.

However, there were still significantly more deaths among those who actually received radiotherapy: nine deaths in the radiotherapy arm versus one in the control arm.

“This is the reason why this kind of radiotherapy should not be given routinely,” Grønberg said.

The causes of death varied and included pneumonitis, encephalitis, infection, heart failure and intestinal perforation. There was no single clear pattern of directly radiation-related toxicity.

Grønberg points to two possible explanations.

“One possibility is that these are fragile patients, and when radiotherapy is added on top of chemotherapy and immunotherapy, it simply becomes too much. The other possibility is that you get an immunological reaction when radiotherapy is given concurrently with immunotherapy, which then increases the severity of adverse events,” he said.

Trial stopped early

TRIPLEX was originally planned to include 302 patients, but enrolment was stopped before completion following a recommendation from the independent safety monitoring committee.

The committee observed more serious adverse events and more deaths from causes other than small cell lung cancer in the radiotherapy arm, while the interim analysis showed no sign of a survival benefit.

For Grønberg, the clinical implication is straightforward.

“Routine radiotherapy, which I know some clinicians offer based on retrospective studies, should be discouraged,” he said.

He stressed, however, that this does not mean radiotherapy should never be used.

“There will of course be patients, for example patients with bleeding or tumours compressing the airways, where radiotherapy may be appropriate — especially if the response to chemoimmunotherapy is poor and the patient has pronounced symptoms,” he said.

The recommendation therefore applies to routine thoracic radiotherapy as an add-on to chemoimmunotherapy — not to palliative radiotherapy for symptomatic disease.

Independent expert: “This is why we run trials”

Åslaug Helland, professor and senior consultant at Oslo University Hospital, was not involved in TRIPLEX. She said the results were surprising but important.

“Bjørn Henning Grønberg and the Trondheim group have done tremendous work over many years, building study after study. We expected there to be a difference in survival and benefit from the treatment. But there was not,” Helland told HealthTalk.

She said the trial illustrates why randomised studies are essential, even when the biological rationale is strong.

“This is exactly why we run trials: to find out whether the effect is what we believe it to be. This is intensive treatment, with substantial toxicity, and it can be burdensome for patients,” she said.

Helland supports Grønberg’s conclusion that routine thoracic radiotherapy on top of chemoimmunotherapy should be avoided outside clinical trials.

“When a treatment causes more toxicity and does not help, there is no point in doing it,” she said.

Before TRIPLEX, several retrospective studies had suggested a benefit from thoracic radiotherapy in extensive-stage small cell lung cancer. Such analyses may be affected by selection bias: patients who receive additional treatment are often fitter than those who do not.

TRIPLEX tested the question in a randomised trial — and found no benefit.

Grønberg also notes that TRIPLEX is not alone. The German randomised TREASURE trial, which investigated a related treatment strategy, was also stopped early for safety reasons.

“It is a negative study. But it is still an important study,” Grønberg said. “There are many retrospective studies suggesting a benefit from radiotherapy, but this is the first large randomised trial to be completed. That is why the results were selected for oral presentation at ASCO.”

The experience from TRIPLEX is already informing new trials, where radiotherapy and immunotherapy are being investigated more sequentially and with clearer safety safeguards.