Foregoing surgery is feasible after successful immunotherapy

20-06-2022

Immunotherapy prior to surgery (neoadjuvant immunotherapy) has once again proven its efficacy in melanoma patients with lymph node metastases (stage 3 melanoma), as shown by the PRADO study, published on June 5.

This phase II study, led by Christian Blank of the Netherlands Cancer Institute and Leiden University Medical Center, confirmed the efficacy of a combination therapy involving the checkpoint inhibitors ipilimumab and nivolumab in a neoadjuvant setting. The PRADO study also showed that extensive surgery can be omitted in patients who respond very well to the therapy, which can increase the patients' quality of life. There are even benefits for patients showing a poor response and who generally face a poor prognosis: postoperative treatment appears to improve recurrence-free survival rates in this patient group as well.

Publication in Nature Medicine, June 5, 2022.

'In the future, melanoma patients who respond very well to neoadjuvant immunotherapy may no longer require surgery,' internist-oncologist and research leader Christian Blank said in 2019, when, the results of the OpACIN-neo study were published under his leadership. Its successor, the recently published PRADO study, verifies that foregoing surgery is indeed a feasible option.

High response rate

The OpACIN-neo had shown that treating stage 3 melanoma patients with a combination of two checkpoint inhibitors (ipilimumab and nivolumab) prior to lymph node surgery, yielded a high response rate of 77%, with acceptable side effects. In addition, a subsequent 2021 study showed that patients who had shown either a high or partial response to immunotherapy also faced an excellent long-term prognosis, with only a few of them seeing recurrences after two years. Two-thirds of patients who responded poorly to neoadjuvant immunotherapy, however, did see disease recurrence.

High predictive value

On June 5, 2022, the renowned journal Nature Medicine published the results of the PRADO study, which was primarily an extension of the OpACIN-neo study involving 99 new patients, aiming to verify its results with a larger group of patients. Because the response to neoadjuvant immunotherapy in the OpACIN-neo study had been shown to have such a high predictive value for the patient's future, the researchers decided to investigate whether follow-up treatment could be adjusted based on a patient's response: less when possible, more when necessary.

Patients showing high responses were not treated with extensive lymph node surgery, while patients with partial responses did undergo the surgery, and patients with poor responses were treated with both surgery and immunotherapy or targeted therapy, and in some cases also radiotherapy.

What kind of treatment do stage 3 melanoma patients receive?

Standard treatment for patients with stage 3 melanoma is the removal of their lymph nodes. Since late 2018, this is followed up by a year of immunotherapy. 'Despite the treatment, almost half of these patients experience recurrence after three to five years,' research leader Christian Blank says.

In 2014, he started conducting research into neoadjuvant immunotherapy. 'This is because we think that the immune system can best learn to recognize and destroy tumor cells, including small metastases, if they are still inside the body.'

Personalized treatment improves patient outcomes

The results of the earlier OpACIN-neo study were largely confirmed in the PRADO study. The patient response percentage was almost equally high (72%) and the side effects of the immunotherapy were deemed acceptable. In addition, 61% of patients achieved a high response rate, where extensive lymph node surgery could be omitted.

This resulted in fewer side effects as a result of surgical procedures and a better quality of life. 'Known risks of a lymph node dissection are lymphedema and wound infections or scarring. These consequences can have a long-lasting effect on a patient's life,' says physician-researcher Irene Reijers, who coordinated the PRADO and conducted her PhD research on the topic. 'I thought to myself: wouldn't patients find it scary to omit surgery? But as it turned out, everyone was very eager to participate in the study to be able to avoid it.'

To date, 93% of the patients who saw a high response have been free of melanoma, and four out of sixty patients saw a melanoma recurrence within two years of the surgery. Reijers: 'In three of these patients, the melanoma returned only in the lymph nodes, which meant that the standard treatment of surgery and postoperative immunotherapy or targeted therapy was still an effective option.

In 2021, Christian Blank and his team were awarded the NKI Patient Impact Award for their pioneering and visionary research into neoadjuvant therapy

Poor and partial responders

Of all patients who showed a poor response, only one-third saw actual occurrence after surgery and additional treatment. In the PRADO’s predecessor, the OpACIN-neo, the patients showing poor responses did not receive this postoperative treatment, and as a result, two-thirds saw a recurrence.

Reijers: 'The additional postoperative immunotherapy or targeted therapy and option for radiotherapy seems to improve the recurrence-free survival of these patients.'

'The one remaining question is whether patients showing partial responses could also benefit from additional postoperative treatment,' she adds. In the PRADO study, four of the 11 patients showing partial responses still experienced a recurrence of the melanoma. 'We don't know what's behind that. In the OpACIN-neo, patients showing partial responses faced prognoses as good as those of patients with very good responses. The numbers involved are small, but we still want to be a little more cautious based on these results and treat patients with partial responses as well in the future.'

The phase III NADINA study: post-treatment compared with pretreatment

Neoadjuvant immunotherapy is currently still an experimental treatment. The NADINA study, a comparative phase III study launched in 2022, randomizes patients in groups receiving post-treatment immunotherapy (adjuvant) with immunotherapy and neoadjuvant immunotherapy (pretreatment) and in case of a partial or poor response, post-treatment therapy as well. The study will have to provide definitive proof that immunotherapy for stage 3 melanoma before surgery is more effective than immunotherapy after surgery. Only then can neoadjuvant immunotherapy be approved as a standard treatment. The omission of surgery is a potential next step. PRADO has already shown that this is a feasible option.

Pathological response explained

The pathological response is determined by the pathologist by looking at the number of remaining tumor cells in the gland:

Very good pathological response: 10% or fewer live tumor cells remaining in the tissue.
Partial pathological response: 10-50% live tumor cells remaining
Poor pathological response: more than 50% of live tumor cells remaining

To determine how many tumor cells remained in the lymph nodes, only the “index gland” was removed after neoadjuvant immunotherapy. This was the largest gland containing melanoma. It had been marked prior to therapy so that it could be retrieved and removed after 6 weeks of therapy.

'By looking back in the data from the prior OpACIN and OpACIN-neo studies, we knew that the response in this index gland was representative of the response of all nearby lymph nodes,' says Reijers. Read the scientific article in JAMA Surgery here

The PRADO study (phase II, extension of OpACIN-neo study)

Objectives:

Confirmation of results from the OpACIN-neo study
To investigate whether extended lymph node surgery can be safely omitted in patients with very good response rates.
To investigate whether the addition of post-treatment with immunotherapy or targeted therapy and possibly radiotherapy can improve recurrence-free survival in patients with poor response.

For whom:

Melanoma patients (99 people) with metastases in the local lymph nodes (stage 3 melanoma)

When:

Accrual between 2018 and 2022. The study has now been closed.

Treatment: 　

Two courses of immunotherapy prior to extensive lymph node resection (neoadjuvant) with the combination of ipilimumab and nivolumab.
Adjust follow-up treatment according to response to immunotherapy:
- High responders: no extensive lymph node surgery and further follow-up treatment, only monitoring
- Partial responders: only extensive lymph node surgery followed by checkup
- Poor responders: extensive lymph node surgery followed by follow-up treatment with immunotherapy/targeted therapy and possibly radiotherapy.