Brendon Stiles: Let’s talk about PACIFIC 2

Brendon Stiles, Professor and Chief, Thoracic Surgery and Surgical Oncology at Montefiore Health System, posted the following on X:

“At the risk of stirring up trouble with my Radiation Oncology friends, let’s talk about PACIFIC 2, presented by Jeff Bradley at ELCC24. To me it disappoints and dispels some mythology about CRT for stage III patients. I would love to hear everyone’s thoughts.

First of all, thanks to all the patients who participated and congratulations to the authors and sponsors for this really important study. This is how we improve clinical care.

Here are the study design and baseline characteristics. Control arm did NOT mandate Durva (pre global approval). Notice high proportion of T4 and maybe not so high proportion of N3 (not so different from AEGEAN, NeoTorch, NADIM 2).

PFS was disappointingly low, with no statistical difference between arms. Although difficult to compare, certainly not near what we see with neoadjuvant chemo/ICI + surgery patients.

Some of this may have been driven by high rate of T4 tumors. But if so, why do so many people still consider RT superior to surgery for these large bulky tumors? Local control likely is lower with RT and irradiating these tumors can cause large areas of necrosis/abscess.

The common refrain I hear frequently is that CRT is “safer”. But is it really? Look at grade 5 AEs: 6.8% and 4.6% mortality at </=4 months. This EXCEEDS surgical mortality in similar neoadjuvant chemo/ICI trials. I am surprised we haven’t heard more about this, Drew Moghanaki

We know many patients won’t get to ICI consolidation after CRT (read further) and the results from PACIFIC have been greatly tempered for me by COAST control arm, GEMSTONE 301, and now PACIFIC 2. We can probably do better.

If using CRT, isn’t it time to move to induction/neoadjuvant chemo/ICI prior to CRT? We need more dynamic thinking in this space, like SPRINT from Nitin Ohri, SteveMartin and team.

At a meeting recently I asked a prominent radiation oncology why not use “induction” ICI therapy? He seemed distressed and told me he would worry about progression during treatment and loss of ability to obtain local control…..

I told him he sounded like a surgeon.

Times change.

Interested to hear what friends and colleagues think.
-Is CRT really as safe as we think? Particularly for T4 tumors?
-When we include all patients, not just those who make it through CRT, are results really that impressive?
-Shouldn’t we be more aspirational w/ neoadj rx?

Source: Brendon Stiles/X