Multidisciplinary Oncology

Hi Team,

Welcome to the start of the new academic year. Now that we've shifted the fellowship year to run August through August, August is our on-ramp month: multidisciplinary oncology, clinical research, and ethics, before we get into the more focused subsite topics for the rest of the year. Our discussion time stays the same, Wednesday Mornings @ 7AM, donuts and coffee for those who can join in person. If you can't make it, reach out by email or grab any of our head and neck surgeons while you're in the OR.

This week's topic is multidisciplinary oncology. The through-line of the articles below is that almost nothing we do for a locally advanced head and neck cancer patient is decided by a surgeon alone. I've kept the seminal papers that built the modern adjuvant and systemic therapy paradigm, then added the two developments that have changed the room in the last eighteen months: KEYNOTE-689, which finally brought immunotherapy into the perioperative window, and the hafnium oxide radioenhancer trials (NANORAY-312 and LUMIRAY), which are a good case study in what running a trial actually demands from a multi-D team.

Why we add chemotherapy after surgery

(Bernier NEJM 2004; EORTC 22931) and (Cooper NEJM 2004; RTOG 9501) are the source material for adjuvant chemoradiation. Each cooperative group enrolled roughly 400 postoperative patients and randomized them to adjuvant RT versus concurrent cisplatin-based CRT. TL;DR: adding chemotherapy buys about a 5–10% advantage in locoregional control and survival in the right patient. The pooled comparative analysis (Bernier Head Neck 2005) is the one to actually memorize, because it tells you which patient: positive margins and extranodal extension are the two features that clearly benefit. Everything else is a discussion.

Food for thought while you read. How do these trials, enrolled long before we separated HPV-associated disease, apply to a p16-positive oropharynx patient today? And what toxicity would a 60-year-old accept for that increment in control versus an 80-year-old? That question is the whole job.

Cetuximab, and the trap of assuming less toxic means safer

Since (Bonner NEJM 2006), cetuximab has been the reflexive answer for the cisplatin-ineligible patient. (Gillison Lancet 2019; NRG/RTOG 1016) tested that assumption head-on: about 800 HPV-associated OPSCC patients randomized to RT with cisplatin versus RT with cetuximab. Cetuximab failed non-inferiority, with roughly 10% worse overall survival and locoregional control, and it did not deliver the toxicity savings everyone expected. The lesson generalizes: substituting a "gentler" agent is a hypothesis, not a favor, and it needs a trial.

The first wave of checkpoint inhibition

(Chow JCO 2016; KEYNOTE-012) was the phase Ib expansion cohort showing an approximately 18% response rate to pembrolizumab in biomarker-unselected recurrent/metastatic disease. (Ferris NEJM 2016; CheckMate 141) randomized 361 platinum-refractory patients to nivolumab versus investigator's-choice single-agent chemotherapy and showed a survival advantage with a far better toxicity profile, which is what moved PD-1 blockade into standard practice. (Moskovitz Curr Oncol Rep 2018) is the readable review of that era. (Burtness Lancet 2019; KEYNOTE-048) then moved pembrolizumab into the first-line R/M setting and gave us the CPS scoring habit we still use.

Worth internalizing that all of this happened in incurable disease. For a decade, immunotherapy was a conversation we had after we had run out of surgical options.

Melanoma as the proving ground

(Weber NEJM 2017; CheckMate 238) randomized 906 resected stage IIIB–IV melanoma patients to adjuvant nivolumab versus ipilimumab. Nivolumab won on recurrence-free survival (12-month RFS 70.5% vs. 60.8%) with dramatically less grade 3/4 toxicity (14.4% vs. 45.9%). Cutaneous oncology has been running ahead of us on perioperative immunotherapy ever since, which is why nearly every melanoma case on our schedule now has a neoadjuvant component. We'll come back to this in detail during cutaneous month.

KEYNOTE-689: immunotherapy comes to the operating room

This is the paper to read this week. (Uppaluri NEJM 2025; KEYNOTE-689) randomized 714 patients with newly diagnosed, resectable, non-metastatic stage III/IVA HNSCC to standard of care (surgery, then risk-adapted adjuvant RT ± cisplatin) versus the same standard of care wrapped in pembrolizumab: two neoadjuvant cycles, then surgery, then adjuvant pembrolizumab with chemoradiation, then maintenance.

TL;DR: median event-free survival was 51.8 versus 30.4 months in the intention-to-treat population (HR 0.73), and 59.7 versus 26.9 months in the CPS ≥ 10 group (HR 0.66), which was the primary population. Major pathologic response, defined as ≤10% residual viable tumor, was roughly 14% versus essentially zero in the control arm. The FDA approved perioperative pembrolizumab for resectable locally advanced HNSCC with CPS ≥ 1 in June 2025.

Three surgeon-specific caveats before you quote the numbers at tumor board. First, the mPR comparison is close to a tautology, since the control arm received no neoadjuvant therapy at all, so a 0% pathologic response rate is expected; the number tells you the drug does something biologically, not that the trial proved a comparative pathologic endpoint. Second, and most important to us, neoadjuvant pembrolizumab did not reduce the likelihood of getting to surgery or completing the planned resection. That was the fear, and it did not materialize. Third, p16-positive oropharynx patients were largely excluded except for T4 disease, so this is not a green light for HPV-associated OPSCC.

The practical consequence is that the timing of our first conversation with medical oncology has moved. A newly diagnosed stage III/IVA patient now needs a CPS result and a multi-D discussion before we book the case, not after the pathology comes back.

Future directions: radioenhancers and what a trial actually costs

NBTXR3 is a first-in-class hafnium oxide nanoparticle injected directly into the tumor, inert on its own, that amplifies the local dose deposited by radiation without increasing dose to surrounding tissue. Phase I data in elderly platinum-ineligible patients were promising enough to launch NANORAY-312 (Le Tourneau Future Oncol 2025), a global randomized phase III of NBTXR3 plus RT ± cetuximab versus RT ± cetuximab in 500 patients aged 60 and older who cannot take platinum. The protocol was amended in 2026 to drop the interim analysis and read out on fewer events, so results should land sooner. LUMIRAY (NCT07219212) is the newer phase I of the same agent, now JNJ-90301900, given intratumorally and intranodally alongside concurrent cisplatin chemoradiation. It opened in January 2026.

I'm flagging these two less for the drug than for what they require. Someone has to inject the nanoparticle under image guidance, someone has to map it to the radiation plan, someone has to manage the cisplatin, and someone has to consent, enroll, and follow the patient. There is no version of this trial that a single specialty runs. When you read the AHNS curriculum's Clinical Research section this month, note that it asks you to distinguish phase I from phase II from phase III, to understand IRB review, and to identify a research mentor across surgery, medical oncology, and radiation oncology. NANORAY and LUMIRAY are what those objectives look like in practice.

Both NANORAY-312 and LUMIRAY are open here at Penn.

Thanks for reading through these. Take the time to read the papers themselves, especially KEYNOTE-689, since they'll shape your practice for decades. Looking forward to discussing on Wednesday.

Have a great week!

Rob