John Cramer, MD

PFS ≠ OS. ORR ≠ OS. No validated surrogate for OS exists in R/M HNSCC. LEAP-010: if lenvatinib had been submitted for accelerated approval on ORR or PFS, we'd be in trouble. OS must be the primary endpoint in HNSCC IO trials.

LEAP-010 results are in: lenvatinib + pembrolizumab improved ORR (+20%) and PFS (HR 0.64) vs pembro alone in R/M HNSCC — but OS was numerically worse (HR 1.15). A cautionary tale about surrogate endpoints. ascopubs.org/doi/10.1200/JC…

🚨 JAMA flags admin and access delays as safety hazards in care. In #headandneckcancer, this can derail trials & immunotherapy starts, likely worsening outcomes. Insightful viewpoint by Drs. Hassid and Kaafarani #JAMA #OncologySafety #Oncology #PatientSafety @MDAndersonnews

7y in the making!!! As I always spoke about this, the field of #NasopharyngealCarcinoma leads the way in driving individualised treatment in #HeadNeckCancer When we published our initial idea of stratifying patients by their early treatment response using #EBVDNA back then in 2018, we decided to test our idea formally with a trial, and kudos to a very talented #biostats and willing collaborators, we came up with EP-STAR Very glad to see it finally published today in @Nature 🍸 nature.com/articles/s4158…

In 2024 we showed that Modifier 22 doesn't actually pay more for complex cases owing to higher denial rates. The @AmCollSurgeons GSCRC committee has been working on this issue ever since... see our summary of what we have tried to do and what's next: jamanetwork.com/journals/jamas…

My take: The study’s strongest message isn’t “surrogate endpoint solved.” It’s “a 24-month checkpoint powerfully separates trajectories.” Use it to detect signal earlier—not to declare victory or stop measuring late harms.

Surrogate endpoints can speed answers—but they can also blind us. In HPV+ OPSCC, does being progression-free 24 months after RT mean we’re basically “done,” or are we missing the real story: late toxicity and non-cancer mortality? pubmed.ncbi.nlm.nih.gov/41643696/

@DrScottFortune @smithnephew Really interesting discussion. Most of the intracapsular data I’ve seen is pediatric-heavy—how confident are you that the bleeding/recovery benefits generalize to adults?

Switched to #Coblation #IntracapsularTonsillectomy in October 2024, and have not looked back! Load this important #podcast for your work commute @smithnephew

Time from cancer diagnosis → treatment is rising: 21 days in 2004 → 28 days in 2015. Much is ⬆️ in stage 1 & may reflect some good - ie careful shared-decision making/planning. But how to support people during the (often) anxious wait? @NicholasZaorsky ascopubs.org/doi/full/10.12…

@DavidSherMD My read is similar: This really highlights the gap between investigator-reported progressive disease and protocol-defined EFS events. A pt can come off study for ‘progressive disease’ undergo a more extensive operation, and still not trigger an EFS event.

@Jdcramer has made a critical point below about KEYNOTE-689. The EFS rules in KN-689 require careful review to interpret these results.  A protocol-specific event was determined by blind independent central review (BICR), but if growth in the pre-surgical CT was perceived to be a “flare” (i.e. potential progression), surgery was supposed to proceed unless unresectable (protocol quote below). In order to be considered an event, repeat imaging was required 4-8 weeks later, and obviously if the tumor was still resectable the patient would go to surgery before then. This definition means it was extremely difficult to have an event before surgery, even if the tumor grew and the surgery was more extensive than initially anticipated. Thus some patients may have been harmed by neoadjuvant treatment, but we would not see that in the event data. Thus there is this important disconnect: 82 patients in the pembro arm stopped the drug due to progression (by the investigator, as shown in the CONSORT diagram), even though there were only 69 progression events (by BICR, used for endpoint analyses). Is perioperative immunotherapy doing something favorable and important in a subset of these patients? Yes, and hopefully we can refine its use to the right population and with the right regimen (adding neoadjuvant chemo or RT?). Is it distinctly possible/probable that some patients are progressing on neoadjuvant pembro, leading to a worse outcome in some domain, but we cannot see that in these data? Yes, unfortunately, also true.

Question for those who’ve dug into KEYNOTE-689: If 43 pts had early ‘clinical progression’ (Table S2B), why isn’t there an early drop in EFS with neoadjuvant pembro? How do you reconcile this?

Interesting conversation on the latest @deepmargin_pod episode with Paul Swiecicki The latest in #HNSCC bispecifics and beyond. 🧪 podcasts.apple.com/gb/podcast/epi… #HeadAndNeckCancer #Oncology

The linked paper is a nice document and summary product, but let's emphasize a few highlights: 1. Statement 16, strong consensus: ctHPVDNA should supplement conventional surveillance tools, rather than reducing or replacing them. Natural corollary: if it is not reducing or replacing surveillance, what is the point? 2. Statement 9, strong consensus: Detectable ctHPVDNA without clinical or radiographic evidence of disease often increases patient distress. 3. Statement 5, strong consensus: Large-scale, prospective randomized controlled trials are necessary to validate ctHPVDNA's role in HPV+ oropharyngeal cancer management. I would change that statement from validate to determine. Validate assumes it has a role today, but as the document states, it doesn't reduce or replace any currently established surveillance tools. There are so many exciting ways that ctHPVDNA may influence care (screening/diagnosis, de-escalation, non-imaging-based surveillance) but these strategies need to be established in prospective randomized trials.

🥳🎆 Kicking of 2026 with our work showing intra-tumoral bacteria 🦠 affect outcomes of Radiotherapy + anti-PD-L1 now out in @NatureCancer with sister paper by @nataliesilvermd! Even when trials "fail" – we can learn from them! nature.com/articles/s4301…. -- w/ @GeneCollector, @imrtlee, @TylerAlban1, @DrHaddadRobert, the Pfizer team and more! (1/N)

@DavidSherMD 2/2 Also worth noting biology may cut the other way: a 2025 Nature paper links perineural invasion/cancer-induced nerve injury to resistance (not sensitivity) to anti–PD-1 across several tumors. Makes me cautious about over-reading the PNI subgroup. nature.com/articles/s4158…

@DavidSherMD 1/2 Agree these are hypothesis-generating. On PNI: because PNI is a locoregional failure risk factor, a regimen that mainly improves locoregional control can look “more effective” in PNI+ pts via risk enrichment—without implying nerve-specific PD-1 sensitivity.

December has been an important and exciting month for head and neck cancer publications: NIVOPOST-OP is out! With the crucial exception of KEYNOTE-689 (perioperative pembro for resectable HNSCC), randomized trials of local therapy +/- immunotherapy have been repeatedly unsuccessful in non-metastatic HNSCC. There have been a host of proposed reasons to explain these negative trials, most of which were in patients who did not undergo surgery. Invoke010 (adjuvant atezo after primary therapy) did include a small cohort of resected patients, without any obvious improvement. Then KN-689 came along, in which patients received 2 cycles of neoadjuvant pembro followed by surgery, adjuvant therapy and more pembro, leading to an improvement in EFS. One burning question (among many…) is whether the neoadjuvant delivery was critical to the success of the paradigm, or if the delivery of any anti-PD1 immunotherapy would be sufficient. Enter NIVOPOST-OP from GORTEC to help answer this question. sciencedirect.com/science/articl…

8/8 My tumor board takeaway: periop pembro is my default when eligible (KEYNOTE-689 EFS HR 0.73). For pts not eligible for neoadjuvant pembro but needing post-op cis-RT, I’d consider adjuvant nivo if coverage is feasible

7/8 Bigger pattern: perioperative PD-1 + surgery has now hit positive phase 3 signals (KEYNOTE-689; NIVOPOST-OP), while adding PD-1/PD-L1 to definitive CRT has repeatedly struggled (e.g., KEYNOTE-412; JAVELIN HN100). Timing/context may be everything.

1/8 NIVOPOST-OP (GORTEC 2018-01): first phase 3 showing statistically significant DFS benefit adding PD-1 blockade to standard post-op cisplatin-RT in resected high-risk LA-SCCHN (DFS HR 0.76, 95% CI 0.60–0.98). thelancet.com/journals/lance…