Head and Neck Cancer Treatment Evolution Leads the Way for Future Developments


For Head and Neck Cancer Awareness Month, Robert L. Ferris, MD, PhD, FACS, elaborated on the significant progress in the head and neck cancer space, as well as potentially practice-changing results that will come with emerging agents In an interview with Targeted Oncology™.

Robert L. Ferris, MD, PhD, FACS

Robert L. Ferris, MD, PhD, FACS

Plenty has changed in the head and neck cancer field in the past 10 years. This time has allowed for key PD-1 inhibitors to gain FDA approval, de-intensification to come into the fold, and specifically, staging for human papillomavirus (HPV) status has evolved to aid oncologists in their prognosis.

Although there have been several negative trial results in recent larger studies, they have been hypothesis generating and have answered significant questions for the treatment of head and neck cancers. Going forward, they may help to generate practice-changing data and improve treatment options for the next 10 years.

In an interview with Targeted Oncology™, Robert L. Ferris, MD, PhD, FACS, director, UPMC Hillman Cancer Center; Hillman Professor of Oncology; associate vice chancellor for cancer research; co-director for the Tumor Microenvironment Center; professor of otolaryngology, immunology, and radiation oncology, University of Pittsburgh; and co-physician editor in chief of Targeted Therapies in Oncology™, elaborated on the significant progress in the head and neck cancer space, as well as potentially practice-changing results that will come with emerging agents, for Head and Neck Cancer Awareness Month.

Targeted Oncology™: How has the field of head and neck cancer changed over the past 10 years?

Ferris: If you go back 10 years ago to 2012…cetuximab [Erbitux] was felt to be just as effective as cisplatin. The RTOG 1016 [NCT01302834] study shows that's not the case.1 There's a superiority of [chemotherapy] over cetuximab for locally advanced disease. We had no FDA-approved PD-1 inhibitors, [but in the past 10 years] nivolumab [Opdivo] and pembrolizumab [Keytruda] are standard in second line and first line. We have the concept of de-intensification of therapy for good prognosis. HPV-positive disease [research] was getting started, and whether that was safe, and how to do that was launching clinical trials. The ECOG 3311 trial [NCT01898494] that we published a couple months ago,2 was just being designed in 2011 or 2012. The concept of de-intensification for HPV-positive, good-prognosis disease was a concept that was tested for the past 10 years, and is now beginning to show clinically relevant, practice-changing data to guide what the appropriate treatment intensity is for this new disease. I think we understood that HPV was a major and increasing subset 10 years ago. We understood that it had a better prognosis but had no impact on treatment. And in the past 10 years, the staging system AJCC [American Join Committee on Cancer] 8 came out,3 which changed the staging system and separated by HPV status. We began having de-intensification clinical trial results, which was just kind of a concept 10 years ago. I think [there has been] pretty substantial progress in 10 years. They have totally new and standard therapies for a good prognosis group of patients and have totally new FDA-approved agents in recurrent metastatic disease, but so far, we don't know how to use it in locally advanced disease.

De-intensification is here. Staging is here now based on HPV status, a different staging system, which didn't exist before. We used to stage it all the same, but now there's HPV-negative and HPV-positive staging, which is separate. Immunotherapy is approved, and cetuximab is inferior to cisplatin in locally advanced disease, though they were felt to be interchangeable 10 years ago.

What trials have been the most practice changing in recent years, and what do you think will be the next wave of practice-changing data?

There are the CheckMate 141 [NCT02105636] and KEYNOTE-048 [NCT02358031] trials that got PD-1 inhibitors, nivolumab and pembrolizumab, approved in the second line and the first line.4,5 [There is] RTOG 1016 for [chemoradiation for] locally advanced disease for non-surgical treatment of HPV-positive head neck cancer and then ECOG 3311 for transoral robotic surgery as de-intensification. I'd say those are probably the biggest. You could say, from a negative standpoint, that the JAVELIN 100 trial [NCT02952586],6 which showed no benefit of adding avelumab [Bavencio] in locally advanced disease wasn't practice changing, but it was impactful because the expectations were high. There is still pembrolizumab added to chemoradiation. [We are waiting for] the KEYNOTE-412 [NCT03040999] trial results, which was designed for high-risk locally advanced disease,7 like JAVELIN, to be reported. You could say that the phase 3 CheckMate 651 trial [NCT02741570],8 which was reported at ESMO [European Society for Medical Oncology], showed that nivolumab and ipilimumab [Yervoy] did not beat the EXTREME regimen [cetuximab, cisplatin/carboplatin, and fluorouracil followed by cetuximab maintenance] like the KEYNOTE-048 trial showed that pembrolizumab did alone. I think that was more of a trial design flaw than it was that nivolumab and ipilimumab doesn't work.

I would say the ones that are affirmative results that have changed practice are the CheckMate 141 and KEYNOTE-048 trials for the PD-1 inhibitors, RTOG 1016, showing superiority of cisplatin, and then the use of transoral robotic surgery, ECOG 3311, permitting omission of chemotherapy and reduced-dose radiation for surgically treated HPV-positive patients.

Obviously, I have a conflict of interest as I've been involved in a couple of those trials. But I think, if you asked someone who was not Bob Ferris, that they would say the same things.

What are some of the new targets that are of interest for the future of head and neck cancer?

In IO [immune oncology], LAG-3 inhibition has recently been approved for melanoma,9 and there's some promising data in head neck cancer. So, I think LAG-3 combined with PD-1 will be intriguing.

I don't know if CTLA-4 is dead. I think it's an active agent. It would be great to see some role for CTLA-4 targeting head and neck cancer. We've published on that recently and have a neoadjuvant trial in it.10 I think the [CheckMate 651 trial] was not as negative. It just barely missed and had great durability. So CTLA-4 and LAG-3 may still be pursued. LAG-3 is earlier in its development. The SMAC mimetic agent, xevinapant, that was [previously] called Debio 1143, is pretty promising and is being used on top of chemoradiation or in place of chemotherapy. So, xevinapant for particularly p53-mutated [malignancies is of interest].

PI3 kinase inhibitors have been pretty disappointing, despite the relatively frequent presence of activating PI3K alterations. I think the field would love to see that because we don't have a lot of oncogene activation, but PIK3CA is present, and yet the PI3 kinase inhibitors don't really seem all that active, particularly not in the mutated ones. The role of circulating tumor DNA, particularly for HPV-positive disease, which dovetails into the next phase of de-intensification, is actually monitoring tumor burden. I think that's an intriguing concept that is not a new target, but I think it's conceptually innovative.

What role would you say that drug sequencing of these therapies plays in head and neck cancer currently?

We think it matters now in the reverse way that we thought it mattered. It's sort of like the RTOG 91-11 trial [NCT04943445] for larynx cancer.11 That trial compared cisplatin chemoradiation given concurrently vs induction chemotherapy followed by radiation. If you looked at the early results, concurrent chemoradiation was the best at 2 years. That was the New England Journal of Medicine paper that Arlene A. Forastiere, MD, published in terms of preserving the larynx.12 If you follow down the road, because concurrent chemoradiation was so toxic, eventually the overall survival was better to give chemotherapy first and separate it from radiation. In the case of IO sequencing, IO therapy, again, the JAVELIN trial was designed concurrently, before, during, and with a year of maintenance of avelumab because the preclinical data seem to suggest that just giving IO separate before or after radiation or chemoradiation would not harness the synergy that now we think there's some biology and that it's actually potentially deleterious to give avelumab during chemoradiation because of the impact of it on the immune system.

We now have lung data from the PACIFIC trial [NCT02125461],13 showing that you can take a high-risk group after chemoradiation, give a year of durvalumab [Imfinzi], and they do fantastic. That analogous trial, called IMvoke010 [NCT03452137],14 giving atezolizumab [Tecentriq] after high-risk treated head and neck cancer, should report any time. We’re all enthusiastic because since JAVELIN failed, that must mean that IMvoke010 will be positive. You say “sequencing,” I might say “separation” of concurrent agents, both of which have activity. We know that PD-1 and PD-L1 inhibitors work, and we know that chemoradiation works. So why, when you put them together, do you not get an added benefit, unless there's some interaction? If you go back to just treat with 1 and then treat with the other, you should get this plus that in terms of activity.

We have our oral abstract at ASCO [American Society of Clinical Oncology]. By pure coincidence, luck, and maybe a little bit of knowledge of the field, we designed a trial here, a relatively small, randomized, phase 2 trial that was just 40 mg/m2 or so in each arm of chemoradiation, concurrent with pembrolizumab or chemoradiation alone followed by pembrolizumab concurrently vs sequentially. Now that we know the JAVELIN trial failed results, we broke the code and put it in for ASCO, and the sequential data look better. This was started in 2015. We designed this trial so it started out as a biomarker trial [with 20 patients] in each arm, and I went back to Merck and got it doubled so we could at least look at some clinical end points. The 1-year progression-free survival rate, and we're getting 2-year and 3-year [progression-free survival rates], looks like sequentially separating them is better than concurrent treatment. We do think sequencing matters.

Currently, 2 immunotherapy agents are approved in HPV-positive and -negative related head and neck cancer. Can you address some of the research that is looking at immunotherapy in the definitive treatment setting in patients who don't have metastatic disease?

At present, there's no approved role for IO. There are trials using it in the pre-treatment stage, usually preoperatively: neoadjuvant for a month to 6 weeks, a single agent or in combination. There are post operative for post treatment with a year of maintenance that ECOG has, EA 3191 [NCT04671667].There are various trials testing in the local advanced setting, but none of them have shown any positive data yet that IMvoke010 already talked about. There's no role in the locally advanced setting for IO therapy outside of a clinical trial.

What are some of the emerging biomarkers in head and neck cancer that researchers are watching?

I would say that most folks are very enthusiastic. We've essentially failed adding anything to standard chemoradiation, and so this concept of xevinapant, adding a SMAC to a DNA damage pathway inhibitor [is promising]. The phase 2 data were very positive and very promising, and it wasn't by a little bit.15 You always expect a little fall off [in the curves] when you go to a phase 3, but this was a big enough phase 2, and it's substantially beneficial that I think the enthusiasm is there and there's a phase 3 running [NCT04459715]. I would say that folks are looking at that. There's also continued efforts at de-intensifying for HPV-positive disease in some ways, continuing to reduce radiation. There was an ASTRO [American Society for Radiation Oncology] with 36 Gy of radiation as opposed to the 50 Gy that we had in ECOG 3311. There's use of circulating tumor DNA to reduce adjuvant therapy. I think getting a little bit more personalized in selecting the best patients who are candidates for reduced doses and then finding ways to intensify therapy for the poor-prognosis HPV-negatives is a key area where we've made no progress in a few decades.

What would you say more community oncologists should know about how to treat head and neck cancers?

HPV is continuing to increase in frequency, primarily in the tonsil and the base of tongue. P16 is the surrogate biomarker to test for it, but don't use p16 unless the tumor is from the base of the tongue or the tonsil. It doesn't work in the oral cavity or the larynx, and we see community oncologists thinking that you just get p16 on every cancer of the head and neck. No. It's only a surrogate in the tonsil or base of tongue primary tumors. Also, you can get it from a neck needle biopsy so it can be useful to localize the primary tumor to the tonsil or the base of the tongue. [I want them to] know it does appear safe for good prognosis [for patients who are] HPV-positive to reduce the radiation and chemotherapy dose. National Comprehensive Cancer Network guidelines are being updated with that. PD-L1 testing is not required for second-line IO therapy, but it is helpful and required in the first line to decide whether to give pembrolizumab monotherapy or pembrolizumab plus chemotherapy. And at present, adding IO in the locally advanced setting does not have a role.


1. Gillison ML, Trotti AM, Harris J, et al. Radiotherapy plus cetuximab or cisplatin in human papillomavirus-positive oropharyngeal cancer (NRG Oncology RTOG 1016): a randomised, multicentre, non-inferiority trial [published correction appears in Lancet. 2020 Mar 7;395(10226):784]. Lancet. 2019;393(10166):40-50. doi:10.1016/S0140-6736(18)32779-X

2. Ferris RL, Flamand Y, Weinstein GS, et al. Phase II randomized trial of transoral surgery and low-dose intensity modulated radiation therapy in resectable p16+ locally advanced oropharynx cancer: an ECOG-ACRIN cancer research group trial (E3311). J Clin Oncol. 2022;40(2):138-149. doi:10.1200/JCO.21.01752

3. Amin MB, Greene FL, Edge SB, et al. The eighth edition AJCC cancer staging manual: continuing to build a bridge from a population-based to a more “personalized” approach to cancer staging. CA Cancer J Clin. 2017;67(2):93-99. doi:10.3322/caac.21388

4. Ferris RL, Blumenschein G Jr, Fayette J, et al. Nivolumab vs investigator's choice in recurrent or metastatic squamous cell carcinoma of the head and neck: 2-year long-term survival update of CheckMate 141 with analyses by tumor PD-L1 expression. Oral Oncol. 2018;81:45-51. doi:10.1016/j.oraloncology.2018.04.008

5. Burtness B, Harrington KJ, Greil R, et al. Pembrolizumab alone or with chemotherapy versus cetuximab with chemotherapy for recurrent or metastatic squamous cell carcinoma of the head and neck (KEYNOTE-048): a randomised, open-label, phase 3 study. Lancet. 2019;394(10212):1915-1928. doi:10.1016/S0140-6736(19)32591-7

6. Lee NY, Ferris RL, Psyrri A, et al. Avelumab plus standard-of-care chemoradiotherapy versus chemoradiotherapy alone in patients with locally advanced squamous cell carcinoma of the head and neck: a randomised, double-blind, placebo-controlled, multicentre, phase 3 trial. Lancet Oncol. 2021;22(4):450-462. doi:10.1016/S1470-2045(20)30737-3

7. Machiels JP, Tao Y, Burtness B, et al. Pembrolizumab given concomitantly with chemoradiation and as maintenance therapy for locally advanced head and neck squamous cell carcinoma: KEYNOTE-412. Future Oncol. 2020;16(18):1235-1243. doi:10.2217/fon-2020-0184

8. Argiris A, Harrington K, Tahara M, et al. Nivolumab (N) + ipilimumab (I) vs EXTREME as first-line (1L) treatment (tx) for recurrent/metastatic squamous cell carcinoma of the head and neck (R/M SCCHN): Final results of CheckMate 651. Ann Oncol. 2021;32(suppl_5):S1283-S1346. doi:10.1016/annonc/annonc741

9. FDA approves first LAG 3 inhibitor antibody Opdualag for metastatic melanoma. News release. BioSpace; March 22, 2022. Accessed April 25, 2022. https://bit.ly/3KgqB65

10. Jie HB, Schuler PJ, Lee SC, et al. CTLA-4⁺ regulatory T cells increased in cetuximab-treated head and neck cancer patients suppress NK cell cytotoxicity and correlate with poor prognosis. Cancer Res. 2015;75(11):2200-2210. doi:10.1158/0008-5472.CAN-14-2788

11. Forastiere AA, Zhang Q, Weber RS, et al. Long-term results of RTOG 91-11: a comparison of three nonsurgical treatment strategies to preserve the larynx in patients with locally advanced larynx cancer. J Clin Oncol. 2013;31(7):845-852. doi:10.1200/JCO.2012.43.6097

12. Forastiere AA, Goepfert H, Maor M, et al. Concurrent chemotherapy and radiotherapy for organ preservation in advanced laryngeal cancer. N Engl J Med. 2003;349(22):2091-2098. doi:10.1056/NEJMoa031317

13. Faivre-Finn C, Vicente D, Kurata T, et al. Four-year survival with durvalumab after chemoradiotherapy in stage III NSCLC-an update from the PACIFIC trial. J Thorac Oncol. 2021;16(5):860-867. doi:10.1016/j.jtho.2020.12.015

14. Wong D, Fayette J, Guo Y, et al. Abstract CT123: IMvoke010: Randomized Phase III study of atezolizumab as adjuvant monotherapy after definitive therapy of squamous cell carcinoma of the head and neck (SCCHN). Cancer Res. 2019;79(13_supplement):CT123. doi:10.1158/1538-7445.AM2019-CT123

15. Bourhis J, Sun X, Le Tourneau C, et al. 3-years follow-up of double-blind randomized phase II comparing concurrent high-dose cisplatin chemo-radiation plus xevinapant or placebo in high-risk patients with locally advanced squamous cell carcinoma of the head and neck. Ann Oncol. 2020;31(suppl_4):S1142-S1215. doi:10.1016/annonc/annonc325

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