Search Continues for Agents to Provide Additive Benefit to Chemoradiation in Head and Neck Cancer

Nabil F. Saba, MD, FACP, discusses the results of the JAVELIN Head and Neck 100 trial, as well as data from other key, recent studies in head and neck cancer.

Findings from multiple studies that were presented during the 2020 ESMO Virtual Congress in locally advanced head and neck cancer raise important questions that will help move the field forward, lending insights on optimized care, said Nabil F. Saba, MD, FACP.

For example, the primary results of the phase 3 JAVELIN Head and Neck 100 trial failed to demonstrate a statistically significant improvement in progression-free survival (PFS) with the addition of avelumab (Bavencio) to chemoradiation compared with placebo plus chemoradiation in treatment-naïve patients.1 At the interim analysis, the hazard ratios for PFS and overall survival (OS) were 1.21 and 1.31, respectively, in favor of the placebo arm. 

“Certainly, the JAVELIN Head and Neck 100 trial is disappointing, but by no means, is it a final verdict on the role of immunotherapy in the locally advanced setting,” said Saba. “Is it the [PD-L1 inhibitor], or is it the cisplatin [plus] radiation schedule? Is it the sequencing of therapy? We will hopefully learn [the answers to these questions] from future trials that are expected to read out.”

However, positive findings from an updated analysis of a phase 2 trial (NCT02022098) evaluating the first-in-class inhibitor of apoptosis protein antagonist xevinapant were also presented during the meeting. Xevinapant plus cisplatin-based fractionated chemoradiotherapy (CRT) led to a significant reduction in the risk of mortality compared with CRT alone in patients with locally advanced squamous cell carcinoma of the head and neck.2 The planned phase 3 TrilynX trial (NCT04459715) will further evaluate event-free survival with xevinapant among this patient population. 

In an interview with OncLive, Saba, director of the Head and Neck Medical Oncology Program at Winship Cancer Institute of Emory University and a professor in the Department of Hematology and Medical Oncology and the Department of Otolaryngology at Emory University School of Medicine, discussed the results of the JAVELIN Head and Neck 100 trial, as well as data from other key, recent studies in head and neck cancer.

OncLive: What key trials were presented during the 2020 ESMO Virtual Congress in locally advanced head and neck cancer?

Saba: It was an exciting ESMO meeting. We [saw] data in locally advanced disease in platinum-eligible and platinum-ineligible patients. We also [saw] some updates on recurrent metastatic trials. However, I think the most important [data presented] really came from the locally advanced setting, namely the JAVELIN [Head and Neck 100] trial and the GORTEC [2015-01] trial. 

The JAVELIN trial was the first of its kind because it basically took the standard of care, which is high-dose cisplatin, in combination with radiation therapy, and added avelumab, a PD-L1 inhibitor, to look for possible improvement in outcome compared with placebo. Very disappointingly, the trial turned out to be negative; there was no signal in terms of improved outcome for patients [who received avelumab]. 

What questions were raised from these findings?

Several questions were raised. Why was this the case? What does radiation therapy and the standard of care do to the tumor microenvironment when it is given? In head and neck cancer, we are not shy about dosing radiation or chemotherapy. We give that to patients when we try to cure them. We go up to 70 Gy of radiation. One of the most widely acceptable [chemotherapy] standards is cisplatin at 100 mg/m2 for 3 cycles. 

Therefore, one cannot help but question whether this intensity of therapy does alter the tumor-specific lymphocytes that are in the tumor microenvironment. How much of this alteration could have affected the overall outcome in the JAVELIN Head and Neck 100 trial? There are other factors, of course. Avelumab is a PD-L1 inhibitor. For some reason we have not really seen very robust activity of these agents in head and neck cancer compared with PD-1 inhibitors. That may be another factor. 

We are waiting for the results of other trials, namely the KEYNOTE-412 trial, which is looking at pembrolizumab [Keytruda] and has basically the same design as the JAVELIN Head and Neck 100 trial. 

[JAVELIN Head and Neck 100] is one of the few trials that attempted to add a checkpoint inhibitor to the backbone of high-dose radiation and chemotherapy. We should remember that the trial was predominantly for HPV [human papillomavirus]-negative patients; however, when we looked at any signal based on HPV status—there was no such signal when we looked at the subset analysis of this trial or the forest plot—we saw a trend favoring avelumab for patients with high PD-L1 expression. This deserves further exploration in this setting. 

Of course, this is not surprising given that these patients tend to benefit from checkpoint inhibitors. In future trial designs, one should probably take these factors into account. Big questions include: What if we use a sequential approach rather than a combination or concurrent approach with checkpoint inhibitors? The IMvoke trial is evaluating a similar patient population but is looking at maintenance atezolizumab [Tecentriq] instead of sequential or concurrent [therapy] followed by maintenance. We have similar instances in lung cancer, where this [approach] was proven to be beneficial. It remains to be seen whether this will be beneficial in head and neck cancer. 

Another study that is accruing specifically for patients with intermediate-risk, HPV-positive disease is the ECOG-ACRIN 3161 trial, which also relies on an active agent, nivolumab [Opdivo], in this disease. The study also relies on a maintenance approach rather than a concurrent approach. [Whether any of these approaches will be beneficial] will be an important question to answer. 

What lessons were learned from the GORTEC-2015-01 trial?

[The GORTEC trial evaluated] pembrolizumab and radiation versus cetuximab [Erbitux] and radiation in cisplatin-ineligible patients. The trial was negative [for all end points], including locoregional control, OS, and PFS. The same questions [that the JAVELIN Head and Neck 100 trial raised] were raised here. Why is it that pembrolizumab, which is fairly active in the recurrent, metastatic setting, does not seem to be active compared with cetuximab [in the locally advanced space]? What is radiation doing? Is this the best way to use these agents in the [locally advanced] setting?

We saw again a revisitation of the cisplatin schedule in the locally advanced setting. Another GORTEC trial looked at this question. Interestingly, similar to the Japanese trial that we saw at the 2020 ASCO Virtual Scientific Program, this trial did not show a difference in outcome in the post-operative, high-risk setting. High-dose cisplatin did not appear to outperform low-dose cisplatin, which was given at 25 mg/m2 daily for 5 days every 3 weeks during radiation therapy. 

Interestingly, there was a higher degree of hematologic toxicity with high-dose cisplatin [versus low-dose cisplatin]. One cannot help but ask the question, again going back to the JAVELIN trial: Does altering the cisplatin schedule benefit patients who are subsequently getting immunotherapy? Those questions are valid and deserve to be explored.

Positive results were observed in the phase 2 study evaluating xevinapant. Could you highlight that trial and the potential utility of the investigational agent in the locally advanced setting?

This trial, which was reported at the [2020] ESMO [Congress], showed a favorable outcome for patients who got [xevinapant]. This is an agent that alters the mitochondrial apoptosis pathway. The update that we saw at the 2020 ESMO meeting showed an improvement in OS compared with the standard arm of cisplatin and radiation. 

[The trial evaluated] an HPV-negative population, so questions are raised as to whether the same approach could be applicable to patients with HPV-positive disease. Other questions of interest include: Is [xevinapant] going to be promising in platinum-ineligible patients? Are we going to see some improvement over what we consider one of the standard options, that being cetuximab and radiation therapy? That remains to be seen, but efforts are [underway] to proceed with a trial along those lines. The FDA granted a [breakthrough therapy designation] to [xevinapant], and the phase 3 confirmatory study is ongoing, and is being launched as a definitive trial in that setting. 

What results were presented in the recurrent metastatic setting?

We saw an update of the KEYNOTE-048 trial, which basically showed an improvement in outcome favoring pembrolizumab and chemotherapy in the overall population with continued long-term follow-up. The trial also showed improvement in outcome favoring single-agent pembrolizumab over the EXTREME regimen in PD-L1–positive patients. That solidifies the use of first-line PD-L1 inhibitors in the recurrent metastatic setting, especially for patients with PD-1/PD-L1–positive disease. 

These are, in a nutshell, the main studies that were reported at the 2020 ESMO Congress. Of course, there were other smaller studies looking at the specific activity of HPV-targeted vaccines that showed encouraging results. Research targeting HPV-related disease with vaccines is ongoing at multiple levels.

Are there any additional agents in the pipeline that look promising?

In head and neck cancer, we should be on the lookout for combination therapies, specifically with immunotherapy. Several efforts are ongoing, such as maturing trials combining EGFR inhibitors with checkpoint inhibitors. Other trials are looking at TKIs, such as lenvatinib [Lenvima], with checkpoint inhibitors. We’ve seen encouraging data with that combination [in head and neck cancer], as well as in thyroid cancer.

As I said, the trials looking at HPV-targeted vaccines in combination with PD-1 inhibitors are ongoing. We also have trials looking at altering the tumor microenvironment with intratumoral injections and using agents, such as STING agonists, to boost the local immune microenvironment and the anti–immune effect of PD-1 inhibitors. Those are also ongoing, so we look forward to seeing more mature results [from those studies].


  1. Cohen EE, Ferris RL, Psyrri A, et al. 910O Primary results of the phase III JAVELIN head & neck 100 trial: avelumab plus chemoradiotherapy (CRT) followed by avelumab maintenance vs CRT in patients with locally advanced squamous cell carcinoma of the head and neck (LA SCCHN). Ann Oncol. 2020;31(4):S658. doi:10.1016/j.annonc.2020.08.1025
  2. Bourhis J, Sun X, Le Tourneau C, et al. LBA39 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(4):S1168. doi:10.1016/j.annonc.2020.08.2269