CheckMate 141 trial: all that glitters is not gold

KEYWORDS:

• Head and neck cancer
• immunological check point inhibitors
• nivolumab
• cetuximab
• pembrolizumab

1. Introduction

The treatment of patients with recurrent/metastatic locally advanced head and neck squamous cell carcinoma (R/M-HNSCC) is rapidly evolving. For these patients, cetuximab in combination with platinum and 5-fluorouracil (PFE) still remains the standard of care (SOC) as the first-line treatment. Until a few months ago, patients who progress after platinum-based therapy have a dismal prognosis and no well-defined standard treatment. The promising clinical results of the second-line phase III trial CheckMate-141 offer a new standard after several years of failures. The anti-PD-1 monoclonal antibody nivolumab represents the new therapeutic option in patients with R/M-HNSCC progressing after platinum-based therapy. This is dependent on the results of CheckMate 141, which showed a survival benefit over standard of care drugs such as single agent weekly cetuximab, methotrexate, or docetaxel. However, only a small part of patients were responsive to Nivolumab and no predictive markers of response were identified. Treatment-related adverse events occurred at similar rates in the two arms, but grade 3–4 toxicities were less frequent with the experimental drug (13%) than the drug of the investigator’s choice (35%). The non-detrimental impact on quality of life and the achievement of the primary end-point overall survival benefit hides the absence of predictive biomarkers of response.

2. Evaluation

Patients with recurrent or metastatic head and neck squamous cell carcinoma (HNSCC) after platinum-based chemotherapy failure continue to have a very poor prognosis. For this setting of patients, with a tumor progression or recurrence within 6 months after the last dose of platinum-containing chemotherapy, Ferris and collaborators published the results of a phase III randomized trial that assessed the efficacy and safety of nivolumab [1]. Over the past decade, patients with second-line relapsed/metastatic (R/M)-HNSCC predominantly received either single-agent chemotherapy (CT) or best supportive care (BSC), without significant results on the survival [2]. In the LUX-H&N 1 trial, after a median follow-up of 6.7 months (IQR 3.1–9.0), progression-free survival (PFS) (primary endpoint) was longer in the afatinib group than in the methotrexate group. However, there was no significant difference in OS between the 322 patients with R/M HNSCC who had progressed on or after first-line platinum-based therapy and were randomly assigned to receive afatinib or weekly intravenous 40 mg/m² methotrexate [3].

In the CheckMate 141 trial, the 361 patients with R/M-HNSCC progressing within 6 months after platinum-based chemotherapy were randomly assigned, in a 2:1 ratio, to receive nivolumab 3 mg/kg every 2 weeks, or standard of care (SOC) medication (single-agent weekly methotrexate, docetaxel, or cetuximab). Nivolumab was administered at a dose of 3 mg per Kg of body weight every 2 weeks. SOC consisted of weekly intravenous administration of methotrexate at a dose of 40 to 60 mg/m² or docetaxel at a dose of 30 to 40 mg/m², or cetuximab at a dose of 250 mg/m² after a loading dose of 400 mg/m².

The study achieved the primary objective. The overall survival (OS) was significantly longer with nivolumab than with SOC, and the estimates of the 1-year survival rate were clearly higher with nivolumab than with standard therapy (36.0% vs. 16.6%). Nivolumab achieved a response rate of 13.3% (95% CI, 9.3 to 18.3), including 6 complete responses (CR) and 26 partial responses (PR) while in the control arm the response rate was 5.8% (95% CI, 2.4 to 11.6), including 1 CR and 6 PRs. Nivolumab improved OS and ORR regardless of prior cetuximab use, although the magnitude of benefit was greater in patients without prior exposure to cetuximab [4].

The efficacy results are similar to those obtained with pembrolizumab, the other anti-PD1 monoclonal antibody, in other clinical trials in patients with R/M-SCCHN, although the activity of pembrolizumab seems to be more related to the expression of PD-L1 [5].

More recently positive results from a trial on pembrolizumb in the treatment of R/M-HNSCC were published [6]. Based on these results, an evidence-based change of practice in second (or more)-line therapy for R/M-SCCHN can be determined. Subset analysis even suggested that nivolumab could be of benefit for patients failing platinum-based chemoradiation <6 months, and KEYNOTE-040 suggested that there might also be an important role for immunotherapy in the first-line R/M-SCCHN (although this needs to be additionally analyzed). However, it has to be considered that in both trials only a minority of patients responded to the treatment and predictive markers of response are still lacking.

The key points are that immune checkpoint inhibitors (ICI), whatever their value as monotherapy for patients with R/M-SCCHN, are still not of benefit for the most part of patients, and this is of particular worry when it concerns symptomatic disease, since theoretically those who do not respond might do worse.

Taken together, nivolumab and pembrolizumab produce a modest ORR of about 15% in second-line treatment, but the tumour regression is usually durable, even in platinum-resistant/refractory cases. Consequently, both drugs have gained FDA approval and have become new SOC options for the second-line treatment of R/M-SCCHN.

Cetuximab leads to survival benefit when combined with radiotherapy or combined with chemotherapy within the locally advanced and the relapsed/metastatic settings, respectively. The anti-EGFR drug, in addition to a proven efficacy, has a rather favorable toxicity profile [7].

Cetuximab in combination with platinum and 5-fluorouracil (PFE) still remains the SOC as the first-line treatment for patients with R/M HNSCC based on the results of the EXTREME trial [8]. Adding cetuximab to PF significantly prolonged OS (primary endpoint) and PFS, and significantly increased overall response rate (ORR). One hundred patients with at least stable disease in the PFE arm continued to receive cetuximab until disease progression or unacceptable toxic effects, whichever occurred first.

In the CheckMate 141 trial only 150 out of 240 patients in the Nivolumab arm were treated with a systemic therapy including Cetuximab, and 54.5% of the patients received two or more lines of systemic therapy. These findings reflect an enrolment with heterogeneous populations according to the setting of the treatment. The consequent mixing of first- and second-line patient populations in the study could lead to inadequate characterization of clinical benefit in second-line patients. Therefore, this scenario is reflective of real-world clinical settings.

A pre-specified, exploratory analysis was performed to evaluate the correlation of the treatment effect in subgroups defined according to tumor PD-L1 expression level and tumor p16 status (positive vs. negative). Among 260 evaluable patients, PD-L1 membrane staining was detected in at least 1% of tumour cells in 57% of cases. About the same proportion (92 of 178, 52%) was found to be positive for p16 as a surrogate marker of HPV infection. Although OS might have been greater for patients treated with nivolumab whose tumours expressed PD-L1 and/or p16, the interactions were not significant and were not corrected for multiple comparisons. However, it should be noted that in the prespecified, exploratory analysis was performed only on a portion of the population enrolled in the study. The most important drawback in this specific issue is the low cut-off used for PD-L1 selection (≥1% vs. <1%) does not allow good patient selection.

In the recurrent and metastatic setting, quality of life and the safety profile of the treatment continue to represent a primary objective to be pursued for any cancer treatment. In the trial, the authors showed that nivolumab was associated with fewer toxic effects of grade 3 or 4 than SOC (13.1% vs. 35.1%). In the nivolumab group, the most frequent adverse events of any grade were fatigue, nausea, rash, decreased appetite, and pruritus. Pneumonitis was observed in 2.1% of the patients treated with nivolumab. Two treatment-related deaths were reported in the nivolumab group and one patient in the SOC group died from a treatment-related lung infection. The data on quality of life suggest that nivolumab has a better impact than chemotherapy even if the number of patients who answered the questionnaires was very small. Therefore, this information requires further objective confirmation on a much larger cohort and a longer observation time more than the 15 weeks described in the Checkmate 141.

Based on these results, nivolumab has been approved by the Food and Drug Administration (FDA) and European Medicines Agency (EMA) for patients with disease progression on or after a platinum-based therapy [9,10]. The results of the trial have objectively determined a breakthrough in the treatment of the refractory platinum patient; the improvement of survival offers for the first time a further valid therapeutic option in this setting with a poor prognosis.

3. Expert opinion

HNSCCs are heterogeneous diseases. The majority of patients with HNSCC are diagnosed with advanced-stage disease (stage III to IVB). The only multidrug regimen with a demonstration of a survival advantage is platinum/FU/cetuximab derived from EXTREME trial. The EXTREME regimen is supported by over 10 years of evidence, and its role in R/M-HNSCC has been fully defined through years of clinical trials and observational studies. Fit patients with R/M-HNSCC should continue to receive the EXTREME regimen in the first-line setting with cetuximab until PD. Conversely, until very recently, there has been a lack of evidence-based second-line treatment options, and the available therapies have shown low response rates and poor survival outcomes. The immune system plays an important role in the development and progression of HNSCC, as the development of such tumors strongly depends on their ability to escape immune surveillance. Presently, the only evidence-based sequence places anti-PD-1 monoclonal antibody nivolumab in the second-line after platinum-refractory settings, where it represents the new SOC respect to historical therapeutic options and has provided new options for an optimized continuum of care in the treatment of R/M-HNSCC, until now unknown and unexpected. Nevertheless, survival benefits for the subset of patients with pretreated R/M-HNSCC who achieve disease control on nivolumab monotherapy are impressive and represent a breakthrough in clinical practice. Maximizing the number of therapy lines and optimizing the order in which therapies are administered has historically been one of the most powerful tools for delivering maximum benefit to the greatest number of patients. On the other hand, only a small percentage of patients with R/M-HNSCC appears to have a benefit with immunotherapy approaches and even if these patients have generally a long-lasting response there is a large number progressing and receiving no advantages excluding the side effects. Therefore, it is essential to only select patients that would be responsive to this kind of therapy, and not allow this opportunity to all patients considering its cost for healthcare systems. It has also to be considered that obtaining a response in R/M-HNSCC patients in a setting of disease with high burden of symptoms (pain, infections, dysphagia, functional impairments) is of paramount relevance. On these bases, ways for better patient selection for ICI therapy continue to be the challenge of ongoing investigations and tumour mutation burden (TMB) in lung cancer and microsatellite instability in colon cancer appear the most useful molecular markers predictive of response to ICIs. It should be advisable to add the evaluation of similar molecular markers also in HNSCC beyond the expression of PDL-1 in the tumour that has not still shown any value, at least in the case of nivolumab. More recently it was reported that TMB and a T cell-inflamed gene expression profile (GEP) exhibited joint predictive utility in identifying responders and nonresponders to the PD-1 antibody pembrolizumab. TMB and GEP were independently predictive of response and demonstrated low correlation, suggesting that they capture distinct features of neoantigenicity and T cell activation. Analysis of The Cancer Genome Atlas database showed TMB and GEP to have a low correlation, and analysis by joint stratification revealed biomarker-defined patterns of targetable-resistance biology [11].

Another development of immune therapies is based upon trials that evaluate immunotherapy combined with current cytotoxic agents at different dose regimens as well as radiation therapy. Additionally, using multiple immunetargeted agents concurrently has been promising as a treatment strategy. Moreover, more studies are required on the involvement of immunotherapy in the treatment of either elderly or platinum unfit patients. A new scenario in HNSCC is opening but a correct mode to proceed in this new path is required based on the biological rationales of the immunological treatment of tumours.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer Disclosures

Peer reviewers on this manuscript have no relevant financial relationships or otherwise to disclose.

Additional information

Funding

This paper was not funded.