Abstract
Background:
This study assessed the maximum tolerated dose (MTD) of the PI3K inhibitor buparlisib given concurrently with cetuximab in recurrent and metastatic (R/M) head and neck squamous cell carcinoma (HNSCC).
Methods:
Twelve patients with R/M HNSCC were enrolled. Patients were given oral buparlisib starting day 7 and daily thereafter. The dose of buparlisib was escalated in a 3 + 3 design followed by a dose expansion cohort of 6 patients. The MTD of buparlisib per protocol was 100 mg daily with cetuximab given intravenously every 14 days starting day 0.
Results:
Ten patients had ≥2 previous treatment regimens (11 with prior cetuximab). There were no dose limiting toxicities observed during dose escalation. One patient achieved a partial response and 4 achieved stable disease.
Conclusion:
Based on this pilot study, buparlisib at 100 mg daily plus cetuximab proved to be well-tolerated. Patients previously treated with cetuximab monotherapy showed benefit from this combination.
Keywords: advanced disease, buparlisib, cetuximab, head and neck squamous cell carcinoma, metastatic disease, PI3K inhibitor, recurrent disease
1 |. INTRODUCTION
Head and neck squamous cell carcinoma (HNSCC) is the fifth most common cause of cancer deaths worldwide with more than 600 000 cases occurring annually.1 In the United States, it is estimated that over 63 000 people had developed head and neck cancer and over 10 000 people were expected to have died from their disease in 2018.2 Due to the location of the disease, HNSCC results in significant morbidity as a result of damage or loss of vital processes involved with nutrition, respiration, and communication.
Approximately two-thirds of patients with HNSCC will present with locoregional disease, and despite aggressive therapy, almost 50% of patients will succumb to recurrent and/or metastatic disease. The median survival for patients with incurable, recurrent, or metastatic disease is poor, at approximately 4 months when untreated.3,4 When treated, R/M head and neck cancer has a median survival of 0-12 months.5
In addition to palliative chemotherapy, the only targeted therapy for the treatment of incurable, recurrent, or metastatic disease until 2016 was the epidermal growth factor receptor (EGFR) antibody cetuximab, showing a response rate of 13% in R/M HNSCC, and stable disease in 40%-50% of patients. Median progression-free survival is poor at only 70 days for cetuximab single agent.5,6 Recently anti-PD-1 agents such as nivolumab and pembrolizumab have demonstrated improvement in median overall survival.7,8 Although these novel agents provide superior clinical efficacy compared to recent treatment standards, the fraction of patients responding is small, with objective response rates ranging from 13.3 to 18%,7,9 resulting in a persistent and significant need for development of better treatment options for patients with R/M HNSCC.
The phosphatidylinositol-3-kinase (PI3K) signaling pathway regulates diverse cellular functions including cell proliferation, survival, cell migration, and angiogenesis.10 Additionally, the PI3K pathway is known to serve a central role in pathogenesis of numerous types of neoplasia, including squamous cell carcinoma of the head and neck, contributing to treatment resistance and overall disease progression. Constitutive activation of PI3K signaling is involved in carcinogenesis and may be a predictor of poor prognosis in numerous cancer types.10 Pre-clinical literature as well as analysis of the mutational profile for HNSCC has demonstrated frequent alterations in the PI3K-AKT-mTOR pathway in ~80% of tumors.11
Buparlisib is an oral pan-class I PI3K inhibitor with activity against all of the catalytic subunits in the class I subgroup of the PI3K enzyme family, including p110a, –β, –δ, –γ. While p110a (PIK3CA) specific PI3K inhibitors are also in development, PI3K aberrations in HNSCC are not limited to PIK3CA, and there is a strong rationale to develop pan-class I PI3K inhibitors in this disease. By contrast, p110a specific inhibitors may have a more favorable side effect profile.
Recent clinical data have suggested efficacy of buparlisib in the treatment of hormone receptor positive, HER2-negative, locally advanced or metastatic breast cancer that relapsed following endocrine therapy and mTOR inhibitors as well as in the setting of R/M HNSCC when combined with paclitaxel.12,13 Based on these observations, the PI3K pathway is an attractive therapeutic target for the treatment of patients with advanced solid malignancies including HNSCC. Head and neck cancers also show frequent aberrations of EGFR including amplification and overexpression as well as an association of EGFR expression with poor prognosis.14 Treatment with cetuximab, alone or in combination with chemotherapy or radiation, is currently approved as a standard of care treatment option.
EGFR downstream signaling is primarily via the MAPK, and PIK3 pathways. Given the high frequency of PI3K aberrations (downstream of membrane bound EGFR), activating aberrations in the PI3K pathway are likely unaffected by EGFR blockade for example, with cetuximab or EGFR tyrosine kinase inhibitors. Recent clinical data support the rationale of PI3K pathway activation for example, via PTEN in a large trial of EGFR inhibitor afatinib in HNC making the combination of cetuximab with buparlisib of high interest.15
Preclinical data have shown that the primary mechanism of compensatory receptor tyrosine kinase upregulation seen in head and neck cancers is via EGFR suggesting that there may be prominent synergy between EGFR and PI3K with cotargeting approaches and demonstrated antitumor activity in preclinical models.16 By contrast PI3K inhibitors, when used as single agents, have shown limited activity.17,18
In this phase Ib, single center, pilot, dose escalation study, we investigate the safety and tolerability of the PI3K inhibitor buparlisib when given concurrently with cetuximab in R/M HNC, as well as assess preliminary efficacy in an expansion cohort.
2 |. MATERIAL AND METHODS
2.1 |. Eligibility
Eligible patients were ≥18 years old with histologically or cytologically confirmed diagnosis of HNSCC not amenable to curative intent therapy who had demonstrated progressive disease following exposure to a platinum agent or another cytotoxic chemotherapy or radiation. Patients were required to have radiographically measurable disease assessed by the local investigator in accordance with the Response Evaluation Criteria in Solid Tumors (RECIST v1.1), an ECOG ≤2, normal organ and marrow function, and no active cardiac disease. Prior cetuximab treatment did not prevent enrollment. Patients who had received prior treatment with a PI3K inhibitor or had greater than two prior lines of cytotoxic chemotherapy in the recurrent or metastatic setting were excluded. Patients who had received anticancer therapy within 4 weeks of treatment were excluded until they allowed for adequate washout of their previous therapy and resolution of any adverse effects from that treatment. Patients with acute or chronic liver or renal disease, patients with untreated brain metastasis, or a history of a major depressive episode or other significant psychiatric history were excluded from the study. The University of Chicago institutional review board approved the study (Univ. of Chicago IRB#12-1972, PI: Seiwert) and all patients were required to provide written informed consent prior to enrollment. All patients were treated at the University of Chicago.
2.2 |. Treatment
Before starting treatment, patients were required to undergo imaging of the head, neck, chest, and abdomen and have laboratory evaluation including comprehensive metabolic profile and complete blood count. The dose of buparlisib was increased in a standard 3 + 3 dose escalation study design. If all 3 patients were free of any dose limiting toxicities at a given dose level after 4 weeks of active treatment, the dose escalation continued to the subsequent increased dose. It was determined that based upon previous studies of buparlisib in combination therapy regimens, that the initial dose administered would be 80 mg daily with the maximum allowable dose of buparlisib during the dose escalation phase capped at 100 mg daily.19 The dose escalation portion of the study was followed by an expansion cohort to further assess the safety and tolerability of the maximum achieved dose of buparlisib when given in combination with cetuximab. All toxicities during treatment were assessed and graded in accordance with the Common Terminology Criteria for Adverse Events (CTCAE) version 4. Dose limiting toxicities were assessed during the dose escalation phase of the study and were defined as any nonhematologic toxicity ≥ CTCAE grade 3, any thrombocytopenia, neutropenia, or anemia ≥ CTCAE grade 4, any toxicity ≥ CTCAE grade 2 that was deemed to be intolerable, and any neuropsychiatric symptoms ≥ CTCAE grade 3.
Buparlisib was self-administered orally on day 7 and daily thereafter. The original purpose of the 7-day run-in period of single agent buparlisib was for patients with accessible tumors to undergo a pretreatment biopsy and a biopsy following the initial 7 days of treatment to assess induction of compensatory singling/feedback loop signaling in a patient’s tissue. Due to a significant majority of patients being screened for enrollment in the protocol not having tumors that were deemed accessible for an experimental biopsy the effort to obtain a tissue specimen was stopped. In an effort to standardize treatment that patients were receiving all patients continued to start with a 7-day run-in period followed by concurrent treatment with buparlisib and cetuximab. Cetuximab (500 mg/m2) was given intravenously on day 0 of treatment and then every 14 days thereafter. All patients were clinically evaluated by physicians every 14 days. Patients had labs drawn at baseline and every 14 days subsequently prior to receiving treatment with intravenous cetuximab. Radiographic studies including imaging of the head, neck, chest, and abdomen were completed every 8 weeks to assess for disease progression. Treatment continued until disease progression or until an unacceptable toxicity.
2.3 |. Endpoints and statistical considerations
The primary objective of this study was to assess the safety and tolerability of buparlisib when given with cetuximab in patients with R/M HNSCC by analyzing toxicities experienced by patients while in treatment and follow up. Secondary endpoints included evaluating tumor shrinkage in patients treated with the combination therapy of buparlisib and cetuximab as well as determining the response rate in the same patient population. Response was assessed with RECIST V1.1. Overall survival, defined as the time from study initiation to death due to any reason, and progression-free survival, defined as the time from study initiation to first evidence of progression of disease, were assessed and compared to current standards for treatment of R/M HNSCC in a heavily pretreated population. Human papillomavirus (HPV) status of all patients with oropharyngeal cancer and patients with unknown anatomic locations of their primary cancer was determined retrospectively utilizing a combination of p16 immunohistochemistry and/or HPV–polymerase chain reaction.
3 |. RESULTS
3.1 |. Patient characteristics
Patients were enrolled between May 2013 and November 2015. Twelve patients were enrolled in the study in total, with 6 being enrolled in the dose escalation phase of the study (3 pts at dose level 1:80 mg buparlisib PO daily and cetuximab 500 mg/m2 IV every 14 days, 3 pts at dose level 2:100 mg buparlisib PO daily and cetuximab 500 mg/m2 IV every 14 days) and six additional patients being enrolled in the dose expansion cohort (100 mg buparlisib PO daily & cetuximab 500 mg/m2 IV every 14 days). Nine patients were screened for the study but did not proceed with treatment for a variety of reasons, including patients pursuing alternative treatment options, or death prior to study enrollment (see Figure 1). Baseline characteristics for all patients enrolled are provided in Table 1. The average age of patients enrolled was 61 years (Range: 47-73 y/o). The majority of patients enrolled in the trial (ClinicalTrials.gov: NCT01816984) were men (83.3%). HPV status was assessed on patients with oropharyngeal cancers (n = 9) as well as the 2 patients enrolled who had an unknown anatomic location of their primary cancer. One patient was enrolled who had a nonoropharyngeal primary tumor, and thus HPV status was not assessed. Five patients were HPV+, 4 patients were HPV−, and 2 patients had unknown HPV status. Of the 12 patients enrolled, 10 patients (83.3%) had ≥2 previous treatment regimens, with 11 patients (91.7%) having recurrence of their disease or metastasis following treatment with cetuximab. Eleven patients (91.7%) had previously been treated with platinum therapy in the R/M setting. All 12 patients had received prior antineoplastic therapy.
FIGURE 1.
Study diagram and patient allocation
TABLE 1.
Baseline demographics and patient characteristics
| Buparlisib + cetuximab (n = 12) |
|
|---|---|
| No. of patients | |
| Age | |
| Median | 61 years |
| Range | 47-73 years |
| Sex | |
| Male | 10 (83.3%) |
| Female | 2 (16.7%) |
| Race | |
| White | 11 (91.7%) |
| African American | 1 (8.3%) |
| Smoking history | |
| Current | 10 (83.3%) |
| Former | 2 (16.7%) |
| HPV | |
| Positive | 5 (41.7%) |
| Negative | 4 (33.3%) |
| Unknown | 3 (25.0%) |
| ECOG | |
| 0 | 5 (41.7%) |
| 1 | 7 (58.3%) |
| Previous treatment with cetuximab | |
| Yes | 11 (91.7%) |
| No | 1 (8.3%) |
| Previous treatment regimens | |
| ≥3 | 6 (50.0%) |
| 2 | 4 (33.3%) |
| 1 | 2 (16.7%) |
3.2 |. Dose escalation
Three patients were treated in the first dose escalation cohort (80 mg buparlisib PO daily & cetuximab 500 mg/m2 IV every 14 days) with no dose-limiting toxicities. An additional 3 patients were treated at the next dose escalation level (100 mg buparlisib PO daily and cetuximab 500 mg/m2 IV every 14 days) with no dose-limiting toxicities. Because the protocol specified maximum allowable dose of buparlisib was reached without dose-limiting toxicity, the cohort treated with 100 mg buparlisib was expanded to include 6 additional patients.
3.3 |. Toxicity
The most common adverse events were hyperglycemia (n = 11, 91.6%), hypomagnesemia (n = 10, 83.3%), anorexia (n = 8, 66.7%), fatigue (n = 8, 66.7%), pain (n = 8, 66.7%), hypoalbuminemia (n = 7, 58.3%), and rash (n = 7, 58.3%). A complete list of adverse events is outlined in Table 2. Four patients experienced grade 1 anxiety and 1 patient experienced grade 2 depression while on study medication. No other psychological toxicities were noted.
TABLE 2.
Most commonly occurring adverse effects defined as those that occurred in >10% of patients
| Grade 1 No. of patients |
Grade 2 No. of patients |
Grade 3 No. of patients |
Grade 4 No. of patients |
Grade 5 No. of patients |
Total No. of patients |
|
|---|---|---|---|---|---|---|
| Hyperglycemia | 7 (58.3%) | 0 (0%) | 4 (33.3%) | 0 (0%) | 0 (0%) | 11 (91.7%) |
| Hypomagnesemia | 6 (50.0%) | 0 (0%) | 4 (33.3%) | 0 (0%) | 0 (0%) | 10 (83.3%) |
| Anorexia | 6 (50.0%) | 2 (16.7%) | 0 (0%) | 0 (0%) | 0 (0%) | 8 (66.7%) |
| Fatigue | 6 (50.0%) | 2 (16.7%) | 0 (0%) | 0 (0%) | 0 (0%) | 8 (66.7%) |
| Pain | 8 (66.7%) | 0 (0%) | 0 (0%) | 0 (0%) | 0 (0%) | 8 (66.7%) |
| Hypoalbuminemia | 5 (41.7%) | 2 (16.7%) | 0 (0%) | 0 (0%) | 0 (0%) | 7 (58.3%) |
| Rash | 6 (50.0%) | 1 (8.3%) | 0 (0%) | 0 (0%) | 0 (0%) | 7 (58.3%) |
| ALT increase | 7 (58.3%) | 0 (0%) | 0 (0%) | 0 (0%) | 0 (0%) | 7 (58.3%) |
| AST increase | 6 (50.0%) | 0 (0%) | 0 (0%) | 0 (0%) | 0 (0%) | 6 (50.0%) |
| Diarrhea | 4 (33.3%) | 0 (0%) | 2 (16.7%) | 0 (0%) | 0 (0%) | 6 (50.0%) |
| Hypokalemia | 5 (41.7%) | 0 (0%) | 0 (0%) | 0 (0%) | 0 (0%) | 5 (41.7%) |
| Anxiety | 4 (33.3%) | 0 (0%) | 0 (0%) | 0 (0%) | 0 (0%) | 4 (33.3%) |
| Constipation | 4 (33.3%) | 0 (0%) | 0 (0%) | 0 (0%) | 0 (0%) | 4 (33.3%) |
| Mood changes | 3 (25.0%) | 0 (0%) | 0 (0%) | 0 (0%) | 0 (0%) | 3 (25.0%) |
| Mucositis | 3 (25.0%) | 0 (0%) | 0 (0%) | 0 (0%) | 0 (0%) | 3 (25.0%) |
| Nausea | 3 (25.0%) | 0 (0%) | 0 (0%) | 0 (0%) | 0 (0%) | 3 (25.0%) |
| Pruritis | 3 (25.0%) | 0 (0%) | 0 (0%) | 0 (0%) | 0 (0%) | 3 (25.0%) |
| Transaminitis | 3 (25.0%) | 0 (0%) | 0 (0%) | 0 (0%) | 0 (0%) | 3 (25.0%) |
| Anemia | 1 (8.3%) | 1 (8.3%) | 0 (0%) | 0 (0%) | 0 (0%) | 2 (16.7%) |
| Dysphagia | 2 (16.7%) | 0 (0%) | 0 (0%) | 0 (0%) | 0 (0%) | 2 (16.7%) |
| Increased BUN | 2 (16.7%) | 0 (0%) | 0 (0%) | 0 (0%) | 0 (0%) | 2 (16.7%) |
| Leg tremor | 2 (16.7%) | 0 (0%) | 0 (0%) | 0 (0%) | 0 (0%) | 2 (16.7%) |
| Total bilirubin increase | 1 (8.3%) | 1 (8.3%) | 0 (0%) | 0 (0%) | 0 (0%) | 2 (16.7%) |
| Vomiting | 2 (16.7%) | 0 (0%) | 0 (0%) | 0 (0%) | 0 (0%) | 2 (16.7%) |
Ten patients experienced a ≥3 grade adverse event during treatment, but none of those toxicities met criteria for a serious adverse event (SAEs). The most common ≥3 grade adverse were hyperglycemia (n = 4, 33.3%), hypomagnesemia (n = 4, 33.3%), and diarrhea (n = 2, 16.7%). SAEs were reported for 4 patients (33.3%) and were determined to be unrelated to the study medication by the treating physician. SAEs included a patient hospitalization for electrolyte abnormalities and anemia, a patient hospitalization for orthostasis, and 2 hospitalizations for acute kidney injury. One on-treatment death occurred due to cardiopulmonary arrest, which was assessed as unrelated to the study medication. One patient was discontinued from study medication due to declining health status.
3.4 |. Efficacy
Ten of 12 patients remained on study beyond 8 weeks following treatment initiation, which was the first protocol-specified radiographic disease evaluation and were evaluable for response. One of 12 patients (n = 1, 8.3%) achieved a partial response based on RECIST V1.1 with a duration of 4 months. Four patients (n = 4, 33.3%) achieved stable disease with a median duration of 4 months. Five patients (n = 5, 41.7%) showed progressive disease at their first radiographic evaluation and were discontinued from treatment.
Eleven patients who had previously received treatment with cetuximab in the curative intent setting or in the R/M setting were enrolled in this study. Four of the 11 patients (36.4%) who previously progressed on therapy including cetuximab achieved a clinically meaningful benefit, defined as either stable disease or a partial response based on RECIST V1.1 criteria, when treated with buparlisib and cetuximab in combination. One patient who was previously treated with the EXTREME regimen (carbo/cisplatin, 5-fluorouracil, cetuximab) and had a partial response to treatment followed by subsequent progression of their disease achieved a partial response to treatment with buparlisib and cetuximab. One patient who had stability of their disease immediately following treatment with EXTREME and subsequent progression during follow-up had stability of their disease when treated with buparlisib and cetuximab. Two patients who previously had progressive disease on cetuximab containing treatment regimens (EXTREME and single agent cetuximab) achieved stability of their disease when treated with buparlisib and cetuximab. One patient had never been treated with cetuximab and achieved a stability of disease when treated with buparlisib and cetuximab. Table 3 provides further details regarding the 5 patients who responded to therapy with buparlisib and cetuximab and their previous treatment regimens.
TABLE 3.
Previous treatment and treatment response of the 5 patients who had stability of disease or response to treatment
| Patient # | Site of origin | Previous cetuximab containing therapy | Best response to previous cetuximab containing therapy | Response to buparlisib + cetuximab |
|---|---|---|---|---|
| 1 | Unknown primary | Carboplatin/5-fluorouracil/cetuximab (extreme) | Partial response | Partial response |
| 2 | Oropharyngeal | Cisplatin/5-fluorouracil/cetuximab (extreme) | Progressive disease | Stable disease |
| 3 | Oropharyngeal | Single agent cetuximab | Progressive disease | Stable disease |
| 4 | Nonoropharyngeal | Cisplatin/5-fluorouracil/cetuximab (extreme) | Stable diseasea | Stable disease |
| 5 | Oropharyngeal | N/A (no prior cetuximab therapy) | N/A (no prior cetuximab therapy) | Stable disease |
Note: 5 (out of 10 response evaluable patients) had progressive disease on buparlisib + cetuximab.
This patient ultimately progressed during the follow-up period after treatment completion.
Progression-free survival and overall survival were analyzed in an exploratory/descriptive fashion for all patients who received treatment. At the progression-free survival and overall survival analysis cutoff (August 1, 2017) all 12 patients who participated in the study had died. The median progression-free survival for all patients was 2 months (see Figure 2A). Retrospective HPV testing was done via p16 immunohistochemistry and/or HPV− polymerase chain reaction for all oropharyngeal cancer patients (n = 9) and patients with unknown primary (n = 2)). Five pts were determined to be HPV+, 4 pts were determined to be HPV−, 2 pts had unknown HPV status, and 1 patient was not tested. Patients who were retrospectively determined to be HPV+ had an average time to progression of 3.5 months, patients who were determined to be HPV− had an average time to progression of 2 months, and those with unknown HPV status had an average time to progression of 1.4 months. The median overall survival was 9.3 months for all 12 patients (see Figure 2B). The 5 patients who were retrospectively determined to be HPV+ had an average survival time of 12.3 months. The 4 patients that were determined to be HPV− had an average survival time of 5.8 months. Those with unknown HPV status had an average survival of 9.3 months.
FIGURE 2.
A, Progression-free survival. B, Overall survival. Reference line included at 12 months [Color figure can be viewed at wileyonlinelibrary.com]
4 |. DISCUSSION
The results of this phase Ib, dose escalation, pilot study assessed the safety and tolerability of buparlisib when given in combination with the EGFR inhibitor cetuximab, in the setting of R/M HNSCC. Per protocol, the maximum tolerated dose that was assessed in this study was 100 mg of buparlisib daily. The lack of dose-limiting toxicities during the dose escalation phase as well as the limited significant toxicity during the expansion cohort and the study as a whole, indicates that the combination of buparlisib and cetuximab was well tolerated and demonstrated an attractive toxicity profile. Although investigators considered continued progression of dose escalation to a higher maximum daily dose of buparlisib as a result of the limited toxicity experienced in this pilot study, investigators chose to maintain the maximum dose administered at 100 mg based on recommend phase 2 dose for single agent buparlisib that has shown clinical activity, good pharmacokinetic characteristics, and good tolerability and toxicity profile in several single agent buparlisib studies.18,19 Additionally, a recently published study further supported the use of 100 mg daily buparlisib as the ideal therapeutic dose when given in combination with paclitaxel in the treatment of R/M HNSCC.13
With the recent approval of the 2 immune checkpoint inhibitors pembrolizumab and nivolumab for platinum-resistant recurrent or metastatic head and neck cancer, there has been significant focus on improving overall survival and progression-free survival in a heavily pretreated patient population where very few quality treatment options existed. These agents have demonstrated significant promise with response rates of 13%-18%.7,8 Although these agents provide meaningful activity for patients with recurrent or metastatic disease, a majority of patients do not respond to immune modulating therapy and both constitutive and acquired resistance remain common problems. In an effort to address this unmet need for quality treatment options beyond immune checkpoint inhibitors for patients with R/M HNSCC, novel agents need to be studied. The randomized phase II BERIL study by Soulieres et al examining the combination of buparlisib and paclitaxel demonstrated a favorable safety profile, a 39% overall response rate (compared to 14% for paclitaxel alone), and a 72% disease control rate (compared to 70% for paclitaxel alone), in patients with R/M HNSCC.13 Furthermore, both progression-free and overall survival were numerically higher in the combination arm. This study suggests meaningful benefit for the PI3K inhibitor buparlisib in combination with paclitaxel and is currently being evaluated in a Phase III trial.
The combination of buparlisib and cetuximab showed activity in patients who had previously received cetuximab in the curative intent setting as well as in the R/M setting (eg, with carboplatin/5-FU/cetuximab), including those who previously had progressive disease following treatment with regimens containing cetuximab. Of the 5 patients that demonstrated clinical meaningful benefit, 4 had previously received cetuximab (Table 3). Two of the 5 patients, including the patient that achieved a partial response, were treated in the curative and recurrent setting with cetuximab regimens, while the other two patients that achieved stable disease were only treated in the recurrent setting with cetuximab. One patient achieved stable disease who had not previously received cetuximab therapy. It is possible that this modest clinical activity was mediated by buparlisib alone; however, similar findings have been reported with the combination of cetuximab and the mTOR inhibitor temsirolimus. In the randomized phase II MAESTRO study, the temsirolimus single-agent control arm did not show activity while the combination of cetuximab and temsirolimus demonstrated potential clinical activity suggesting that combined inhibition of EGFR and PI3K/mTOR pathway may play an important role in the treatment of R/M HNSCC.20 Furthermore, single agent buparlisib had minimal activity in a Phase 1 study.19 Hence, the early sign of clinical activity in cetuximab-refractory patients may warrant further investigation. Based upon current treatment options that are approved for the treatment of R/M HNSCC, patients treated with cetuximab who had not been challenged with a platinum-containing cytotoxic chemotherapy regimen would not be eligible for checkpoint inhibitors, demonstrating a clear clinical need.
In summary, the results of this study demonstrated that the dose of 100 mg of buparlisib daily, as established in prior studies, was found to be well tolerated when given in combination with cetuximab in R/M HNSCC. This study also showed preliminary evidence of activity of the combination of buparlisib and cetuximab in the R/M HNSCC. Previous failure of treatment containing cetuximab did not appear to impact response when buparlisib was added to the treatment regimen. Further study of the combination of buparlisib in combination with cetuximab may be warranted given the favorable toxicity profile especially in cetuximab resistant HNSCC patients.
ACKNOWLEDGMENT
This work was supported by Novartis Pharmaceuticals Corporation.
Footnotes
CONFLICT OF INTEREST
E.E.V. has a consultant/advisory role with AbbVie, Amgen, AstraZeneca, Biolumina, Bristol-Myers Squibb, Celgene, Eli Lilly, EMD Serono, Genentech, Merck, Novartis, and Regeneron. T.Y.S. has received research funding from Bristol-Myers Squibb, Jounce Therapeutics, and Merck as well as honoraria from Aduro, Astra-Zeneca, Bayer, Bristol-Myers Squibb, Celgene, Cue Pharmaceuticals, Innate Pharmaceuticals, Maverick, Merck, Nanobiotix, Oncolys, and Roche Diagnostics.
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