Over the past 30 years, nearly 40 Phase II clinical trials were designed specifically for ACC patients or for salivary gland cancer patients with a large group of ACC patients. The key findings from these studies may be summarized as:
- No chemotherapies or targeted drugs are approved by regulatory authorities for ACC because none have demonstrated yet the ability to shrink tumors significantly or extend lives in a large proportion of ACC patients. Fortunately, a greater understanding of the biology of ACC tumors most likely will lead to improved results from targeted drugs and immunotherapies. Recent studies of Lenvatinib and Apatinib have demonstrated the highest rates of objective responses in ACC patients.
- Several targeted drugs appear to stabilize ACC tumors in a large proportion of ACC patients. The drugs are not cures, but may keep the disease from progressing for 6 months or a year – an important benefit for patients with progressive disease. These “buying time” drugs include Vorinostat, Everolimus, Sorafenib, Regorafenib, Sunitinib and Cetuximab, and patients sometimes cycle through multiple drugs over the course of months and, hopefully, years.
- ACC tumors usually are resistant to chemotherapy. Medical oncologists tend to resort to cisplatin, vinorelbine or gemcitabine when prescribing chemotherapy, but only a small proportion of ACC patients derive significant or sustained benefits. Low-dose chemotherapy is sometimes used to reduce tumor-related pain or to sensitize tumors to radiation.
The table below provides summary data on most of the Phase II clinical trials involving ACC patients that have been completed since 2001, the year when tumor response measurements were standardized (RECIST criteria). Some smaller studies with fewer than 9 ACC patients are excluded, as are some privately-funded studies that were not published. Chemical names are used for each compound, followed by trade names in parentheses. Hyperlinks provide general descriptions of the drugs as well as published articles or abstracts (marked with *) on each study. Studies with drugs inhibiting similar targets are grouped together.
History of Phase II Clinical Trials with ACC Patients
Drug Targets ACC Patients Objective ResponsePercentage of patients whose tumors shrank by at least 30% in volume Median Progression Free Survival Length of time before half of patients had tumor progression (tumors grew at least 20% in volume or new tumors appeared) Progression Free DurationPercentage of patients whose tumors did not progress over the specified time period Progression RequiredWhether the clinical trial included only patients with progressive disease (growing or new tumors) Publication Year & Link Lenvatenib (Lenvima) VEGFR, FGFR, PDGFR, KIT 32 16% 17.5 months Yes 2019 Lenvatenib (Lenvima) VEGFR, FGFR, PDGFR, KIT 28 11% 9 months Yes 2018* Apatinib VEGFR 56 47% (downward
No 2018* Regorafenib (Stivarga) FGFR, VEGFR, PDGFR, KIT 38 0% 45% > 6 months Yes 2016* Dovitinib FGFR, VEGFR, PDGFR 34 6% 8.2 months 65% > 4 months Yes 2017 Dovitinib FGFR, VEGFR, PDGFR 32 3% 6 months 80% > 4 months Yes 2015 Axitinib (Inlyta) VEGFR, PDGFR, KIT 33 9% 5.7 months 39% > 6 months Yes 2016
Pazopanib (Votrient) VEGFR, PDGFR, KIT 45 2% 5.9 months 46% > 6 months Yes 2016* Sorafenib (Nexavar) VEGFR, PDGRF, KIT, RAF, RET 19 11% 8.9 months No 2016 Sorafenib (Nexavar) VEGFR, PDGFR, KIT, RAF, RET 19 11% 11.3 months 69% > 6 months
46% > 1 year
No 2015 Sunitinib (Sutent) VEGFR, PDGFR, KIT, RET 13 0% 7.2 months 62% > 6 months Yes 2011 Nivolumab (Opdivo) PD-1 45 9% 4.9 months 33% > 6 months Yes 2019* Nivolumab (Opdivo) and Ipilumumab (Yervoy) PD-1, CTLA-4 32 6% 5 months Yes 2019* Pembrolizumab (Keytruda) PD-1 10 0% 6.6 months 60% > 6 months Yes 2019* Pembrolizumab (Keytruda) & Radiation PD-1 10 0% 4.5 months 44% > 6 months Yes 2019* Pembrolizumab (Keytruda) & Vorinostat (Zolinza) PD-1, HDAC 12 8% Yes 2018* Vorinostat (Zolinza) HDAC 30 7% 11.4 months 46% > 1 year No
2017 BBI503 Cancer stemness 13 0% 38% > 6 months No 2016* MK-2206 AKT 14 0% 9.2 months 16% > 1 year Yes 2015* Nelfinavir AKT, HIV protease 15 0% 5.5 months 13% > 6 months Yes 2015 Everolimus (Afinitor) mTOR 31 0% 11.2 months 66% > 4 months Yes 2014 Dasatinib (Sprycel) BCR-ABL, SRC, KIT 40 3% 4.8 months 36% > 6 months Yes 2015 Imatinib & Cisplatin BCR-ABL, KIT, PDGFR 28 11% 15 months 79% > 6 months
57% > 1 year
No 2011 Imatinib (Gleevec) BCR-ABL, KIT, PDGFR 12 0% 5.7 months 50% > 5.7 months No 2008 Imatinib (Gleevec) BCR-ABL, KIT, PDGFR 10 0% 2007 Imatinib (Gleevec) BCR-ABL, KIT, PDGFR 15 0% 2.5 months 13% > 6 months No 2005 Gefitinib (Iressa) EGFR 18 0% 4.3 months 39% > 9 months No 2015 Cetuximab (Erbitux) EGFR 23 0% 6 months 52% > 6 months No 2009 Lapatinib (Tykerb) EGFR, HER2 19 0% 3.5 months 35% > 6 months Yes 2007 Bortezomib (Velcade) NFKB, 26S Proteasome 21 0% 6.4 months 18% > 1 year Yes 2011 Eribulin Chemotherapy 11 9% Yes 2018 Gemcitabine & Cisplatin Chemotherapy 10 20% No 2009 Gemcitabine Chemotherapy 21 0% 48% > 6 months No 2008 Paclitaxel Chemotherapy 13 0% 38% > 6 months No 2006
Objective response = Percentage of patients whose tumors shrank by at least 30% in volume
Median Progression Free Survival = Length of time before half of patients had tumor progression (tumors grew at least 20% in volume or new tumors appeared)
Progression Free Duration = Percentage of patients whose tumors did not progress over the specified time period
Progression Requirement = Whether the clinical trial included only patients with progressive disease (growing or new tumors)
* Abstract (not article)
Download History of Phase II Clinical Trials with ACC Patients
In reviewing the history of Phase II clinical trials in ACC, it is important to take note of two key factors:
- Progression Requirements – Did the clinical trial require ACC patients to have documented progression prior to starting therapy? ACC patients with metastases may have long periods of stable disease, making it difficult to determine whether stable disease in a study was the natural course of the disease or the result of the drug. Clinical trials that require progression prior to entry give a better indication of the drug’s effectiveness. Whether disease progression was an inclusion criterion for each study is indicated in the second column from the right in the table above.
- Clinical Benefit Greater than 6 Months – Did the patient have an objective response (tumor shrinkage of at least 30%) or stable disease, either of which lasted longer than 6 months? Sometimes patients have rapid tumor shrinkage that qualifies as an objective response, but then there is a rapid reversal and progression. Or a slow-growing ACC tumor, unaffected by the drug, may take 3 months to reach 20% growth; the patient will be classified as having stable disease despite the drug’s lack of efficacy. By using a longer horizon, this metric attempts to measure meaningful patient benefit. “Progression Free Duration”, the third column from the right in the table above, indicates what portion of treated patients did not have disease progression over 4, 6 and/or 12 months.
Patients should keep in mind that objective responses and stable disease are measures of tumor volume, not overall survival. It is reasonable to assume that smaller tumors mean a longer lifespan, but it is not always the case. Once a treatment stops being effective, tumors may grow back more quickly.
Patients must weigh the potential side effects of any treatment against the possibility of extended survival and reduced pain from tumor shrinkage. More fragile patients may be able to tolerate only drugs with moderate side effects (Vorinostat), while more robust patients may be willing to tolerate drugs with significant side effects (Everolimus, Sorafenib, Regorafenib and Sunitinib). Progressing ACC patients should discuss these issues with their physicians.
Patients enrolling in clinical trials perform an incredibly honorable service for the entire patient community. Without them, it would not be possible to determine systematically whether a particular treatment is effective or safe. Even clinical trials that show that a drug is ineffective are valuable as future patients are spared the unnecessary side effects and may try more promising drugs. Some physicians prescribe approved cancer drugs “off-label” (i.e., approved for tumor types different from the treated tumor) to their patients who cannot travel to or do not qualify for a clinical trial. Unfortunately, those results are not tabulated and shared with others as is the case with clinical trials. Without a doubt, current ACC patients owe a debt of gratitude to those who have helped guide our current understanding of how ACC responds to systemic therapies.
For more background and details on clinical trials, please read ACCRF’s Guide to Systemic Therapy for Patients With Progressive ACC.