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, immunotherapies 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 is leading to improved results from targeted drugs and immunotherapies.
• Recent studies of Lenvatinib and Apatinib (also named Rivoceranib) have demonstrated the highest rates of objective responses in ACC patients. Several similar targeted drugs such as Axitinib and Sorafenib also 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 longer – an important benefit for patients with progressive disease. Recent clinical guidelines from ASCO suggest the use of multitargeted tyrosine kinase inhibitors (TKIs) such as Lenvatinib, Sorafenib, Axitinib or Pazopanib if clinical trials are not available. NCCN guidelines point to Lenvatinib as a reasonable option. ESMO guidelines, however, suggest the use of chemotherapy, perhaps due to access issues for TKIs. Some medical oncologists also offer Vorinostat to their progressing patients who may not tolerate more toxic regimens. Patients sometimes cycle through multiple drugs over the course of many months and, hopefully, years.
• ACC tumors usually are resistant to chemotherapy with only a small proportion deriving significant or sustained benefits. However, medical oncologists often resort to chemotherapy when their ACC patients face rapid progression, significant symptoms, central nervous system involvement or limited options. Cisplatin is the most commonly prescribed chemotherapy, often in combination with doxorubicin and cyclophosphamide (referred to as “CAP”) or in combination with vinorelbine. 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. The “Search” bar may be used with keywords such as drug names or targets.

¹ Percentage of patients whose tumors shrank by at least 30% in volume
² Length of time before half of patients had tumor progression (tumors grew at least 20% in volume or new tumors appeared)
³ Percentage of patients whose tumors did not progress over the specified time period
⁴ Whether the clinical trial included only patients with progressive disease (growing or new tumors)
* Abstract (not article)

In reviewing the history of Phase II clinical trials in ACC, it is important to take note of some 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 various time periods.
• Patient Selection – The types of patients included in a trial may impact the efficacy and toxicity of a treatment. For example, ACC patients with NOTCH-activated tumors may have more aggressive disease, leading to lower response rates and/or progression free survival than other ACC patients. Similarly, patients with later-stage disease may respond less impressively than those with earlier-stage disease, and this may reflect geographic differences in when patients enroll in clinical trials.

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.