Completed Studies

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 such as Lenvatinib, Sorafenib, Axitinib or Pazopanib if clinical trials are not available. NCCN guidelines point to Lenvatinib as a reasonable option. Some medical oncologists also offer Vorinostat to their progressing patients. 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 limited options, rapid progression, significant symptoms or central nervous system involvement. 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.

History of Phase II Clinical Trials with ACC Patients
Drug Targets ACC Patients Objective Response 1 Median Progression Free Survival 2 Progression Free Duration 3 Progression Required 4 Sponsor (Location) Publication Year
& Link

Apatinib/Rivoceranib

VEGRF 80 15% 9.0 months 77% > 6 months; 43% > 1 year Yes Elevar (USA, Korea) 2022*

Apatinib/Rivoceranib

VEGFR 65 46% 19.8 months 92% > 6 months No SNPH (China) 2021

Apatinib/Rivoceranib & ATRA (All-Trans Retinoic Acid)

VEGFR, MYB 16 19% 100% > 6 months; 80% > 1 year No SNPH (China) 2021*

Lenvatinib (Lenvima)

VEGFR, FGFR, PDGFR, KIT 32 16% 17.5 months Yes MSK (USA) 2019

Lenvatinib (Lenvima)

VEGFR, FGFR, PDGFR, KIT 26 12% 9.1 months Yes INT (Italy) 2020

Axitinib (Inlyta) & Avelumab (Bavencio)

VEGFR, PDGFR, KIT, PD-L1 28 18% 7.2 months 57% > 6 months Yes MDA (USA) 2022*

Axitinib (Inlyta)

VEGFR, PDGFR, KIT 30 0% 10.8 months 73% > 6 months (vs. 23% observation) Yes SNUH (Korea) 2021

Axitinib (Inlyta)

VEGFR, PDGFR, KIT 33 9% 5.7 months 39% > 6 months Yes MSK (USA) 2016

Sorafenib (Nexavar)

VEGFR, PDGRF, KIT, RAF, RET 19 11% 8.9 months No INT (Italy) 2016

Sorafenib (Nexavar)

VEGFR, PDGFR, KIT, RAF, RET 19 11% 11.3 months 69% > 6 months; 46% > 1 year No NHS Christie (UK) 2015

Pazopanib (Votrient)

VEGFR, PDGFR, KIT 45 2% 5.9 months 46% > 6 months Yes UNICANCER (France) 2016*

Regorafenib (Stivarga)

VEGFR, PDGFR, FGFR, KIT 38 0% 45% > 6 months Yes MSK (USA) 2016*

Dovitinib

VEGFR, PDGFR, FGFR 34 6% 8.2 months 65% > 4 months Yes UVA (USA) 2017

Dovitinib

VEGFR, PDGFR, FGFR 32 3% 6 months 80% > 4 months Yes SNUH (Korea) 2015

Sunitinib (Sutent)

VEGFR, PDGFR, KIT, RET 13 0% 7.2 months 62% > 6 months Yes UHN (Canada) 2011

Anlotinib (retrospective study)

VEGFR, PDGFR, FGFR, KIT 19 5% 10.1 months No Sun Yat-sen University (China) 2022

Cabozantinib – Stopped early due to wound complications

VEGFR, MET, AXL, RET 15 7% 9.4 months Yes Radboud (Netherlands) 2021

ATRA (All-Trans Retinoic Acid)

MYB 18 0% 3.2 months 22% > 6 months Yes DFCI (USA) 2021

AL101 (among NOTCH+ patients)

NOTCH 77 12% 57% >2 months Yes Ayala (USA, UK) 2022*

CB-103

NOTCH 19 0% 5.4 months 58% > 5 months No Cellestia (Europe, US) 2021*

Brontictuzumab (OMP-52M51)

NOTCH1 12 17% No OncoMed (USA) 2018

Crenigacestat (LY3039478 )

NOTCH1 22 0% 5.3 months 18% > 6 months No Lilly (USA) 2017

APG-115

MDM2 12 17% 11.4 months 91% > 6 months Yes University of Michigan 2022*

JNJ-64619178 (Onametostat)

PRMT5 11 9% No Janssen (Europe, Canada, USA) 2020*

GSK3326595

PRMT5 14 21% No GSK (USA) 2019*

Lenalidomide (Revlimid) & Everolimus (Afinitor)

CEREBLON, mTOR 15 20% 27% > 1 year No Emory (USA) 2020

Everolimus (Afinitor)

mTOR 31 0% 11.2 months 66% > 4 months Yes SNUH (Korea) 2014

Nivolumab (Opdivo)

PD-1 45 9% 4.9 months 33% > 6 months Yes UNICANCER (France) 2019*

Nivolumab (Opdivo) & Ipilumumab (Yervoy)

PD-1, CTLA-4 32 6% 5 months Yes MSK (USA) 2019*

Pembrolizumab (Keytruda)

PD-1 10 0% 6.6 months 60% > 6 months Yes DFCI (USA) 2019*

Pembrolizumab (Keytruda) & Radiation

PD-1 10 0% 4.5 months 44% > 6 months Yes DFCI (USA) 2019*

Pembrolizumab (Keytruda) & Vorinostat (Zolinza)

PD-1, HDAC 12 8% Yes UW (USA) 2019

Vorinostat (Zolinza)

HDAC 30 7% 11.4 months 46% > 1 year No (90% Yes) NCI (USA) 2017

BBI503

Cancer stemness 13 0% 38% > 6 months No Sumitomo (USA) 2016*

MK-2206

AKT 14 0% 9.2 months 16% > 1 year Yes MSK (USA) 2015*

Nelfinavir

AKT, HIV protease 15 0% 5.5 months 13% > 6 months Yes Iowa (USA) 2015

Dasatinib (Sprycel)

BCR-ABL, SRC, KIT 40 3% 4.8 months 36% > 6 months Yes NCI (USA) 2015

ImatinibCisplatin

BCR-ABL, KIT, PDGFR 28 11% 15 months 79% > 6 months 57% > 1 year Yes NHS 2011

Imatinib (Gleevec)

BCR-ABL, KIT, PDGFR 12 0% 5.7 months 50% > 5.7 months No Novartis (USA) 2008

Imatinib (Gleevec)

BCR-ABL, KIT, PDGFR 10 0% Tel Aviv U (Israel) 2007

Imatinib (Gleevec)

BCR-ABL, KIT, PDGFR 15 0% 2.5 months 13% > 6 months No UHN (Canada) 2005

Gefitinib (Iressa)

EGFR 18 0% 4.3 months 39% > 9 months No MDA (USA) 2015

Cetuximab (Erbitux)

EGFR 23 0% 6 months 52% > 6 months No INT (Italy) 2009

Lapatinib (Tykerb)

EGFR, HER2 19 0% 3.5 months 35% > 6 months Yes UHN (Canada) 2007

Bortezomib (Velcade)

NFKB, 26S Proteasome 21 0% 6.4 months 18% > 1 year Yes NCI (USA) 2011

Eribulin (Liposomal)

Chemotherapy 12 17% 16.6 months 67% > 5.3 months No Eisai (Japan) 2022

Eribulin

Chemotherapy 11 9% Yes UW (USA) 2018

GemcitabineCisplatin

Chemotherapy 10 20% No NCIC (Canada) 2009

Gemcitabine

Chemotherapy 21 0% 48% > 6 months No EORTC (Europe) 2008

Paclitaxel

Chemotherapy 13 0% 38% > 6 months No ECOG (USA) 2006

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.