Companies vying for accelerated approval and devising strategies for confirmatory trials would be best served by seeking prospective sign-off from FDA, agency officials say.
Officials from the FDA Oncology Center of Excellence described these best practices in a perspective piece in the Sept. 21 issue of The New England Journal of Medicine and discussed the issues in greater detail in a conversation with The Cancer Letter.
The agency has conducted a systematic analysis of the outcomes of all accelerated approvals granted in oncology from 1992 to the present. A table with all accelerated approvals and their ultimate outcomes appears HERE.
The agency found that about 12% of oncology accelerated approval indications have been withdrawn from the market.
“Ultimately, [accelerated approval] is the trade-off to allow for approval of transformative therapies years earlier,” said Julia Beaver, chief of medical oncology at the FDA Oncology Center of Excellence and acting deputy director of the Office of Oncologic Diseases. “I would argue it is an appropriate trade-off. Some might even contend that this number could, in fact, be higher, and perhaps we are being too cautious in the drugs we approve using this pathway.”
Having a comprehensive plan would help sponsors avoid “pitfalls related to moving too quickly, such as incorrect dose, study design, population, or biomarker,” Beaver said. “While there is not a regulatory requirement that the confirmatory trial be well underway if not fully enrolled, that is the recommended advice we give companies and would be the ideal situation.”
The agency’s systematic analysis found that the time from accelerated approval to verification of benefit took a median of 3.1 years, with outliers reported at half a year to over 17 years.
“Overall, having a confirmatory trial ongoing at the time of accelerated approval appears to reduce the period of uncertainty between the approval and verification of clinical benefit,’’ said Gautam Mehta, a clinical reviewer at OCE clinical lead at the center’s Project Confirm.
“We found that if the confirmatory trial was ongoing at the time of accelerated approval, which was the case for 75% of the confirmed indications, the median time to converting the approval to traditional approval was 3.0 years, compared to 5.0 years if this trial was not yet started,” Mehta said. “This also appeared to affect the time to withdrawal,” Mehta said. “If the confirmatory trial was ongoing at the time of accelerated approval, the median time to withdrawal was 3.8 years, compared to 7.3 years if this trial was not yet started.”
Also, the agency is urging sponsors to conduct dose-finding studies before proceeding to pivotal trials.
“Our dosing initiative, Project Optimus, critically looks at correct dose finding prior to pivotal trial initiation. Because accelerated approval accelerates timelines, it is even more critical to conduct dose finding early on in drug development so that we minimize approval of incorrect dosing,” said Lola Fashoyin-Aje, deputy division director in the Office of Oncologic Diseases and associate director and lead for OCE’s Project Equity and Project FrontRunner.
“As a sub-initiative to Project Optimus, we will be taking a closer look at how we can address some of the pitfalls of dose selection that may be a particular consequence of drug development programs that follow an expedited course, such as those granted breakthrough therapy designation,” Fashoyin-Aje said.
Beaver, Mehta, and Fashoyin-Aje spoke with Paul Goldberg, editor and publisher of The Cancer Letter.
Paul Goldberg: This was a busy week for FDA Oncology, with multiple advisory committee meetings, some dealing with different aspects of accelerated approval. With the publication of your accelerated approval paper [Sept. 21] in NEJM, what positions on accelerated approval are you trying to communicate?
We’ve been talking about accelerated approval since 1992. Should there be clear rules based on today’s drugs, on what meets the bar for accelerated approval and what doesn’t? Should there be a standard set of rules by which the game is played?
Julia Beaver: Thanks for discussing these important topics with us.
We wrote the perspective to convey multiple thoughts regarding accelerated approval, all leading to the conclusion that for successful drug development, a comprehensive development plan, for both the initial accelerated approval and the confirmatory trial, should be prospectively discussed and agreed upon with FDA.
Such a comprehensive plan would facilitate the avoidance of potential pitfalls of accelerated approval—pitfalls related to moving too quickly, such as incorrect dose, study design, population, or biomarker.
While there is not a regulatory requirement that the confirmatory trial be well underway if not fully enrolled, that is the recommended advice we give companies and would be the ideal situation.
The goal of a comprehensive approach would be to prevent a delay in obtaining the confirmatory evidence and therefore minimize the potential risk to patients of having an ineffective drug on the market.
I see in your paper you are referring to the accelerated approval on-ramp and off-ramp. How does this work? Could I ask you to explain?
Lola Fashoyin-Aje: Would be glad to. While accelerated approval is often thought of as simply a mechanism to get drugs on the market quickly, we think of accelerated approval as the “accelerated” part of the approval pathway to ultimately demonstrate clinical benefit.
Some of the important factors to consider to enter the “on-ramp” of this accelerated portion include study population, trial design, and endpoints for accelerated approval and for verification of benefit, as well as the timelines for obtaining data to support accelerated approval and to confirm clinical benefit.
These factors are foundational and should be discussed with the FDA very early on in clinical development.
The “off-ramp” factors are essentially the elements of the accelerated clinical development pathway that result in either granting traditional approval or removing the indication if clinical benefit is not verified.
Part of the “off-ramp” removal of an indication can include additional regulatory procedures, which may be required if a company does not voluntarily withdraw, and delays of this process can be lengthy.
And you have new efforts related to dose—how does this fit into the “on-ramp” considerations of accelerated approval? If you don’t know what the dose is, what’s the point of continuing?
LFA: Yes, we have several initiatives in the Oncology Center of Excellence to address the longstanding acceptance of toxic and intolerable oncology drug dosing that adversely impacts the quality of many patients’ lives.
Our dosing initiative, Project Optimus, critically looks at correct dose finding prior to pivotal trial initiation. Because accelerated approval accelerates timelines, it is even more critical to conduct dose finding early on in drug development so that we minimize approval of incorrect dosing.
As a sub-initiative to Project Optimus, we will be taking a closer look at how we can address some of the pitfalls of dose selection that may be a particular consequence of drug development programs that follow an expedited course, such as those granted breakthrough therapy designation.
So, breakthrough doesn’t need to be break-neck. In the paper you present some data regarding time to verification. Can you take me through those data and what conclusions are related to that?
Gautam Mehta: We have started to systematically analyze the outcomes of accelerated approval in oncology through the OCE’s Project Confirm, which aims to promote the transparency of these approvals.
Generally, the time from accelerated approval to verification of clinical benefit has been short, taking a median of 3.1 years; however, the range of times has been quite broad, from half a year to over 17 years. We wanted to understand if any factors impacted how long it took to verify clinical benefit, and if having the confirmatory trial ongoing at the time of accelerated approval affected this.
We found that if the confirmatory trial was ongoing at the time of accelerated approval, which was the case for 75% of the confirmed indications, the median time to converting the approval to traditional approval was 3.0 years, compared to 5.0 years if this trial was not yet started. This also appeared to affect the time to withdrawal.
If the confirmatory trial was ongoing at the time of accelerated approval, the median time to withdrawal was 3.8 years, compared to 7.3 years if this trial was not yet started. Overall, having a confirmatory trial ongoing at the time of accelerated approval appears to reduce the period of uncertainty between the approval and verification of clinical benefit.
Minimizing this period of uncertainty is important, particularly for drugs that eventually are withdrawn, because this can reduce the amount of time potentially ineffective or unsafe drugs remain on the market.
Let me get it through my thick skull, what you’re saying is that you want the confirmatory trial to be ongoing at the time of an accelerated approval?
About 20 years ago in a very different regulatory environment, Dr. Pazdur was trying to get me to understand how accelerated approval should be handled and those ideas came from HIV where accelerated approval would be granted on viral load reduction and full approval granted based on survival in the same studies. There’s now no need for accelerated approval in HIV. It’s an example of where you want to be in 10 years.
JB: Yes, exactly. The accelerated approval regulations are the same regardless of serious or life-threatening indication—be that in oncology, or other disease area. As you mention, initially accelerated approval was most used for drug approvals in the treatment of patients with HIV.
In HIV there were early endpoints related to plasma HIV-RNA used as reasonably likely to predict decreased risk for AIDs progression and death. Over time HIV-RNA was validated for predicting efficacy of antiretrovirals thus the accelerated approval paradigm was no longer needed in this space.
The preponderance of accelerated approvals in oncology, now accounting for 85% of accelerated approvals, is due to several factors. Oncology indications across the board qualify for the accelerated approval program as all oncologic diseases are serious and life-threatening.
In addition, due to multiple advances in immunology and precision oncology, understanding the biological underpinnings of cancer has led to recent oncology drug development with large gains in efficacy or unprecedented results that have facilitated the use of the accelerated approval pathway.
Lastly, in oncology we are able to use response rate, which allows for an objective and standardized assessment of drug activity in order to support accelerated approval.
One criticism of oncology accelerated approval is the use of the same endpoints for both the initial accelerated approval and confirmation. How can you verify on the same endpoint?
GM: We do have cases where we use the same endpoint for verification of benefit. Most often this use of response rate is for initial accelerated approval as well as verification of benefit.
This occurs in select indications; usually rare, biomarker selected populations, where response rate is high and can be used for the initial accelerated approval, because a decrease in tumor burden can be attributed to drug activity rather than spontaneous regression or other confounding factors.
In these cases, randomization may not be possible, so further description of the response rate and confirmation of duration of response can lead to the verification of benefit.
These cases consider the rarity of the population, strong scientific rational for drug, degree of unmet need, a high and durable response, location of the tumor, as well as other context-dependent considerations that ultimately lead to an overall positive benefit-risk profile for use of this endpoint.
Are there specific concerns regarding verification of benefit? And initiation of the confirmatory trial? What are potential solutions for this?
GM: Historically in oncology, the typical development paradigm targeting accelerated approval has started with a large single-arm trial in a refractory population, looking at response rates as the primary endpoint.
To verify clinical benefit, a randomized confirmatory trial that assesses progression-free or overall survival is typically conducted. Once an accelerated approval is granted and the drug or biologic product is on the market, patients for whom the drug is approved may not want to enroll in a trial with a control arm.
Unless conducted in tandem, the confirmatory trial is frequently conducted in earlier lines of therapy than the original indication in which the accelerated approval was granted. That may improve the ability to enroll and also may move the treatment paradigm earlier where benefit may be greater. While this approach has been largely successful to date, it does have some limitations.
First, this process has supported the development of large single-arm trials in oncology. While these trials can be informative if they show durable effects of a product on tumor size, as we discussed, they have challenges capturing safety, contribution of effect, and ultimately may limit the ability to conduct subsequent randomized studies with clinical equipoise.
This can be a problem when trying to understand the risks of these therapies, because overall survival, measured in randomized studies, is a key measure of safety.
Another issue is that these single-arm trials have usually been performed in refractory populations, where no effective available therapy exists. This delays the conduct of trials in earlier disease settings and in populations that may derive greater benefit from these drug or biologic products.
LFA: As we point out in the paper, there are several limitations to the current implementation of accelerated approval in oncology, which can be addressed by early planning.
Sponsors contemplating accelerated approval often emphasize the trial that would potentially support accelerated approval, with the second trial to confirm clinical benefit being almost an afterthought. We emphasize in the paper that sponsors should discuss and implement the strategy for obtaining data to verify clinical benefit nearly concurrent with discussing the accelerated approval trial.
Sponsors will need to determine whether clinical development will include separate trials for accelerated approval and for confirming clinical benefit as they typically have done, or whether as we propose in the paper, a single trial could be designed to support accelerated approval based on an interim analysis of response rate, as an example, and subsequently verify clinical benefit based on survival.
In this latter scenario, careful attention to preserving the trial’s integrity and statistical rigor and ensuring that it can be completed in a timely fashion are paramount considerations.
If the sponsor chooses to employ a two-trial approach, interim data from the trial intended to verify clinical benefit could provide more supportive evidence of the benefit-risk assessment for the accelerated approval.
Whether confirmatory trials can be feasibly completed given the approval of the indication through accelerated approval and the evolving landscape of available treatments is critical.
In the end, we want to ensure that the data package submitted to verify clinical benefit addresses the residual uncertainties regarding clinical benefit that existed at the time of accelerated approval, and that the results of the confirmatory trial are relevant to U.S. medical practice.
Should we be expecting a guidance related to specific oncology accelerated approval trial designs?
LFA: We are considering whether a guidance to industry would be the best vehicle to discuss some of the critical points related to accelerated approval in oncology. Until we make a final determination, I will note that while guidance is always useful in providing our current thinking on a particular issue to a wider audience, we have already begun having these discussions with sponsors.
With the passage of time, there are more and more accelerated approval withdrawals. How should this increase in withdrawals be viewed?
JB: Even with the recent reevaluation of some of the accelerated approval indications, with a few coming off the market, still only about 12% of oncology accelerated approval indications have been withdrawn.
Ultimately, this is the trade-off to allow for approval of transformative therapies years earlier. I would argue it is an appropriate trade-off. Some might even contend that this number could, in fact, be higher, and perhaps we are being too cautious in the drugs we approve using this pathway.
To minimize the period of uncertainty between accelerated approval and confirmation of benefit, a comprehensive strategy for promising drugs will allow for up-front determination of the accelerated approval and confirmatory trial plan.
Potentially incorporating the single trial design option, with interim look at an accelerated approval endpoint followed by longer term outcomes to convert to traditional approval, can also build greater confidence in the program and allow for accelerated approvals in earlier lines of therapy.
We are excited to continue future dialogue and multistakeholder collaboration on this approach via OCE’s Project FrontRunner.
So, if you had all the answers, you wouldn’t need accelerated approval?
JB: Exactly. Accelerated approval allows for the ability to balance uncertainty against that ultimate goal of patient benefit.
Tables listing all accelerated approvals in oncology, arranged by time to withdrawal or granting of traditional approval, follow.
WITHDRAWN ACCELERATED APPROVALS
| Proprietary Name | Established Name | Indication | AA Date | Time to Withdrawal (years) | Confirmatory Trial Ongoing at Time of AA? |
|---|---|---|---|---|---|
| Keytruda | pembrolizumab | Metastatic SCLC with disease progression on or after platinum-based chemotherapy and at least one other prior line of therapy | 6/17/2019 | 1.8 | Yes |
| Opdivo | nivolumab | Metastatic SCLC with progression after platinum-based chemotherapy and at least one other line of therapy | 8/16/2018 | 2.4 | Yes |
| Tecentriq | atezolizumab | In combination with paclitaxel protein-bound for unresectable locally advanced or metastatic triple-negative breast cancer whose tumors express PD-L1 (PD-L1 stained tumor-infiltrating immune cells of any intensity covering = 1% of the tumor area), as determined by an FDA-approved test. | 8/3/2019 | 2.6 | Yes |
| Lartruvo | olaratumab | In combination with doxorubicin for adults with soft tissue sarcoma with a histologic subtype for which an anthracycline-containing regimen is appropriate and which is not amenable to curative treatment with radiotherapy or surgery | 10/19/2016 | 3.4 | Yes |
| Avastin | bevacizumab | In combination with paclitaxel for patients who have not received chemotherapy for metastatic HER2 negative breast cancer | 2/22/2008 | 3.7 | Yes |
| Imfinzi | durvalumab | Locally advanced or metastatic urothelial carcinoma that progressed during or following platinum-containing chemotherapy or within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy | 1/5/2017 | 3.8 | Yes |
| Opdivo | nivolumab | Hepatocellular carcinoma previously treated with sorafenib | 9/22/2017 | 3.8 | Yes |
| Keytruda | pembrolizumab | For patients with recurrent or locally advanced or metastatic gastric or GEJ adenocarcinoma whose tumors express PD-L1 [CPS ≥1] as determined by an FDA-approved test, with disease progresson on/after two or more prior lines of therapy including fluoropyrimidine and platinum containing chemotherapy and if appropriate, HER2/NEU targeted therapy | 9/22/2017 | 4.4 | Yes |
| Tecentriq | atezolizumab | Locally advanced or metastatic urothelial carcinoma that progressed during or following platinum-containing chemotherapy or within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy | 5/18/2016 | 4.9 | Yes |
| Bexxar | tositumomab and iodine i 131 tositumomab | For patients with relapsed or refractory low-grade follicular or transformed CD20+ NHL who have not received rituximab | 12/22/2004 | 8.8 | Yes |
| Marqibo | vincristine sulfate liposomal | For the treatment of adults with Philadelphia (PH) chromosome negative(-) acute lymphoblastic leukemia (ALL) in second relapse or greater relapse or whose disease has progressed following 2 or greater treatment lines of anti-leukemia therapies | 9/8/2012 | 9.7 | Yes |
| Ukoniq | umbralisib | Treatment of adult patients with relapsed or refractory marginal zone lymphoma (MZL) who have received at least one prior anti-CD20- based regimen | 5/2/2021 | 1.3 | No |
| Ukoniq | umbralisib | adult patients with relapsed or refractory follicular lymphoma (FL) who have received at least three prior lines of systemic therapy | 5/2/2021 | 1.3 | No |
| Oforta | fludarabine phosphate | For adults with B-cell CLL that has not responded to or progressed during or after treatment with at least one standard alkylating agent containing regimen | 12/18/2008 | 3 | No |
| Copiktra | duvelisib | treatment of adult patients with relapsed or refractory follicular lymphoma (FL) after at least two prior systemic therapies | 9/24/2018 | 3.2 | No |
| Farydak | panobinostat | In combination with bortezomib (BTZ) and dexamethasone (DEX) for the treatment of patients with multiple myeloma (MM) who have received at least 2 prior regimens, including BTZ and an immunomodulatory agent. | 2/23/2015 | 7.1 | No |
| Zydelig | idelalisib | For the treatment of relapsed follicular B-cell Non-Hodgkin Lymphoma (FL) in patients who have received at least 2 prior systemic therapies and relapsed small lymphocytic lymphoma (SLL) in patients who have received at least 2 prior systemic therapies | 7/23/2014 | 7.6 | No |
| Iressa | gefitinib | As monotherapy for locally advanced or metastatic NSCLC after failure of platinum-based and docetaxel chemotherapy | 5/5/2003 | 9 | No |
| Istodax | romidepsin | Peripheral T-cell lymphoma in patients who have received at least one prior therapy | 6/16/2011 | 10.1 | No |
| Mylotarg | gemtuzumab ozogamicin | For patients with CD33+ AML in first relapse 60 years of age or older and not candidates for cytotoxic chemotherapy | 5/17/2000 | 11.5 | No |
| Celebrex | celecoxib | To reduce the number of adenomatous colorectal polyps in familial adenomatous polyposis patients, as an adjunct to usual care | 12/23/1999 | 12.5 | No |
ACCELERATED APPROVAL INDICATIONS GRANTED TRADITIONAL APPROVAL
| Proprietary Name | Established Name | Indication | AA Date | Time to Traditional Approval (years) | Confirmatory Trial Ongoing at Time of AA? |
|---|---|---|---|---|---|
| Imbruvica | ibrutinib | Chronic lymphocytic leukemia after at least one prior therapy | 12/2/2014 | 0.5 | Yes |
| Alimta | pemetrexed disodium | In combination with pembrolizumab and carboplatin for first-line treatment of metastatic non-squamous NSCLC | 4/6/2018 | 0.7 | Yes |
| Keytruda | pembrolizumab | In combination with chemotherapy for locally recurrent unresectable or metastatic TNBC expressing PD L1 [CPS =10] as determined by an FDA-approved test | 11/13/2020 | 0.7 | Yes |
| Alimta | pemetrexed disodium | Non-squamous NSCLC: 1) as initial treatment with cisplatin; 2) as a single agent after prior chemotherapy | 9/26/2008 | 0.8 | Yes |
| Trodelvy | sacituzumab govitecan-hziy | Adults with metastatic TNBC following at least 2 prior therapies for metastatic disease | 4/22/2020 | 1 | Yes |
| Darzalex | daratumumab | Multiple myeloma after at least 3 prior lines of therapy including a proteasome inhibitor and an immunomodulatory agent or double refractory to a proteasome inhibitor and an immunomodulatory agent | 11/16/2015 | 1 | Yes |
| Sutent | sunitinib maleate | Advanced renal cell carcinoma | 1/26/2006 | 1 | Yes |
| Keytruda | pembrolizumab | Metastatic PD-L1 positive NSCLC, as determined by an FDA-approved test, with progression on or after platinum-containing chemotherapy | 2/10/2015 | 1 | Yes |
| Keytruda | pembrolizumab | In combination with pemetrexed and carboplating for first-line treatment of metastatic non-squamous NSCLC | 10/5/2017 | 1.3 | Yes |
| Synribo | omacetaxine mepesuccinate | Adults with chronic or accelerated phase chronic myeloid leukemia with resistance or intolerance to 2 or more TKIs | 10/26/2012 | 1.3 | Yes |
| Rubraca | rucaparib | Deleterious BRCA mutation (germline and/or somatic) associated advanced ovarian cancer treated with 2 or more chemotherapies | 12/19/2016 | 1.3 | Yes |
| Tagrisso | osimertinib | Metastatic EGFR T790M mutation-positive NSCLC, as detected by an FDA-approved test, that progressed on or after EGFR TKI therapy | 11/13/2015 | 1.4 | Yes |
| Eloxatin | oxaliplatin | In combination with infusional 5-FU/LV for metastatic color or rectal carcinoma that progressed during or within 6 months of completion of first-line therapy with bolus 5 -FU/LV and irinotectan | 9/8/2002 | 1.4 | Yes |
| Xpovio | selinexor | In combination with dexamethasone for adults with relapsed/refractory multiple myeloma after at least 4 prior therapies and refractory to at least 2 proteasome inhibitors, 2 immunomodulatory agents, and an anti-CD38 monoclonal antibody | 3/7/2019 | 1.4 | Yes |
| Keytruda | pembrolizumab | In combination with lenvatinib for advanced endometrial carcinoma not MSI-H or dMMR, with progression following systemic therapy and not candidates for curative surgery or radiation | 9/17/2019 | 1.8 | Yes |
| Lenvima | lenvatinib | In combination with pembrolizumab for advanced endometrial carcinoma not MSI-H or dMMR, with progression following systemic therapy and not candidates for curative surgery or radiation | 9/17/2019 | 1.8 | Yes |
| Tafinlar | dabrafenib | In combination with trametinib for unresectable or metastatic melanoma with BRAF V600E or V600K mutations, as detected by an FDA-approved test | 9/1/2014 | 1.9 | Yes |
| Mekinist | trametinib | In combination with dabrafenib for unresectable or metastatic melanoma with BRAF V600E or V600K mutations, as detected by an FDA-approved test | 8/1/2014 | 1.9 | Yes |
| Velcade | bortezomib | Multiple myeloma patients who received at least two prior therapies and demontrated disease progression on the last therapy | 5/13/2003 | 1.9 | Yes |
| Venclexta | venetoclax | In combination with azacitidine or decitabine or low-dose cytarabine for newly-diagnosed AML in adults 75 years or older, or who have comorbidities that preclude use of intensive induction chemotherapy | 11/21/2018 | 1.9 | Yes |
| Alecensa | alectinib | ALK-positive metastatic NSCLC that progressed on or is intolerant to crizotinib | 11/12/2015 | 1.9 | Yes |
| Taxotere | docetaxel | Locally advanced or metastatic breast carcinoma that progressed during anthracycline-based therapy or relapsed during anthracycline-based adjuvant therapy | 5/14/1996 | 2.1 | Yes |
| Venclexta | venetoclax | Chronic lymphocytic leukemia with 17P deletion as detected by an FDA-approved test, after at least one prior therapy | 11/4/2016 | 2.1 | Yes |
| Casodex | bicalutamide | In combination with an LHRH analogue for advanced prostate cancer | 4/10/1995 | 2.2 | Yes |
| Pomalyst | pomalidomide | Multiple myeloma after at least 2 prior therapies including lenalidomide and bortezomib and disease progression on or within 60 days of completion of the last therapy | 8/2/2013 | 2.2 | Yes |
| Xalkori | crizotinib | Locally advanced or metastatic NSCLC that is ALK-positive as detected by an FDA-approved test | 8/26/2011 | 2.2 | Yes |
| Tabrecta | capmatinib | Treatment of adult patients with metastatic non-small cell lung cancer (NSCLC) whose tumors have a mutation that leads to mesenchymal-epithelial transition (MET) exon 14 skipping as detected by an FDA-approved test. | 6/5/2020 | 2.3 | Yes |
| Lorbrena | lorlatinib | ALK-positive metastatic NSCLC that has progressed on: • Crizotinib and at least one other ALK inhibitor for metastatic disease; or • Alectinib as the first ALK inhibitor therapy for metastatic disease; or • Ceritinib as the first ALK inhibitor therapy for metastatic disease | 2/11/2018 | 2.3 | Yes |
| Camptosar | irinotecan hcl trihydrote | Metastatic colon or rectal carcinoma that progressed following 5-FU therapy | 6/14/1996 | 2.3 | Yes |
| Enhertu | fam-trastuzumab deruxtecan-nxki | treatment of adult patients with unresectable or metastatic HER2-positive breast cancer who have received two or more prior anti-HER2-based regimens in the metastatic setting | 12/20/2019 | 2.4 | Yes |
| Lynparza | olaparib | Deleterious or suspected deleterious germline BRCA-mutated advanced ovarian cancer after treatment with 3 or more lines of chemotherapy | 12/19/2014 | 2.7 | Yes |
| Keytruda | pembrolizumab | Recurrent or metastatic head and neck squamous cell carcinoma that progressed on or after platinum-containing chemotherapy | 5/8/2016 | 2.8 | Yes |
| Sprycel | dasatinib | Chronic myeloid leukemia with resistance or intolerance to prior therapy including imatinib | 6/28/2006 | 2.9 | Yes |
| Arimidex | anastrozole | Adjuvant treatment of postmenopausal women with hormone receptor positive early breast cancer | 5/9/2002 | 3 | Yes |
| Alunbrig | brigatinib | Patients with ALK-positive metastatic NSCLC that have progressed or are intolerant to crizotinib | 4/28/2017 | 3.1 | Yes |
| Zykadia | ceritinib | ALK-positive metastatic NSCLC that progressed on or is intolerant to crizotinib | 4/29/2014 | 3.1 | Yes |
| Gleevec | imatinib mesylate | Adjuvant treatment of adults following complete gross resection of KIT (CD117) positive gastrointestinal stromal tumors (GIST) | 12/19/2008 | 3.1 | Yes |
| Opdivo | nivolumab | 1) In combination with ipilimumab for unresectable or metastatic melanoma to remove the restriction for treatment of only patients with BRAF wild-type melanoma; 2) As a single agent for BRAF V600 mutation positive unresectable or metastatic melanoma to remove the restriction that such patients should have disease progression following ipilimumab and a BRAF inhibitor | 1/23/2016 | 3.1 | Yes |
| Bavencio | avelumab | Locally advanced or metastatic urothelial carcinoma following diease progression on platinum-containing chemotherapy or disease progression within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy | 9/5/2017 | 3.1 | Yes |
| Tasigna | nilotinib | Chronic phase and accelerated phase Philadelphia chromosome positive CML in adults resistant or intolerant to prior therapy that included Gleevec (imatinib) | 10/29/2007 | 3.2 | Yes |
| Xeloda | capecitabine | Metastatic breast cancer resistant to paclitaxel and an anthracycline-containing chemotherapy regimen or resistant to paclitaxel and further anthracycline therapy is contraindicated | 4/30/1998 | 3.4 | Yes |
| Gleevec | imatinib mesylate | Pediatric patients with recurrent PH+ chronic phase CML after stem cell transplant or who are resistant to interferon alpha therapy | 5/20/2003 | 3.4 | Yes |
| Bosulif | bosutinib | Adults with newly diagnosed chronic phase Philadelphia chromosome positive CML | 12/19/2017 | 3.4 | Yes |
| Kyprolis | carfilzomib | Multiple myeloma after at least 2 prior therapies including bortezomib and an immunomodulatory agent and disease progression on or within 60 days of completion of the last therapy | 7/20/2012 | 3.5 | Yes |
| Keytruda | pembrolizumab | Adult and pediatric patients with refractory classical Hodgkin Lymphoma or who have relapsed after 3 or more prior lines of therapy | 3/14/2017 | 3.6 | Yes |
| Erbitux | cetuximab | As a single agent for EGFR-expressing metastatic colorectal carcinoma intolerant to irinotecan-based chemotherapy | 12/2/2004 | 3.6 | Yes |
| Afinitor | everolimus | Adults with renal angiomyolipma and tuberous sclerosis complex not requiring immediate surgery | 4/26/2012 | 3.8 | Yes |
| Iclusig | ponatinib | Adults with chronic phase, accelerated phase, or blast phase chronic myeloid leukemia resistant or intolerant to TKI therapy or or Philadelphia chromosome positive acute lymphoblastic leukemia resistant or intolerant to prior TKI therapy | 12/14/2012 | 4 | Yes |
| Adcetris | brentuximab vedotin | Hodgkin lymphoma after failure of autologous stem cell transplant (ASCT), or after failure of at least 2 multi-agent chemotherapy regimens in patients who are not ASCT candidates | 8/19/2011 | 4 | Yes |
| Perjeta | pertuzumab | In combination with trastuzumab and docetaxel for neoadjuvant treatment of HER2-positive locally advanced inflammatory or early-stage breast cancer (either greater than 2 cm in diameter or node-positive) as part of a complete treatment regimen for early early breast cancer | 9/30/2013 | 4.2 | Yes |
| Keytruda | pembrolizumab | Locally advanced or metastatic urothelial carcinoma ineligible for cisplatin-containing chemotherapy | 5/18/2017 | 4.3 | Yes |
| Femara | letrozole | Postmenopausal women with HR positive early breast cancer | 12/28/2005 | 4.3 | Yes |
| Arzerra | ofatumumab | Chronic lymphocytic leukemia refractory to fludarabine and alemtuzumab | 10/26/2009 | 4.5 | Yes |
| Gleevec | imatinib mesylate | Newly diagnosed Philadelphia positive CML in pediatric patients | 9/27/2006 | 4.5 | Yes |
| Opdivo | nivolumab | Locally advanced or metastatic urothelial carcinoma that: • progressed during or following platinum-containing chemotherapy • progressed within 12 months of neoadjuvant or adjuvant platinum-containing chemotherapy | 2/2/2017 | 4.5 | Yes |
| Tasigna | nilotinib | Newly diagnosed adults with with Philadelphia chromosome-positive CML in chronic phase | 6/17/2010 | 4.6 | Yes |
| Sprycel | dasatinib | Newly diagnosed adults with Philadelphia chromosome-positive CML in chronic phase | 10/28/2010 | 4.8 | Yes |
| Doxil | doxorubicin hydrochloride | Metastatic ovarian carcinoma refractory to paclitaxel and platinum-based chemotherapy | 6/28/1999 | 5.6 | Yes |
| Temodar | temozolomide | Adults with refractory anaplastic astrocytoma | 11/8/1999 | 5.6 | Yes |
| Gleevec | imatinib mesylate | Newly diagnosed adults with Philadelphia chromosome positive CML | 12/20/2002 | 6.4 | Yes |
| Gleevec | imatinib mesylate | KIT (CD117) positive unresectable and/or metastatic GIST | 1/2/2002 | 6.7 | Yes |
| Vectibix | panitumumab | EGFR-expressing metastatic colorectal carcinoma with progression on or following fluoropyrimidine-, oxaliplatin-, and irinotecan-containing chemotherapy regimens | 9/27/2006 | 7.7 | Yes |
| Erbitux | cetuximab | In combination with irinotecan for EGFR-expressing metastatic colorectal carcinoma refractory to irinotecan-based chemotherapy | 12/2/2004 | 8.4 | Yes |
| Avastin | bevacizumab | Progressive glioblastoma following prior therapy | 5/5/2009 | 8.6 | Yes |
| Tykerb | lapatinib | In combination with letrozole for post-menopausal women with HR-positive metastatic breast cancer that overexpresses the HER2 receptor for whom hormonal therapy is indicated | 1/29/2010 | 8.9 | Yes |
| Ontak | denileukin diftitox | Persistent or recurrent cutaneous T-cell lymphoma expressing the CD25 component of IL-2 receptor | 5/2/1999 | 9.7 | Yes |
| Keytruda | pembrolizumab | Unresectable or metastatic melanoma and disease progression following ipilimumab and, if BRAF V600 mutation positive, a BRAF inhibitor | 4/9/2014 | 1.3 | No |
| Padcev | enfortumab vedotin-ejfv | Adults with locally advanced or metastatic urothelial cancer who received a PD-1 or PD-L1 inhibitor and a platinum-containing chemotherapy in the neoadjuvant, locally advanced, or metastatic setting | 12/18/2019 | 1.6 | No |
| Ibrance | palbociclib | In combination with letrozole for postmenopausal women with ER-positive, HER2-negative advanced breast cancer as initial endocrine-based therapy for metastatic disease | 3/2/2015 | 2.2 | No |
| Keytruda | pembrolizumab | Adult and pediatric patients with refractory primary mediastinal large B-cell lymphoma, or who have relapsed after 2 or more prior lines of therapy | 6/13/2018 | 2.3 | No |
| Gleevec | imatinib mesylate | CML in blast crisis, accelerated phase, or in chronic phase after failure of of interferon-alpha | 10/5/2001 | 2.6 | No |
| Blincyto | blinatumomab | Philadelphia chromosome negative relapsed or refractory B-cell precursor acute lymphoblastic leukemia | 3/12/2014 | 2.6 | No |
| Keytruda | pembrolizumab | Treatment of patients with recurrent or metastatic cervical cancer with disease progression on or after chemotherapy whose tumors express PD-L1 (CPS >/=1) as determined by an FDA approved test | 12/6/2018 | 3.4 | No |
| Opdivo | nivolumab | In combination with ipilimumab for BRAF V600 wild-type unresectable or metastatic melanoma | 9/30/2015 | 3.4 | No |
| Opdivo | nivolumab | Unresectable or metastatic melanoma and progression following ipilimumab and, if BRAF V600 mutation positive, a BRAF inhibitor | 12/22/2014 | 4.2 | No |
| Alimta | pemetrexed disodium | As a single agent for locally advanced or metastatic NSCLC after prior chemotherapy | 8/19/2004 | 4.9 | No |
| Afinitor | everolimus | Patients with subependymal giant cell astrocytoma associated with tuberous sclerosis who require therapeutic intervention but are not candidates for curative surgical resection | 10/29/2010 | 5.3 | No |
| Femara | letrozole | Extended adjuvant treatment of early breast cancer in postmenopausal women who received 5 years of adjuvant tamoxifen | 10/29/2004 | 5.5 | No |
| Campath | alemtuzumab | B-cell CLL treated with alkylating agents and failed fludarabine therapy | 7/5/2001 | 6.4 | No |
| Adcetris | brentuximab vedotin | Systemic anaplastic large cell lymphoma after failure of at least one multi-agent chemotherapy regimen | 8/19/2011 | 6.6 | No |
| Zevalin | ibritumomab tiuxetan | Relapsed or refractory low-grade follicular or transformed B-cell NHL other than rituximab-refractory follicular NHL | 2/19/2002 | 7.5 | No |
| Depocyt | cytarabine (liposomal) | Intrathecal treatment of lymphomatous meningitis | 1/4/1999 | 8.1 | No |
| Thalomid | thalidomide | Newly diagnosed multiple myeloma | 5/25/2006 | 8.1 | No |
| Doxil | doxorubicin hydrochloride | Kaposi’s sarcoma in AIDS patients with disease progression on prior combination chemotherapy or who are intolerant to such therapy | 11/17/1995 | 12.6 | No |
| Arranon | nelarabine | Relapsed/refractory T-cell acute lymphoblastic leukemia and T-cell lymphoblastic leukemia following at least 2 chemotherapy regimens | 10/28/2005 | 13.8 | No |
| Clolar | clofarabine | Treatment of pediatric patients 1 to 21 yrs old with relapsed or refractory acute lymphocytic leukemia (ALL) after at least 2 prior regimens | 12/28/2004 | 17.6 | No |
