2021 Approvals Expand Access to Care for Patients Across Tumor Types

Yelena Y. Janjigian, MD

Last year marked the 50th anniversary of the National Cancer Act of 1971, a landmark legislation that committed to funding biomedical research, establishing oncology training programs, and building a nationwide network of cancer treatment centers. In this anniversary year, 13 novel agents were approved across hematology/oncology. Additionally, there were many other notable approvals—whether they were new formulations, expanded indications, or biosimilar approvals—across tumor types that expanded accessibility for varying patient populations.

Four novel drugs advanced the treatment paradigm for patients with non–small cell lung cancer (NSCLC): tepotinib (Tepmetko), amivantamab-vmjw (Rybrevant), sotorasib (Lumakras), and mobocertinib (Exkivity).

Expanded indications were added for nivolumab (Opdivo), including the pivotal approval for frontline treatment of esophageal cancer, gastric cancer, and gastroesophageal junction (GEJ) adenocarcinoma. Notably, nivolumab also entered the arena for frontline treatment of advanced renal cell carcinoma (RCC), adjuvant treatment of completely resected esophageal or GEJ cancer, and adjuvant treatment of urothelial carcinoma. Meanwhile, fam-trastuzumab deruxtecan-nxki (Enhertu) and pembrolizumab (Keytruda) were cleared for HER2-positive gastric cancer and GEJ adenocarcinoma.

Approved for rare cancers were infigratinib (Truseltiq) and ivosidenib (Tibsovo) for cholangiocarcinoma; belzutifan (Welireg) for von Hippel-Lindau disease; daratumumab and hyaluronidase-fihj (Darzalex Faspro) for light-chain amyloidosis; and sirolimus albumin-bound particles (Fyarro) for perivascular epithelioid cell tumor (PEComa), the first approved treatment for this disease.¹ A win for patients with triple-negative breast cancer (TNBC) came with the approval of sacituzumab govitecan-hziy (Trodelvy). The agent simultaneously received approval for urothelial cancer.

Not all agents with accelerated approvals fared as well during the FDA’s Oncologic Drugs Advisory Committee (ODAC) special 3-day public hearing in April. The committee evaluated 6 indications for immune checkpoint inhibitors—across malignancies including TNBC, metastatic urothelial carcinoma (mUC), gastric cancers, and hepatocellular carcinoma (HCC)—that were granted under the FDA’s accelerated approval process but later failed confirmatory clinical trials. The hearings, which allowed expert commentary and patient testimony about the drugs, involved 2 indications for atezolizumab (Tecentriq), 3 for pembrolizumab, and 1 for nivolumab.²

Ultimately, ODAC voted in favor of pembrolizumab and atezolizumab for frontline mUC and atezolizumab plus nab-paclitaxel for PD–L1 positive metastatic TNBC; pembrolizumab for second-line advanced HCC was unanimously backed. The FDA panel voted against pembrolizumab for PD-L—positive gastric cancer and GEJ cancer, along with nivolumab for second-line advanced HCC.

January

• Crizotinib (Xalkori): for pediatric patients 1 year or older and young adults with relapsed or refractory ALK-positive anaplastic large cell lymphoma, a rare form of non-Hodgkin lymphoma
• Fam-trastuzumab deruxtecan-nxki (Enhertu): for adult patients with locally advanced or metastatic HER2-positive gastric or GEJ adenocarcinoma who have received a previous trastuzumab (Herceptin)-based regimen

“Trastuzumab deruxtecan has shown efficacy in [HER2positive gastric cancers]," Yelena Y. Janjigian, MD, said. "It’s important to build on that efficacy and continue to try to understand which patients need to continue on HER2 inhibition and which patients need to be changed to other types of therapy because of loss of HER2.”

• Daratumumab and hyaluronidase-fihj (Darzalex Faspro): for use in combination with bortezomib (Velcade), cyclophosphamide, and dexamethasone (D-VCd; VCd) in the treatment of patients with newly diagnosed lightchain amyloidosis
• Nivolumab (Opdivo) plus cabozantinib (Cabometyx): for the frontline treatment of patients with advanced RCC

“[Nivolumab plus cabozantinib is] going to be another option for frontline clear cell RCC," Toni K. Choueiri, MD, said. "It’s not the only combination that is approved, but I think there are some distinctions, especially with the quality-of-life data.”

February

• Tepotinib (Tepmetko): for adult patients with metastatic NSCLC harboring MET exon 14 skip-ping alterations

“These are patients who generally are not represented in the pivotal upfront trials," Paul K. Paik, MD, said. "There’s been a need for better treatments for these patients. The approval of tepotinib is 1 step forward in that regard, [in] having a fairly well-tolerated oral agent that is effective in this patient population. That’s probably the most important aspect of the approval.”

• Umbralisib (Ukoniq): for patients with relapsed or refractory marginal zone lymphoma (MZL) who have previously received at least 1 anti-CD20–based regimen and patients with relapsed or refractory follicular lymphoma (FL) who have received at least 3 prior lines of systemic therapy

“Umbralisib represents another drug in a unique class that is relatively tolerable and has tumor activity in the vast majority of patients [in which] it is used," Nathan H. Fowler, MD, said. "I believe this option will be utilized by clinicians for patients with third- or fourth-line FL....This treatment is very active and it is associated with a very limited toxicity profile. Plus, it is oral, so it is easy to give, the toxicity is not too high, and it appears very active in patients after multiple other lines of therapy.”

• Lisocabtagene maraleucel (Breyanzi): for adult patients with certain types of large B-cell lymphoma who have not responded to, or who have relapsed after, at least 2 other types of systemic treatment. Specifically, the indication includes patients with diffuse large B-cell lymphoma (DLBCL) not otherwise specified, including that which arises from indolent lymphoma, high-grade B-cell lymphoma, primary mediastinal large B-cell lymphoma, or follicular lymphoma grade 3B
• Cemiplimab-rwlc (Libtayo): for patients with locally advanced basal cell carcinoma (BCC) who have previously been treated with a Hedgehog pathway inhibitor (HHI) or for whom an HHI is not appropriate. The agent also was granted accelerated approval for patients with metastatic BCC previously treated with an HHI or for whom an HHI is not appropriate.
• Melphalan flufenamide (Pepaxto): in combination with dexamethasone for adult patients with relapsed or refractory multiple myeloma who have received at least 4 prior lines of therapy and whose disease is refractory to at least 1 proteasome inhibitor, 1 immunomodulatory drug, and 1 CD38-directed monoclonal antibody

March

• Lorlatinib (Lorbrena): for patients with ALK-positive metastatic NCSLC as detected by an FDA-approved test
• Axicabtagene ciloleucel (Yescarta): for adult patients with relapsed or refractory follicular lymphoma following 2 or more lines of systemic therapy

“I think this is a breakthrough of CAR T-cell therapy. The first T-cell infusion I did in clinical trial was around 1996," Henry Chi Hang Fung, MD, said. "Now we’re in 2021, a quarter of a century [later]. There’s been a lot of work and [there have been] a lot of failures. But finally it has come to fruition and there are 4 indications now. It is exciting for our patients, [and although it is] limited to relapsed/refractory disease, we can, hopefully soon, prove its use earlier with better outcomes that could potentially be curative. This is just a step; we have to [keep moving forward].”

• Tivozanib (Fotivda): for adult patients with relapsed or refractory advanced RCC following 2 or more prior systemic therapies
• Pembrolizumab: in combination with platinum and fluoropyrimidine-based chemotherapy for patients with metastatic or locally advanced esophageal or gastroesophageal carcinoma who are ineligible for surgical resection or definitive chemoradiation
• Idecabtagene vicleucel (Abecma): for patients with relapsed or refractory multiple myeloma after 4 or more prior lines of therapy, including an immunomodulatory agent, a proteasome inhibitor, and an anti-CD38 monoclonal antibody

“This treatment has been so incredibly effective. When we treated patients, they had a median of 6 lines of [prior] treatment; they almost had everything they could have had," Nikhil C. Munshi, MD, said. "[Idecabtagene vicleucel] works approximately 80% of the time with deep, good responses. We were waiting for its approval so we could offer it. It opens up a new chapter; this is the first real cellular therapy for myeloma.”

• Isatuximab-irfc (Sarclisa): in combination with carfilzomib (Kyprolis) and dexamethasone for adult patients with relapsed or refractory multiple myeloma who have received 1 to 3 prior lines of therapy

April

• Cetuximab (Erbitux): with the new biweekly dosing regimen of 500 mg/m² as a 120-minute intravenous infusion for patients with KRAS wild-type, EGFR-expressing metastatic colorectal cancer or squamous cell carcinoma of the head and neck
• Sacituzumab govitecan-hziy (Trodelvy): for patients with locally advanced or metastatic urothelial cancer who previously received platinum-containing chemotherapy and a PD-1 or PD-L1 inhibitor. Additionally, the agent was granted regular approval for patients with unresectable locally advanced or metastatic TNBC who have previously received 2 or more systemic therapies, at least 1 of them for metastatic disease

“[The difference with sacituzumab govitecan] has to do with the target, meaning Trop-2, which is a different target than other available drugs," Scott T. Tagawa, MD, said. "The target is more important in terms of differentiation in the toxin, [and for sacituzumab govitecan] SM 38, which is the toxin, is a bit weaker than some of the toxins used in [antibody-drug conjugates]….The landscape is shifting, and we hope [to move these agents] upstream. We’re looking not just for improvements in survival and quality of life, but increased cures in the either non–muscle-invasive setting or muscle-invasive setting in combination with local therapy.”

• Nivolumab: in combination with select types of chemotherapy for the frontline treatment of patients with advanced or metastatic gastric cancer, GEJ cancer, or esophageal adenocarcinoma
• Dostarlimab-gxly (Jemperli): for patients with recurrent or advanced endometrial cancer who have progressed on or following a prior platinum- containing chemotherapy regimen and whose cancers are mismatch repair deficient

“[The approval is] important in terms of understanding that endometrial cancer is the most common gynecologic cancer in the United States," Bhavana Pothuri, MD, said. "The incidence, as well as the mortality [rates associated with the disease, has] been increasing because of a greater proportion of obesity, as well as an increase in the number of patients with high-risk histologic subtypes. Having new additional therapies is very important. This is an exciting advance for gynecologic cancer and especially endometrial cancer.”

• Loncastuximab tesirine-lpyl (Zynlonta): for adult patients with relapsed or refractory large B-cell lymphoma following 2 or more lines of systemic therapy. The indication covers DLBCL not otherwise specified, DLBCL arising from low-grade lymphoma, and high-grade B-cell lymphoma

May

• Pembrolizumab: in combination with trastuzumab (Herceptin) and fluoropyrimidine- and platinum-containing chemotherapy for the frontline treatment of patients with locally advanced unresectable or metastatic HER2-positive gastric or GEJ adenocarcinoma
• Nivolumab: for the adjuvant treatment of patients with completely resected esophageal or GEJ cancer with residual pathologic disease who have received neoadjuvant chemoradiotherapy
• Amivantamab-vmjw (Rybrevant): for adult patients with NSCLC who harbor EGFR exon 20 insertion-mutations and whose disease has progressed on or following platinum-based chemotherapy

“Prior to this [approval], there was no targeted therapy approved for patients with NSCLC and [with] EGFR exon 20 alteration," Melina Elpi Marmarelis, MD, said. "A real-world study out of France that showed that patients with EGFR exon 20-altered NSCLC treated with conventional chemotherapies did just [as well as] individuals without [the] alterations. [Amivantamab will] hopefully start to fill that gap.”

• Sotorasib (Lumakras): for adult patients with NSCLC whose tumors harbor KRAS G12C mutations and who have received at least 1 prior systemic therapy

“The approval of sotorasib underscores the critical importance of offering molecular profiling to every patient with metastatic nonsquamous NSCLC," Ferdinandos Skoulidis, MD, PhD, said. "We now have a well-tolerated approved oral therapy at our disposal that confers durable clinical benefit in approximately 13% of patients with nonsquamous NSCLC. There is an urgent need to expand and promote equitable access to screening across the US, particularly among underserved patient populations.”

• Infigratinib (Truseltiq): for patients with previously treated locally advanced or metastatic cholangiocarcinoma harboring an FGFR2 fusion or rearrangement

June

• Avapritinib (Ayvakit): for adult patients with advanced systemic mastocytosis, including patients with aggressive systemic mastocytosis, systemic mastocytosis with an associated hematological neoplasm, or mast cell leukemia
• Asparaginase erwinia chrysanthemi (recombinant)-rywn (Rylaze): as a component of a multiagent acute lymphoblastic leukemia and lymphoblastic lymphoma for adult and pediatric patients 1 month or older who have developed hypersensitivity to E coli–derived asparaginase

July

• Enfortumab vedotin-ejfv (Padcev): for patients who have received a prior PD-1 or PD-L1 inhibitor and a platinum-containing chemotherapy. The indication for this agent was also expanded to include adult patients who are ineligible for cisplatin-containing chemotherapy who have received at least 1 prior therapy

“After progression occurs [following chemotherapy sequenced with immunotherapy], there’s a lot of uncertainty around treatment options, so we tend to rechallenge with chemotherapy then test some patients for FGF alterations. The data are limited for this patient group, and so it’s an area where we need to develop new drugs.”

• Daratumumab and hyaluronidase-fihj: in combination with pomalidomide (Pomalyst) and dexamethasone for adult patients with multiple myeloma after receiving at least 1 prior line of therapy including lenalidomide (Revlimid) and a proteasome inhibitor
• Belumosudil (Rezurock): for patients 12 years and older with chronic graft-vs-host disease (GVHD) following failure of at least 2 prior lines of systemic therapy

“Ibrutinib [was] the first approved therapy [for] this disease and was a great step forward for us, [however] it’s not effective in all patients," Corey S. Cutler, MD, MPH, FRCPC, said. "Many patients who initially respond to ibrutinib eventually progress and require later [lines of] therapy. Having more than 1 option for these patients is really something that our patients need.”

• Pembrolizumab: in combination with lenvatinib (Lenvima) for patients with advanced endometrial carcinoma that is not microsatellite instability high or mismatch repair deficient, who have disease progression after previous systemic therapy in any setting, and who are not candidates for curative surgery or radiation
• Pembrolizumab: in combination with chemotherapy for patients with high-risk, early-stage TNBC for a total of 8 cycles prior to surgery followed by pembrolizumab monotherapy for 9 cycles following surgery

August

• Pembrolizumab: in combination with lenvatinib (Lenvima) for the frontline treatment of patients with advanced RCC

“Now with these TKI and [immunotherapy] combinations you can see [that with] the degree of response rates [including] the complete responses and a median PFS of almost 24 months how much of a therapeutic gain it is for our patients," Robert J. Motzer, MD, said."

• Dostarlimab-gxly: for adult patients with mismatch repair–deficient recurrent or advanced solid tumors who have progressed on or following previous treatment and who have no satisfactory alternative options
• Belzutifan (Welireg): for adult patients with von Hippel-Lindau disease who require therapy for associated RCC, central nervous system hemangioblastomas, or pancreatic neuroendocrine tumors that do not require immediate surgery
• Nivolumab: for the adjuvant treatment of patients with urothelial carcinoma who are at high risk of recurrence after undergoing radical cystectomy, irrespective of prior neoadjuvant chemotherapy, nodal involvement, or PD-L1 status
• Ivosidenib (Tibsovo): for oral use in adult patients with previously treated, locally advanced, or metastatic cholangiocarcinoma with an IDH1 mutation
• Zanubrutinib (Brukinsa): for adult patients with Waldenström macroglobulinemia

September

• Zanubrutinib (Brukinsa): for adult patients with relapsed or refractory MZL who have received at least 1 anti-CD20–based regimen
• Mobocertinib (Exkivity): for adult patients with locally advanced or metastatic NSCLC with EGFR exon 20 insertion mutations as detected by an FDA-approved test whose disease has progressed on or after platinum-based chemotherapy

“This [approval] represents a tremendous step forward based on research and rationally designed drugs for this group of patients with an unmet need," Joel Neal, MD, PhD, said. "As we move forward with the combinations with chemotherapy and between different agents, [we must ask] how we better [develop] these drugs to [permeate] the brain. [We need to look] at how we target and refine these drugs for better central nervous system penetration, better efficacy, and higher response rates across the population.”

• Cabozantinib (Cabometyx): for patients 12 years and older with locally advanced or metastatic differentiated thyroid cancer that has progressed after prior VEGF-targeted therapy and who are ineligible or refractory to radioactive iodine
• Tisotumab vedotin-tftv (Tivdak): for adult patients with recurrent or metastatic cervical cancer with disease progression on or after chemotherapy

“This new agent adds to our armamentarium for patients with recurrent metastatic cervical cancer. That’s the bottom line," Robert L. Coleman, MD, said. "We have very few effective options. I include immunotherapy in that statement because the vast majority of patients with cervical cancer don’t benefit from immunotherapy. The need for effective therapies, ones that act rapidly, is desperately present in our day-to-day care of patients with advanced metastatic cervical cancer.”

• Ruxolitinib (Jakafi): for patients 12 years and older with chronic GVHD following failure of 1 or 2 lines of systemic therapy

October

• Brexucabtagene autoleucel (Tecartus): for adult patients with relapsed or refractory B-cell precursor acute lymphoblastic leukemia
• Abemaciclib (Verzenio): in combination with endocrine therapy in the form of tamoxifen or an aromatase inhibitor for the adjuvant treatment of adult patients with hormone receptor–positive, HER2-negative, node-positive, early breast cancer at high risk of recurrence and a Ki-67 score of 20% or higher as determined by an FDA-approved test

“[The approval represents] a paradigm shift because the last new treatment were aromatase inhibitors in 2002," Stephen Johnston, MD, PhD, said. "This represents our progress in understanding primary endocrine resistance, [identifying] patients who are destined to relapse despite the best therapies, and developing interventions to stop those early recurrences. This is a highly significant milestone for the small group of patients with high-risk disease for whom endocrine therapy [alone] isn’t going to be the solution. We can make a significant difference for them."

• Pembrolizumab: in combination with chemotherapy, with or without bevacizumab (Avastin), for patients with persistent, recurrent, or metastatic cervical cancer with tumors expressing a PD-L1 combined positive score of at least 1 as determined by an FDA-approved test
• Atezolizumab (Tecentriq): for the adjuvant treatment of patients with stage II to IIIA NSCLC with tumor PD-L1 expression of at least 1% as determined by an FDA-approved test following resection and platinum-based chemotherapy
• Asciminib (Scemblix): for patients with Philadelphia chromosome–positive chronic myeloid leukemia (CML) in chronic phase previously treated with 2 or more tyrosine kinase inhibitors

“Asciminib represents a huge advance in CML. We haven’t had a new drug approved in several years," Michael J. Mauro, MD, said. "This is a different class of ABL inhibitor; it works by a different mechanism. It’s not just another medication targeting the same region of this abnormal enzyme or kinase. It is novel, highly effective, very safe, [and] unique.”

November

• Pembrolizumab: for the adjuvant treatment of patients with RCC at intermediate-high or high risk of recurrence following nephrectomy alone or with resection of metastatic lesions
• Sirolimus albumin-bound particles (Fyarro): for injectable suspension for adult patients with locally advanced unresectable or metastatic malignant PEComa
• Pafolacianine (Cytalux): an optical imaging agent as an adjunct for interoperative identification of malignant lesions for adult patients with ovarian cancer

December

• Daratumumab and hyaluronidase-fihj plus carfilzomib (Kyprolis) plus dexamethasone: for adult patients with relapsed or refractory multiple myeloma who have received 1 to 3 prior lines of therapy

“One of the most important additions to our arsenal for myeloma [was daratumumab, which] was initially approved in 2015 as a monotherapy but quickly moved throughout the myeloma continuum in combination with many other agents: [intravenous] daratumumab was approved with bortezomib, lenalidomide, and pomalidomide," Ajai Chari, MD, said. "Subsequently, the arrival of subcutaneous daratumumab is a game changer because [it has] comparable efficacy with much shorter infusion time. Median infusion time can be 6 to 8 hours, and [the subcutaneous treatment] is 3 to 5 minutes, which is particularly important in the era of COVID[-19] to minimize exposure for both patients and hospital workers.”

• Rituximab (Rituxan): in combination with chemotherapy for pediatric patients aged 6 months to 18 years with previously untreated, advanced stage, CD20-positive DLBCL, Burkitt lymphoma, Burkitt-like lymphoma, or mature B-cell acute leukemia
• Pembrolizumab: for the adjuvant treatment of patients 12 years and older with stage IIB or IIC melanoma following complete resection

“There were some naysayers when we started this trial [who said] that [patients with] stage IIB and IIC disease were too low risk to treat in a clinical trial," Jason Luke, MD, said. "I think the results really emphasize that patients with [those disease] stages truly are at high risk for rapid and distant metastatic recurrence. Treatment with pembrolizumab improves that situation quite substantially. I think…this treatment should be offered to all patients with stage IIB and IIC [disease] and we should stop thinking about nonmodal melanoma as low risk; in fact, it is high risk and these patients deserve the opportunity to be treated.”

• Abatacept (Orencia): for the prophylaxis of acute GVHD in combination with a calcineurin inhibitor and methotrexate, in adult and pediatric patients 2 years and older undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor

References

1. Advancing Health Through Innovation: New Drug Therapy Approvals 2021. FDA’s Center for Drug Evaluation and Research. January 6, 2022. Accessed January 13, 2022. bit.ly/33byHxx
2. FDA in brief: FDA Oncologic Drugs Advisory Committee to review status of six indications granted accelerated approval. FDA. April 29, 2021. Accessed January 13, 2022. bit.ly/3cgG1bm