The development of additional molecularly targeted therapies and the search for enhanced immunotherapy regimens are expected to permeate the oncology landscape across a broad range of malignancies as 2021 unfolds.
The development of additional molecularly targeted therapies and the search for enhanced immunotherapy regimens are expected to permeate the oncology landscape across a broad range of malignancies as 2021 unfolds, according to experts.
Those were among the key trends for the New Year that experts in breast, lung, genitourinary, and hematologic malignancies described in interviews with OncologyLive®. Many of the expectations for the coming year grew out of the advances of 2020, in which new targeted therapies emerged for patient subsets across multiple tumor types and novel immunotherapies continued to expand.
These developments include FDA approvals for the first RET inhibitors, selpercatinib (Retevmo) and pralsetinib (Gavreto), in non–small cell lung cancer (NSCLC) and thyroid cancer settings, and a third chimeric antigen receptor (CAR) T-cell therapy for an oncology indication, brexucabtagene autoleucel (Tecartus), for mantle cell lymphoma.
Continuing progress in the optimal use of antibodies aimed at immune checkpoints is also anticipated. This year will mark a decade since the first checkpoint inhibitor, the anti–CTLA-4 antibody ipilimumab (Yervoy), gained FDA approval for patients with unresectable or metastatic melanoma. Since then, antibodies directed at the PD-1/PD-L1 pathway have dominated the field. Research findings that shed light on how best to use these agents in combinations, as well as new checkpoint therapies, are expected this year.
Novel therapeutic strategies that are likely to advance this year include expansion of uses for tyrosine kinase inhibitors, new combinations incorporating checkpoint immunotherapy, and progress in developing personalized cancer vaccines, according to Howard A. “Skip” Burris III, MD.
“Across all of oncology, there are several common buckets,” said Burris, chief medical officer and president of clinical operations at Sarah Cannon in Nashville, Tennessee, and a 2014 Giants of Cancer Care® award winner in the Drug Development category. “There is a lot of promise across most of the disease entities from the research that’s been done.”
Molecularly targeted therapies continue to gain traction, some in multiple tumor types, Burris said, citing agents directed at FGFR2, KRAS, and RET activity as examples. “We have seen that with pemigatinib [Pemazyre], the FGFR2 inhibitor, in cholangiocarcinoma, which will certainly play in some other areas. KRAS—the long, undruggable target—has seen the KRAS G12C inhibitors, and we’ve had the approval of the RET inhibitors in lung cancer and thyroid cancer. We are seeing that we no longer have undruggable targets, and we know that we can find driver mutations in small sets of patients; it’s certainly a place to go to pursue development,” he said.
In immunotherapy, clinical findings are starting to emerge for combination therapies involving PD-1/PD-L1 inhibitors, including some regimens that pair immune checkpoint agents, Burris noted. “We’re seeing that combinations with other antibodies, TIGIT and LAG3, are showing improved activity over what seemed to be a checkpoint inhibitor alone, as well as activity in patients who previously had a checkpoint inhibitor, and that’s playing out in tumors as diverse as lung cancer, colon cancer, and melanoma—so really, this is across the spectrum. There’s a lot of excitement there.”
Furthermore, Burris anticipates that CAR T-cell therapies, or other types of genetically modified treatments will move forward in clinical development, including in solid tumor trials. “We’ve got more than a dozen trials ongoing at Sarah Cannon, and patients are being matched to those studies. There’s a great deal of enthusiasm, and I’m optimistic that we’re going to see this class of immune effector cells begin to help more patients than just [those] who have hematologic malignancies.”
In breast cancer, antibody-drug conjugates (ADCs) such as fam-trastuzumab deruxtecan-nxki (Enhertu) and sacituzumab govitecan-hziy (Trodelvy), approved in refractory settings, may move into earlier lines of therapy. “Those trials are now moving into the frontline setting in HER2-positive patients, even including HER2-low patients, and of course, with sacituzumab govitecan in TNBC [triple negative breast cancer]. We’re doing what we need to do, which is having these drugs approved in late-line settings, seeing them overcome relapsed/refractory disease, and having a quick move into the frontline arena.”
On the heels of the December 2020 emergency use authorization of Pfizer-BioNTECH’s BNT162b2, the first vaccine for the prevention of coronavirus disease 2019 (COVID-19), the oncology community can expect to hear more about platforms for personalized cancer vaccines. BNT162b2, cleared for individuals 16 years and older, contains messenger RNA.1
“Interestingly, I’ve heard from several of the scientists that the COVID-19 vaccine was pretty simple compared with what they’re working on for cancer vaccines,” Burris said. “We’re going to see the play of cancer vaccines coming in. There are already some personalized cancer vaccine trials ongoing, for example, in melanoma, plus or minus the immunotherapies—we’ll see that in several other disease settings.”
Debu Tripathy, MD, is looking forward to gaining deeper insights into immunotherapy, ADCs, oral formulations of chemotherapy, and AKT inhibitors in breast cancer. “2021 is going to be a refreshing year in many ways, with a lot of new data and advances for our patients with breast cancer,” said Tripathy, a professor and chairman of the Department of Breast Medical Oncology in the Division of Cancer Medicine at The University of Texas MD Anderson Cancer Center in Houston.
Although more data are needed, Tripathy emphasized that findings from the phase 3 CONTESSA trial (NCT03326674) could advance the arena of oral taxane therapy over intravenous options. The combination of tesetaxel, a novel oral taxane, plus a reduced dose of oral capecitabine demonstrated improved outcomes over capecitabine alone in patients with hormone receptor–positive, HER2-negative meta-static breast cancer previously treated with a taxane, according to findings presented at the 2020 San Antonio Breast Cancer Symposium. The tesetaxel regimen resulted in median progression-free survival (PFS) of 9.8 months (95% CI, 8.4-12.0) compared with 6.9 months (95% CI, 5.6-8.3) with capecitabine alone (HR, 0.716; 95% CI, 0.573-0.895; P = .003).2
Unlike standard paclitaxel and docetaxel, tesetaxel can be orally administered because of its improved bioavailability and resistance to the P-glycoprotein efflux pump, which mediates gastric absorption and chemotherapy resistance.2 “Because it can be used as a stand-alone regimen, it may make adjuvant and metastatic therapy easier to tolerate,” said Tripathy, adding that the tesetaxel regimen does carry more neuropathy than capecitabine alone. “We could have oral regimens where people don’t even have to come to infusion centers.”
In targeted therapies, Tripathy expects the science to move forward on AKT inhibitors even though 1 agent in this class, ipatasertib, failed to show a significant improvement in PFS in combination with paclitaxel compared with placebo plus paclitaxel in patients with locally advanced, unresectable or metastatic TNBC with PIK3CA/AKT1/PTEN alterations in the IPATunity130 trial (NCT03337724). Investigator-assessed median PFS was 7.4 months (95% CI, 5.6-8.5) in the ipatasertib arm versus 6.1 months (95% CI, 5.5-9.0) with paclitaxel alone (HR, 1.02; 95% CI, 0.71-1.45; log-rank P = .9237). Nevertheless, the overall response rate (ORR) was 39% (95% CI, 31%-47%) with ipatasertib versus 35% (95% CI, 25%-46%) with paclitaxel alone.3
“Unfortunately, the PFS was no different. Patients who had aberrations in this path-way did appear to have a benefit from the use of ipatasertib, so we look forward to more data,” Tripathy said.
Another AKT inhibitor, capivasertib, is currently being explored in the phase 3 CAPItello-290 study (NCT03997123) in combination with paclitaxel as a front-line treatment for patients with locally advanced or metastatic TNBC. In summary, Tripathy noted, there will be more data from this class of drugs.
For immunotherapy, a constantly evolving field, Tripathy predicted that nearly every medical meeting in 2021 will provide updates. Following the read-outs of the IMpassion031 (NCT03197935) and KEYNOTE-355 (NCT02819518) trials, which led to the approvals of atezolizumab (Tecentriq) plus nab-paclitaxel (Abraxane)4 and pembrolizumab (Keytruda) plus chemotherapy5 in patients with unresectable locally advanced or metastatic PD-L1–positive TNBC, more findings from immunotherapy studies in earlier stages of disease are expected.
“There are trials going on in [hormone receptor]–positive breast cancer in the neoadjuvant setting with pembrolizumab in patients with [stage] III breast cancer, so we’re going to be getting a lot of output from trials in the ones that are in the early-stage setting—which are very important for preventing a recurrence in the first place—if it can be given with good quality of life,” Tripathy said.
In the lung cancer field, 2021 will encompass a greater focus on adjuvant trials, additional novel molecular compounds for select patient subgroups, and a migration of circulating tumor DNA (ctDNA) analysis into a more minimal residual disease (MRD)–based setting, according to Balazs Halmos, MD, MS.
“2020, despite being a terrible year as a result of COVID-19, actually has been a good year for thoracic oncology,” said Halmos, a professor of clinical medicine at Albert Einstein College of Medicine and director of both the Multidisciplinary Thoracic Oncology Program and Clinical Cancer Genomics at Montefiore Medical Center, both in Bronx, New York. “As for next year, I think it will be hard to replicate what we’ve seen this year in terms of the great successes, but there are definitely a number of stories that will continue to unfold.”
The KRAS story, a molecular target long considered undruggable, is certainly an area where advances will continue, Halmos predicted. The agent that has attracted the most attention in this category so far is sotorasib (formerly AMG 510), a KRAS inhibitor being developed under a breakthrough therapy designation for patients with locally advanced or metastatic NSCLC with KRAS G12C mutations.6
In the phase 2 CodeBreaK100 study (NCT03600883), sotorasib demonstrated an ORR of 32.2% (95% CI, 20.62%-45.64%) among previously treated patients with mutated NSCLC.7 Studies of other KRAS pathway inhibitors are under way, and Halmos said next steps will include combining these agents in the first-line setting with chemotherapy and/or immunotherapy. “There are some of the downstream inhibitors—for example, the SOX-inhibiting compounds—so there is great excitement in that field,” he said.
Other targets of interest that will gain more traction this year include therapies aimed at EGFR exon 20 insertion and HER2 (ERBB2), as data sets continue to mature and results are reported. The challenge, Halmos said, will be to identify which patient subgroups are the best candidates to receive novel ADCs such as trastuzumab deruxtecan and patritumab deruxtecan (U3-1402), which have demonstrated antitumor activity in HER2-expressing or HER2-mutant and HER3-expressing/EGFR mutant NSCLC, respectively.
“ERBB2 is emerging as a real target now in lung cancer with these excellent antibody-drug conjugates that have shown success in breast, colon, and gastric cancers and likely will yield great benefits in ERBB2–positive lung cancer patients, as well,” Halmos said.
In immunotherapy, Halmos is hoping for further advances in the adjuvant setting, both as monotherapy and in combination, for stage III disease. The phase 3 PACIFIC trial (NCT02125461), which led to the approval of the PD-L1 inhibitor durvalumab (Imfinzi) for patients with unresectable stage III NSCLC,8 initiated a new journey for checkpoint inhibitors as adjuvant therapy. “In PACIFIC, we’ve seen a major advance, but why not take another step forward?” Halmos said.
As for new molecules, tiragolumab, a monoclonal antibody directed at the TIGIT inhibitory immune checkpoint, is part of a new wave of developing strategies to leverage the immune system for anticancer therapy. These include vaccines that expand lymphocytes. “It can also be a more individualized approach; it’s almost like the CAR T-cell therapy approaches that are being investigated in some of these particular subsets,” Halmos said. “There is a lot of excitement there.”
Anticipation is also building with canakinumab (Ilaris), which is currently indicated for the treatment of a spectrum of autoinflammatory conditions, such as rheumatologic disorders. The agent demonstrated tolerability when used in combination with pembrolizumab and platinum-based doublet chemotherapy in the phase 2 CANOPY-1 trial (NCT03631199) in patients with advanced or metastatic NSCLC.
In addition to therapeutic changes, Halmos is anticipating growing clinical utility for ctDNA assays. Given their convenience and ease, Halmos emphasized, practitioners should already be familiar with utilizing ctDNA testing to make individualized treatment decisions for patients with lung cancer. However, he is ready for the technology to move to the next level.
“I’m very eager to see ctDNA moving into the MRD platforms, where we can detect MRD after surgery or definitive chemoradiation and can use it to monitor immunotherapy responses. We’ve seen a lot of exciting technologies this year reflecting that, so that’s the next wave,” Halmos said.
Major developments that unfolded in late 2020 will shape practice and research for prostate, bladder, and kidney cancers going forward, said Neeraj Agarwal, MD. He is a professor of medicine and holds a Presidential endowed chair of cancer research at the University of Utah Huntsman Cancer Institute (HCI). He also serves as director of the Genitourinary Oncology Program and the Center of Investigational Therapeutics, and coleads the Experimental Therapeutic Program at the HCI.
Agarwal called the FDA approvals of the PARP inhibitors olaparib (Lynparza) and rucaparib (Rubraca) the biggest highlight in the treatment of patients with metastatic castration-resistant prostate cancer (mCRPC) in 2020. Rucaparib is indicated for men with a deleterious BRCA mutation (germline and/or somatic) who have been treated with a novel androgen signaling– directed therapy and a taxane-based chemotherapy.9 Olaparib is approved for men with multiple deleterious or suspected deleterious germline or somatic homologous recombination repair gene mutations including BRCA1 and BRCA2 who have progressed following prior treatment with enzalutamide (Xtandi) or abiraterone acetate (Zytiga).10
“We are going to see movement of PARP inhibitors to earlier lines of therapies with 3 trials going on in the first-line mCRPC setting, which will be declaring results in 2021 or 2022,” Agarwal said. These studies, all phase 3 trials, are TALAPRO-2 (NCT03395197), testing talazoparib (Talzenna) plus enzalutamide; MAGNITUDE (NCT03748641), evaluating niraparib (Zejula) plus abiraterone and prednisone; and PROpel (NCT03732820), exploring olaparib plus abiraterone (Table).
In advanced bladder cancer, results from the JAVELIN Bladder 100 trial (NCT02603432) published in September established maintenance avelumab (Bavencio), as the standard of care. Maintenance avelumab plus best supportive care (BSC) induced a median overall survival of 21.4 months (95% CI, 18.9-26.1) compared with 14.3 months (95% CI, 12.917.9) for BSC alone (HR for death, 0.69; 95% CI, 0.56-0.86; P = .001). At 1 year, 71.3% of patients in the experimental arm were alive versus 58.4% of those in the BSC arm. Patients in the trial had unresectable locally advanced or metastatic urothelial carcinoma without disease progression after 4 to 6 cycles of platinum-based chemotherapy.11
The finding “undoubtedly places avelumab as the treatment of choice with category 1 evidence endorsed by all major guidelines,” Agarwal said. “I don’t think we have seen a similar magnitude of survival benefit with any treatment ever in the setting of metastatic bladder cancer.”
In 2021, Agarwal expects the ADCs enfortumab vedotin-ejfv (Padcev) and sacituzumab govitecan to be important developing agents. “We will see various combinations of these drugs coming up,” Agarwal said. “The phase 3 trial [EV-302; NCT04223856] has already started in the first-line setting, where enfortumab vedotin is being combined with pembrolizumab, and I think similar trials of sacituzumab are expected down the line,” he said. “This will mean that this highly well-tolerated chemotherapy delivering ADCs will be available to our patients who are newly diagnosed with metastatic bladder cancer in the very near future; I’m really hoping in the next few years at most.”
In metastatic renal cell carcinoma (RCC), Agarwal expects a new class of drugs, hypoxia-inducible factor-2α (HIF-2α) inhibitors, to become “a huge story.” In July 2020, the FDA granted breakthrough therapy designation to MK-6482 for the treatment of patients with von Hippel-Lindau (VHL) disease–associated RCC with nonmetastatic tumors less than 3 cm who do not require immediate surgery. The agency also granted the HIF-2α inhibitor orphan drug designation for patients with VHL disease.12
Investigators are exploring the novel agent in a phase 3 trial (NCT04195750) in advanced clear cell RCC, a phase 2 trial (NCT03401788) in VHL-associated RCC, and a phase 1/2 dose-escalation and dose-expansion trial (NCT02974738) in advanced solid tumors, including advanced RCC.
Development of established agents will continue as well, Agarwal added. “We will be seeing the field of metastatic RCC rapidly evolving in 2021, with approval of cabozantinib [Cabometyx] with nivolumab [Opdivo], approval of pembrolizumab plus lenvatinib [Lenvima], and newer trials testing HIF-2α inhibitors in various combinations and, hopefully, approval of HIF-2α inhibitors for our patients.”
Cellular and targeted therapies continued to dominate the trends in the treatment of hematologic malignancies last year. Although practice-changing data did not shake up the treatment landscape dramatically in 2020, research presented at the 62nd American Society of Hematology (ASH) Annual Meeting and Exposition set the stage for where the field is headed in 2021, according to Lori A. Leslie, MD.
“I’m very hopeful that we will gain more data about how to individualize treatment using targeted therapies in a way that we’re able to offer time-limited rather than indefinite therapy, hopefully for all patients,” said Leslie, director of indolent lymphoma and chronic lymphocytic leukemia research programs at Hackensack Meridian Health John Theurer Cancer Center and assistant professor at Hackensack Meridian School of Medicine in New Jersey.
Progress with CAR T-cell therapy has continued; however, despite success in certain patients, efforts to increase response rates and reduce relapse rates have been an ongoing focus of research. Other strategies garnering attention across hematologic malignancies include the development of next-generation CAR constructs such as dual-targeting of CD20 and CD3, combination therapy with immune checkpoint inhibitors, and the identification of high-risk patients prior to induction therapy.
“I’m most excited about CAR T-cell therapy as well as bispecific antibody therapies. We’ve seen a lot of data at 2020 ASH, including those from ZUMA-5, which looked at CD19 CAR T-cell therapy in patients with relapsed/refractory follicular lymphoma or marginal zone lymphoma [and] showed a high overall response rate,” Leslie said.
In updated data from ZUMA-5 (NCT03105336), axicabtagene ciloleucel (Yescarta) had an ORR by independent radiology review committee of 92% (95% CI, 85%-97%), with a complete response (CR) rate of 76% (95% CI, 67%-84%) and a partial response (PR) rate of 16% in patients with indolent non-Hodgkin lymphoma.13 In patients with follicular lymphoma, the ORR was 94%, with a CR rate of 80% and a PR rate of 14%. Leslie cited these data as hopeful, adding, “This will transform how we treat relapsed/refractory follicular lymphoma, at least in the near future.”
In the area of bispecific T-cell engagers, data from several phase 1 trials were presented, including findings for mosunetuzumab and glofitamab, designed to target CD20 on the surface of B cells and CD3 on the surface of T cells, respectively. Data from the phase 1/1b GO29781 study (NCT02500407) in relapsed/refractory follicular lymphoma showed a 51.6% CR rate among 62 patients treated with mosunetuzumab. Further, glofitamab elicited a 53.6% CR rate in 28 patients with aggressive non-Hodgkin lymphoma in the phase 1/1b NP30179 study (NCT03075696).14 “I think in 2021 we should certainly keep our eyes open for more data on bispecific antibodies in certain hematologic malignancies,” Leslie said.
Investigators are also focusing on combining agents with nonoverlapping toxicity profiles that have demonstrated synergy in preclinical settings. “We have a number of single agents [that have] modest activity, but are easy to tolerate,” Leslie said. “And we will continue to learn how to rationally combine them moving forward, particularly in relapsed/refractory indolent lymphomas.” Leslie cited the results from the phase 1/2 trial (NCT02956382) of ibrutinib (Imbruvica) and venetoclax (Venclexta) in patients with relapsed/refractory follicular lymphoma.15
As monotherapy, the Bruton tyrosine inhibitor and the BCL2 inhibitor have response rates of approximately 20% and 38%, respectively, according to Leslie. When administered at the phase 2 recommended dose of 560-mg ibrutinib with 600-mg venetoclax, the response rate was 83% with a CR rate of 33% (n = 6).15 “I’m hopeful that we’ll be shifting toward a personalized, molecularly driven combination nonchemotherapy approach for more patients with relapsed/ refractory indolent lymphomas,” Leslie said.
However, an area of study that deserves attention in the clinic moving forward is the importance of checking patients for high risk features before the initiation of therapy, especially in patients with chronic lymphocytic leukemia (CLL). “[Evaluating patients for these features] has not only prognostic value in terms of telling the patient how you expect them to respond to therapy, but it also has significant predictive value in that it can help with treatment selection and patients with high risk,” Leslie said. “For example, patients with CLL really should not be treated with chemoimmunotherapy outside extenuating circumstances.”
Data from a real-world study, presented by Leslie at 2020 ASH, compared clinical outcomes in patients with high-risk CLL who received first-line ibrutinib versus those who received chemoimmunotherapy. In the retrospective analysis, patients were defined as high risk if their disease harbored a 17p deletion (del), del(11q), a TP53 mutation, an unmutated IGHV, or a complex karyotype of 3 or more chromosomal abnormalities.16
Of the 516 patients included in the analysis, which spanned 40 treatment sites in the United States, 271 were identified as having high-risk CLL, of whom 175 received ibrutinib and 96 received chemoimmunotherapy. Time to next treatment (TTNT) was used as a surrogate end point for PFS and was significantly longer in those treated with ibrutinib, with a median TTNT not yet reached compared with 34.4 months with chemoimmunotherapy (HR, 0.46; 95% CI, 0.34-0.62; P < .01).16
“Another way to look at longer-term outcomes was looking at the number of patients who required only 1 line of therapy during the study period,” said Leslie. “For those on ibrutinib, 74.7% needed only 1 line of therapy compared with 47.0% of patients treated with chemoimmunotherapy. The remainder of those treated with chemoimmunotherapy went on to a second line of therapy. Treating patients with targeted therapy in some way at least partially neutralizes the poor prognostic indication or implication of a TP53 abnormality or a mutated IGHV.”