Agents with novel mechanisms of action distinct from available ATP-competitive tyrosine kinase inhibitors (TKIs) have been tested in patients with previously treated, Philadelphia chromosome–positive (Ph+) chronic myeloid leukemia (CML) and offer promise to facilitate deeper remissions.

Jorge E. Cortes, MD, director of the Georgia Cancer Center at Augusta University, said key considerations for treating this patient population are achieving sufficiently deep responses to consider treatment discontinuation and improving quality of life; however, challenges to realizing these goals remain.

“[Existing agents for treating CML] work very well. So, showing improvement becomes a little harder,” Cortes said in an interview with 

“I think there is still room for improvement. We still don’t get enough patients to the deepest molecular responses so they can consider treatment discontinuation.”

Almost all cases of CML are driven by the presence of the Philadelphia chromosome, the result of a translocation event producing the BCR-ABL1 fusion gene. The resulting hybrid protein possesses dysregulated tyrosine kinase activity.1 Although patients with CML generally do well on current treatments and can have a near-normal life expectancy, there are aspects of CML therapy that could be improved.

Developing New Strategies to Address Unmet Needs in Standard Treatment Sequences

Newly diagnosed chronic-phase (CP) CML is effectively treated with currently available TKIs, including the first-generation BCR-ABL1 inhibitor imatinib (Gleevec) and second-generation agents dasatinib (Sprycel), nilotinib (Tasigna), and bosutinib (Bosulif). Mutations in the BCR-ABL1 kinase domain, such as T315I, frequently confer resistance to TKIs. The third-generation ponatinib (Iclusig) is the only FDA-approved TKI active against CML with the T315I mutation, which renders the disease completely resistant to other BCR-ABL1–targeting agents.1 However, ponatinib is associated with potentially life-threatening adverse effects (AEs).

As there are few options for CML-CP resistant to multiple TKIs,1 there is an unmet medical need for new therapies for patients who have TKI-resistant CML or who cannot tolerate the toxicity associated with current agents.

Currently available TKIs for CML are orthosteric inhibitors, all of which directly target the ATP-binding site of the BCR-ABL1 kinase.

The wild-type ABL1 kinase is myristoylated at its N-terminal end. This myristoyl group can bind to a myristoyl pocket in the kinase domain of the molecule, changing ABL1’s conformation and acting as an allosteric auto-inhibitor to keep its kinase activity in check. During the translocation event that produces BCR-ABL1, the myristoylated ABL1 region is lost and the kinase becomes constitutively active. Therefore, the myristoyl pocket, which is located in a different region of the kinase domain from the ATP-binding site, provides a new therapeutic target (FIGURE).

Recent data from a phase 3 trial demonstrated that the novel investigational agent asciminib (ABL001), which targets the ABL1 myristoyl pocket, was superior to bosutinib in producing a major molecular response (MMR) in patients with Ph+ CML.

As an allosteric inhibitor that Specifically Targets ABL1 Myristoyl Pocket (STAMP), the novel agent asciminib is active against BCR-ABL1 with resistance mutations in the ATP-binding site, including T315I, and is expected to have lower off-target activity, resulting in a better safety profile compared with ATP-competitive TKIs.

Preclinical Development of STAMP Inhibition for Ph+ CML

In preclinical studies, asciminib inhibited the growth of primary cells from patients with CML as well as human Ph+ leukemia cell lines but did not inhibit cells from healthy donors. Asciminib also inhibited the growth of some, but not all, cell lines with point mutations in BCR-ABL1 that confer resistance to approved TKIs. Combining asciminib with either nilotinib or ponatinib largely overcame resistance to single-agent asciminib.

The preclinical activity of asciminib formed the basis for testing it in clinical trials. The allosteric inhibitors GNF-2 and GNF-5 have structures similar to that of asciminib, and, like asciminib, they both bind to the myristoyl pocket of BCR-ABL1. Although GNF-2 and GNF-5 have preclinical activity, they have not been tested in clinical trials in CML.

Clinical Development of Asciminib for Ph+ CML

In an ongoing, phase 1, study (NCT02081378), asciminib was administered (as monotherapy or in combination with nilotinib, imatinib, or dasatinib) to patients with heavily pretreated CML that had relapsed or was refractory to prior TKIs. In a report of findings for the asciminib monotherapy arm, most of the 150 enrolled patients (n = 141) had CML-CP.

 Median follow-up was 59 weeks, and the maximum tolerated dose of asciminib was not reached.

Among the 113 patients with CML-CP without the T315I mutation, a complete hematologic response (CHR) was achieved in 34 of 37 (92%) who did not have CHR at baseline, and a complete cytogenetic response (CCR) was seen in 31 of 57 (54%) patients without CCR at baseline. MMR (defined as BCR-ABL1IS ≤0.1%, ie, presence of the BCR-ABL1 fusion in ≤0.1% of cells in a blood sample) was achieved or maintained by 12 months in 44 of 91 (48%) evaluable patients without T315I and in 5 of 18 patients (28%) with T315I at baseline.

Dose-limiting toxicities (DLTs) of asciminib monotherapy included pancreatitis and asymptomatic elevated lipase levels. Common AEs included fatigue, headache, arthralgia, hypertension, and thrombocytopenia.10 Asciminib treatment is also being assessed in a larger cohort of patients with the T315I mutation in this study.

In the same trial, asciminib monotherapy was examined in a cohort of 48 patients with BCR-ABL1IS ≤1% at baseline, a population that is especially likely to experience intolerance of traditional TKIs. At a median duration of treatment of just over 3 years, 87.5% of patients remained on treatment, and 75% had achieved MMR or better. The most common grade 3/4 AEs were increased lipase and hypertension.

The asciminib plus imatinib arm of this study enrolled 25 patients with CML-CP. MMR was observed by 48 weeks in 8 of 19 (42%) evaluable patients who did not have MMR at baseline.

Grade 3/4 treatment-related AEs (TRAEs) occurred in 44% of patients. DLTs included decreased neutrophil count, abdominal pain, nausea, pancreatitis, and increased lipase. The most common any-grade AEs were nausea, increased lipase, abdominal pain, peripheral edema, and vomiting.

The asciminib plus nilotinib and asciminib plus dasatinib arms of this study each enrolled 17 patients; all but 1 patient in each arm had CML-CP. The choice of agent to combine with asciminib was based on prior intolerance. In the nilotinib group, there was 1 DLT of maculopapular rash during the first cycle. Additionally, 53% of patients had grade 3/4 TRAEs, with the most common any-grade AEs being myalgia, increased lipase, increased amylase, fatigue, and pruritus. In the dasatinib group, there was 1 DLT of increased lipase during cycle 1; 29% of patients had grade 3/4 TRAEs, with the most common any-grade AEs being increased lipase, diarrhea, headache, and nausea. Approximately one-third of patients in each arm without MMR at baseline experienced MMR by 48 weeks.

The ASC4MORE trial is an ongoing phase 2, open-label, randomized efficacy and safety study (NCT03578367) recruiting an estimated 80 patients with CML-CP who have not experienced a deep molecular response (BCR-ABL1IS ≤0.01%) on frontline imatinib. Patients are randomized to either continue imatinib monotherapy, add asciminib (40 mg or 60 mg) to the imatinib regimen, or switch to nilotinib.

The ongoing phase 3 ASCEMBL study (NCT03106779) is evaluating asciminib monotherapy versus bosutinib in patients with CML-CP who have previously been treated with at least 2 ATP–binding-site TKIs.3 Patients are randomly assigned to asciminib 40 mg twice daily (n = 148) or bosutinib 500 mg once daily (n = 74). Patients who experience treatment failure on bosutinib are allowed to cross over to asciminib. The primary end point is MMR at 24 weeks, with a key secondary end point of MMR at 96 weeks. Other secondary objectives include efficacy and safety.

At primary analysis, the ASCEMBL trial was reported to have met its primary end point. Asciminib was associated with statistically significant superiority in terms of the MMR rate at 24 weeks compared with bosutinib, although investigators have not reported any specifics. Data will be presented at an upcoming medical meeting. Novartis, the manufacturer of the agent, reported that the FDA has granted asciminib a fast track designation.

Agents with mechanisms of action differing from TKIs targeting the ATP-binding site of BCR-ABL1 have been tested in Ph+ CML, particularly in patients who have the T315I mutation or have experienced treatment failure with TKIs approved for CML, and the results have been mixed. The farnesyl transferase inhibitors lonafarnib (SCH 66336) and tipifarnib (Zarnestra; R115777) were tested as monotherapies or in combination with imatinib in small, early-phase studies (NCT00047502; NCT00038597; NCT00040105), after which their development in CML was apparently halted.

Other agents that have been tested in TKI-resistant CML include pan-aurora kinase (serine/threonine kinase) inhibitors, such as danusertib, which showed activity in a small. trial (EudraCT number 2007-004070-18)17 but has no further ongoing trials in CML. Clinical trials in CML (NCT00405054; NCT00500006) of another pan-aurora kinase inhibitor, tozasertib (MK-0457), were terminated, in part because the agent showed only minimal efficacy even at high doses with intolerable toxicity.

Other agents under investigation include the PPAR-g agonist pioglitazone (Actos), which is approved for treatment of diabetes. In the ACTIW trial, patients with CML-CP are randomized to either pioglitazone or the PD-L1 inhibitor avelumab (Bavencio), taken sequentially or in combination with 1 of several TKIs (NCT02767063). Vildagliptin (Galvus), another antidiabetic agent, is being investigated in patients taking nilotinib as pretreatment prior to attempting discontinuation of nilotinib (EudraCT: 2017-000899-28).

Cortes said he expects asciminib to be approved initially for use in patients with CML after the failure of at least 2 TKIs, noting promising data in patients with the T315I mutation. However, he did point out that patients with this mutation were excluded from the phase 3 ASCEMBL study because the comparator, bosutinib, is inactive against this mutation.

 He said he hoped asciminib would be considered for approval for treating this mutation because “in that context, we only have 1 drug, ponatinib. Even putting aside the issues of safety, having 1 drug only form any given scenario is never a good idea.”


Regarding asciminib’s potential in an earlier setting, Cortes said, “it’s likely that it would work better in the second line than any of the other drugs that we [currently have].”

When asked about future development of targeted agents for patients with CML, Cortes said there is an unmet need due to a lack of effective therapies for blast-phase CML. “We don’t have good outcomes in blast-phase [disease]…but certainly, the need is not as immediate as it is for patients [with CML-CP] who have [prior treatment failure with] 2 TKIs or more, or patients who have the T315I [mutation].”

1. NCCN. Clinical Practice Guidelines in Oncology. Chronic myeloid leukemia, version 2.2021. Accessed August 28, 2020. https://bit.ly/34AY9u4

2. Iclusig. Prescribing information. Takeda Pharmaceutical Company Limited; 2020. Accessed October 6, 2020. https://bit.ly/34tPDMe

3. Mauro MJ, Hochhaus A, Boquimpani C, et al. A multicenter, randomized phase III study of asciminib (ABL001) versus bosutinib in patients (pts) with chronic myeloid leukemia in chronic phase (CML-CP) previously treated with ≥ 2 tyrosine kinase inhibitors (TKIs). J Clin Oncol. 2019;37(suppl 15):TPS7070. doi:10.1200/JCO.2019.37.15_suppl.TPS7070

4. Carofiglio F, Trisciuzzi D, Gambacorta N, Leonetti F, Stefanachi A, Nicolotti O. Bcr-Abl allosteric inhibitors: where we are and where we are going to. Molecules. 2020;25(18):E4210. doi:10.3390/molecules25184210

5. Westerweel PE, Te Boekhorst PAW, Levin MD, Cornelissen JJ. New approaches and treatment combinations for the management of chronic myeloid leukemia. Front Oncol. 2019;9:665. doi:10.3389/fonc.2019.00665

6. Manley PW, Barys L, Cowan-Jacob SW. The specificity of asciminib, a potential treatment for chronic myeloid leukemia, as a myristate-pocket binding ABL inhibitor and analysis of its interactions with mutant forms of BCR-ABL1 kinase. Leuk Res. 2020;98:106458. doi: 10.1016/j.leukres.2020.106458

7. Novartis investigational novel STAMP inhibitor asciminib (ABL001) meets primary endpoint of phase III chronic myeloid leukemia study. News release. Novartis. August 26, 2020. Accessed August 26, 2020. https://bit.ly/2SAuwC8

8. Eide CA, Zabriskie MS, Savage Stevens SL, et al. Combining the allosteric inhibitor asciminib with ponatinib suppresses emergence of and restores efficacy against highly resistant BCR-ABL1 mutants. Cancer Cell. 2019;36(4):431-443.e5. doi:10.1016/j.ccell.2019.08.004

9. Jones JK, Thompson EM. Allosteric inhibition of ABL kinases: therapeutic potential in cancer. Mol Cancer Ther. 2020;19(9):1763-1769. doi:10.1158/1535-7163.MCT-20-0069

10. Hughes TP, Mauro MJ, Cortes JE, et al. Asciminib in chronic myeloid leukemia after ABL kinase inhibitor failure. N Engl J Med. 2019;381(24):2315-2326. doi:10.1056/NEJMoa1902328

11. Rea D, Lang F, Kim DW, et al. Asciminib, a specific allosteric BCR-ABL1 inhibitor, in patients with chronic myeloid leukemia carrying the T315I mutation in a phase 1 trial. Blood. 2018;132(suppl 1):792. doi:10.1182/blood-2018-99-113609

12. Hughes T, Mauro MJ, Kim DW, et al. Asciminib in heavily pretreated patients (pts) with Philadelphia chromosome–positive (Ph+) chronic myeloid leukemia in chronic phase (CML-CP) sensitive to tyrosine kinase inhibitor (TKI) therapy. Presented at: 25th European Hematology Association Annual Congress; June 11-21, 2020; Virtual. Abstract S170. Accessed October 22, 2020. https://bit.ly/30CTbe3

13. Cortes J, Lang F, Kim DW, et al. Combination therapy using asciminib plus imatinib (IMA) in patients (pts) with chronic myeloid leukemia (CML): results from a phase 1 study. Presented at: 25th European Hematology Association Annual Congress; June 11-21, 2020; Virtual. Abstract S883. Accessed October 22, 2020. https://bit.ly/35mefXP

14. Mauro MJ, Kim DW, Cortes J, et al. Combination of asciminib plus nilotinib (NIL) or dasatinib (DAS) in patients (pts) with chronic myeloid leukemia (CML): results from a phase 1 study. Presented at: 25th European Hematology Association Annual Congress; June 11-21, 2020; Virtual. Abstract S884. Accessed October 22, 2020. https://bit.ly/3lkFWXb

15. Cortes J, Jabbour E, Daley GQ, et al. Phase 1 study of lonafarnib (SCH 66336) and imatinib mesylate in patients with chronic myeloid leukemia who have failed prior single-agent therapy with imatinib. Cancer. 2007;110(6):1295-1302. doi:10.1002/cncr.22901

16. Cortes J, Quintás-Cardama A, Garcia-Manero G, et al. Phase 1 study of tipifarnib in combination with imatinib for patients with chronic myelogenous leukemia in chronic phase after imatinib failure. Cancer. 2007;110(9):2000-2006. doi:10.1002/cncr.23006

17. Borthakur G, Dombret H, Schafhausen P, et al. A phase I study of danusertib (PHA-739358) in adult patients with accelerated or blastic phase chronic myeloid leukemia and Philadelphia chromosome-positive acute lymphoblastic leukemia resistant or intolerant to imatinib and/or other second generation c-ABL therapy. Haematologica. 2015;100(7):898-904. doi:10.3324/haematol.2014.115279

18. Seymour JF, Kim DW, Rubin E, et al. A phase 2 study of MK-0457 in patients with BCR-ABL T315I mutant chronic myelogenous leukemia and Philadelphia chromosome-positive acute lymphoblastic leukemia. Blood Cancer J. 2014;4(8):e238. doi:10.1038/bcj.2014.60

Articles

Clinical Articles

Agents with novel mechanisms of action distinct from available ATP-competitive tyrosine kinase inhibitors have been tested in patients with previously treated, Philadelphia chromosome–positive chronic myeloid leukemia  and offer promise to facilitate deeper remissions.

Clinical Trials Are Underway on Novel Approaches to CML-Resistant BCR-ABL1 Inhibitors

Multiple clinical trials in the treatment of metastatic urothelial cancer across lines of therapy were presented at the European Society for Medical Oncology Virtual Congress 2020, with investigational and established agents explored in areas of unmet medical need.

Newly presented and follow-up data from phase 3 trials further served to clarify the role of immunotherapy in the treatment of patients with frontline metastatic disease and introduced interesting research questions for further exploration (TABLE).

 For example, subgroup analyses from the pivotal JAVELIN Bladder 100 trial (NCT02603432) demonstrated that avelumab (Bavencio) as maintenance therapy in patients without disease progression following frontline chemotherapy is effective across subgroups stratified by best therapy response, creatinine clearance, as well as ECOG and PD-L1 expression status.

Other promising data at the meeting involved earlier-phase trials exploring investigational agents in the treatment of tumors in the second-line and later settings.

Following presentations of abstracts related to the treatment of metastatic urothelial cancer across settings, invited discussants Jürgen Gschwend, MD, and Richard Cathomas, MD, stepped in to assess and posit the newly available data in relation to the current treatment landscape and address hypothesis-generating questions about the treatment landscape of metastatic urothelial carcinoma.

Placing Immunotherapy in the Frontline Setting

Checkpoint inhibitors are already approved for use in urothelial carcinoma in patients who have previously received or are ineligible for platinum therapy, but interest regarding the potential role of these agents in the frontline setting has been the motivation behind large, randomized phase 3 trials.

Following on a supplementary approval of avelumab in the maintenance treatment of patients with urothelial cancer receiving frontline platinum therapy,4 additional examinations into the JAVELIN Bladder 100 were presented during the conference. Updated survival data showed a 7.1-month median OS improvement with avelumab maintenance plus best supportive care (BSC) versus BSC alone (HR, 0.69; 95% CI, 0.56-0.86; 2-side 

 < .001). In subgroup analysis, the median PFS also favored the avelumab arm at 3.7 months versus 2.0 months in the BSC-alone arm per blinded independent central review (HR, 0.62; 95% CI, 0.52-0.75; P <.001).

Survival was not significantly correlated with avelumab therapy in patients, regardless of ECOG performance score. Patients stratified to groups of performance score 0 (HR, 0.64; 95% CI, 0.48-0.85) and 1 or greater (HR, 0.74; 95% CI, 0.54-1.03) saw similar benefit with immunotherapy maintenance. The hazard ratio for survival improvement was 0.69 favoring avelumab for patients with creatinine clearance of 60 mL/min or greater (95% CI, 0.50-0.92) as well as for those with less than 60 mL/min (95% CI, 0.50-0.94).

The median OS was not reach for either the avelumab or best supportive care arm in patients with a best response to therapy of complete response, with available data favoring the experimental arm (HR, 0.81; 95% CI, 0.47-1.38). In those with partial responses, median OS was 19.2 months with avelumab versus 12.1 months with best supportive case (HR, 0.62; 95% CI, 0.46-0.83).

Another analysis attempted to determine biomarkers of response and survival with avelumab and demonstrated that established biomarkers of immunotherapy response, such as PD-L1, were not capable of optimally predicting OS benefit with maintenance avelumab.

“The presentation here was about exploratory end points—the assessment of tumor biomarkers that may be potentially related to antitumor immune activity or OS benefit with avelumab,” said Gschwend, who is professor of urology and vice dean at the Technical University of Munich School of Medicine in Germany. “In this study, PD-L1 was [found to be] more predictive than prognostic…there was no clear prediction by either TMB [tumor mutational burden] or PD-L1 status.”

Gschwend said multiple other biomarkers, including gene expression signatures, were identified as potentially predictive. Immune-related genes crossing the prespecified significance threshold of 0.001 included 

, but he said these are more hypothesis generating than clinically relevant.

These results together led the investigators to conclude that avelumab may be used in patients as maintenance therapy, regardless of the PD-L1 expression and that combinations of biomarkers may help further characterize those who may receive the most benefit with avelumab.

“[Questions remain regarding] whether the tissue comes from the primary or metastatic [site] and the time of tissue sampling,” added Gschwend. “This is critical during the course of the disease [because] there is proven tumor heterogeneity within the same tumor.”

In addition to these data, the anticipated phase 3 DANUBE trial (NCT02516241) comparing durvalumab (Imfinzi) monotherapy or durvalumab plus the CTLA-4 inhibitor tremelimumab versus chemotherapy in patients with metastatic urothelial cancer in the frontline setting were presented. Although the study failed to meet its coprimary end points of overall survival (OS) with the experimental regimens versus standard of care, secondary analyses suggested that the combination had improved antitumor activity, particularly in the group of patients with high PD-L1 expression.

“Long-awaited [trial data were presented that] help answer some important clinical questions of best uses of immunotherapy in the first-line setting,

” said Cathomas, who is deputy head physician at the Cantonal Hospital of Graubünden in Loestrasse, Switzerland. “The most interesting subgroup analysis… in my view is the PD-L1–positive group of the DANUBE trial treated with the tremelimumab/durvalumab combination, reaching a significant and interesting overall survival benefit of almost 6 months.

Cathomas detailed findings from DANUBE as well as those of the phase 3 KEYNOTE-361
trial (NCT02853305) of pembrolizumab with or without chemotherapy versus chemotherapy alone in patients with treatment-naïve disease.

 “The overall survival results for the [intention-to-treat] populations for either combination did not reach statistically significant differences in either of the trials,” Cathomas said. “Looking at the results of single-agent therapy in patients with high PD-L1 expression, no overall survival advantage over chemotherapy can be found.”

Also notable were lower rates of response with single-agent immunotherapy versus chemotherapy in these trials; yet when responses were achieved, duration of responses appeared to be longer in patients receiving immunotherapy versus chemotherapy.

Looking to the results of DANUBE for signals that may motivate further exploration into the use of immunotherapy in these populations, Cathomas noted that the secondary end point of median OS in the PD-L1–high positive subgroup reached statistical significance with the durvalumab/tremelimumab combination versus chemotherapy, at 17.9 months versus 12.1 months, respectively (HR, 0.74; 95% CI, 0.59-0.93).

Although these data are only hypothesis generating at this point, Thomas Powles, MD, MBBS, MRCP, lead study author and presenter of DANUBE, thought the results could warrant further investigation. “We pursued a biomarker strategy that included 60% of the population, and it’s possible that further enrichment may have improved these data,” said Powles, who is also director of the Barts Cancer Centre in London, United Kingdom.

Another immune checkpoint inhibitor combination being explored in this setting, nivolumab plus ipilimumab showed continued antitumor activity and survival benefits in an extended follow-up of the CheckMate 032 trial (NCT01928394) with benefits observed regardless of PD-L1 status. Patients included in the metastatic urothelial cancer cohort of the trial had previously treated disease and received either single-agent nivolumab at 3 mg/kg (NIVO3), NIVO3 plus ipilimumab at 1 mg/kg, or nivolumab at 1 mg/kg plus ipilimumab at 3 mg/kg (NIVO1/IPI3). Median OS results were 9.9, 7.4, and 15.3 months, respectively. Based on these results and an expected safety profile, the investigators concluded that the NIVO1/IPI3 dosing schedule shows promise and that these data further support the development of NIVO1/IPI3 versus chemotherapy in the phase 3 CheckMate 901 trial (NCT03036098) in treatment-naïve patients.

Potential for New Agents in Second and Later Lines

Most cases of metastatic urothelial carcinoma are not curable, making the introduction of effective regimens for therapy in the second-line setting and beyond a salient need for improved outcomes in this disease…. There [has been] an evolution of systemic treatment options in metastatic [urothelial carcinoma] in the last 20 years…most recently, we have seen second-line options with erdafitinib [Balversa] and enfortumab vedotin [Padcev], and at this meeting, we have seen data for sacituzumab govitecan [Trodelvy] in the second- and third-line settings.”

Gschwend discussed findings from the phase 2 TROPHY U-01 trial (NCT03547973), which included 113 patients with metastatic urothelialcarcinoma who were treated with sacituzumab govitecan following progression on prior platinum- based chemotherapy and immunotherapy.9

Sacituzumab govitecan is a TROP-2–directed antibody-drug conjugate (ADC) coupled to SN-38, the active metabolite of irinotecan, and has a high drug-to-antibody ratio. It is distinct from other ADCs thanks to its bystander effect due to hydrolysable linker hydrolysis.

In cohort 1 of the trial, promising response rates were observed with the use of single-agent sacituzumab govitecan. The antibody-drug conjugate induced an objective response rate (ORR) of 27% (95% CI, 19.0%-37.0%), comprising 6 complete responses (CRs) and 25 partial responses (PRs). The median duration of response was 5.9 months with a median response onset time of 1.6 months.

“When we look at the results, they are promising,” said Gschwend, who compared the sacituzumab govitecan data with previously reported trial results from the pivotal EV-201 trial (NCT03219333) of enfortumab vedotin. He used the Nectin-4–directed antibody as a comparator in this case because the drug recently received FDA approval for the treatment of patients who previously received both platinum chemotherapy and immunotherapy for urothelial cancer based on phase 2 trial data, thus closely mirroring the patient population in the TROPHY-U 01 trial.

The median progression-free survival (PFS) was 5.4 months with sacituzumab govitecan in TROPHY U-01 compared with 5.8 months with enfortumab vedotin in EV-201. These results demonstrated that the agent is still effective, even after use of an immune checkpoint inhibitor in earlier lines of therapy.

In the phase 1/2 BGB-900-101 study (NCT03379259), the addition of the investigational PD-L1 inhibitor BGB-A333 to the PD-1 inhibitor tislelizumab led to marked antitumor activity and durable responses in patients with locally advanced or metastatic urothelial carcinoma following progression on 1 platinum-containing regimen.

 Patients in the phase 2b, dose-expansion portion (n = 12) who were evaluated for responses had an ORR of 42% (95% CI, 15.2%-72.3%) with the combination. Patients in the PD-L1–high group (n = 6), defined as having 25% or more of tumor or immune cells positive for PD-L1 staining by the Ventana SP263 assay, had an ORR of 67% (95% CI, 22.3%-95.7%), which comprised 2 CRs and 2 PRs. Patients in the PD-L1–low group (n = 6) had an ORR of 17% (95% CI, 0.42%-64.1%), which comprised 1 CR.

The median PFS was 6.1 months in the overall population. In the PD-L1–high subgroup, the median PFS was 10.0 months versus 4.1 months in patients with low PD-L1 expression. In the entire trial cohort (n = 39), 20 patients had adverse events (AEs) of any grade, and 7 patients experienced AEs of grade 3 or higher; no patients experienced fatal treatment-related AEs.

“Simultaneous PD-L1 and PD-1 blockade has been hypothesized to provide synergistic antitumor effects, as inhibitors may have distinct mechanisms of action,” said lead study author Juan Martin-Liberal, MD, PhD, a consulting medical oncologist in the Melanoma, Sarcoma, and Genitourinary Tumors Unit at Institut Català d’Oncologia Hospitalet in Barcelona, Spain. “[Although] these differences should be taken cautiously given the sample size, these data have provided insights into combining tislelizumab, a clinical-stage anti– PD-1 antibody, with anti–PD-L1 antibodies.”

The results presented at the conference have brought investigators closer to answering important clinical questions about the placement of immunotherapy in the urothelial carcinoma treatment paradigm. The practice-changing potential of these data offer exciting possibilities that may provide options for patients for whom limited systemic options currently exist.

“Numerous trials using different combinations of the aforementioned treatments are already ongoing and will likely alter the treatment landscape of urothelial cancer in the near. future,” Cathomas said.

It is clear from trial results that positioning of immunotherapy-based combinations in treatment sequencing needs further clarification, but many more results and improvements are expected in the future.

“We will soon have final results of combination trials, including IMvigor130 [NCT02807636], CheckMate 901, and the NILE trial [NCT03682068; TABLE2],” Cathomas said. “Another step forward might be the identification of subgroups to predict responders from nonresponders.”

Cathomas added that he is especially interested to see phase 3 results of nivolumab/ipilimumab in tumors with high PD-L1 expression.

“The next major step appears to be the integration of novel drugs in the frontline setting,” Cathomas said, referring to positive phase 2 trial results of agents showing efficacy in metastatic disease. He went on to list multiple agents, such as the ADC enfortumab vedotin, sacituzumab govitecan, and targeted treatments for patients with 

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4. FDA approves avelumab for urothelial carcinoma maintenance treatment. FDA. June 30, 2020. Accessed October 1, 2020. https://bit.ly/3iplzWW

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8. Sharma P, Siefker-Radtke AO, de Braud F, et al. Nivolumab (N) alone or  in combination with ipilimumab (I) in patients (pts) with platinum-pretreated metastatic urothelial carcinoma (mUC): extended follow-up from CheckMate 032. 

9. Loriot Y, Balar AV, Petrylak DP, et al. TROPHY-U-01 cohort 1 final results: a phase II study of sacituzumab govitecan (SG) in metastatic urothelial cancer (mUC) that has progressed after platinum (PLT) and checkpoint inhibitors (CPI).

. 2020;31(suppl 4):S1142-S1215. doi:10.1016/annonc/annonc325

10. FDA grants accelerated approval to enfortumab vedotin-ejfv for metastatic urothelial cancer. FDA. December 18, 2019. Accessed October 2, 2020. https://bit.ly/2GrSc9k

11. Martin-Liberal H, Fong PC, Moreno V, et al. BGB-A333, an anti-PD-L1 monoclonal antibody, in combination with tislelizumab in patients with urothelial carcinoma.

. 2020;31(suppl 4):S462-S504 doi:10.1016/annonc/annonc271

Treatment strategies that build on standard therapies plus the use of novel agents in metastatic urothelial carcinoma were spotlighted at the European Society for Medical Oncology Virtual Congress 2020, with some having the potential to affect treatment regimens of patients who are receiving therapy in the frontline setting.

November 1 2020 | Targeted Therapies in Oncology

Clinical Trials Are Underway on Novel Approaches to CML-Resistant BCR-ABL1 Inhibitors

Meeting Updates Refine Approaches Toward Urothelial Carcinoma