FDA Takes a Stand on Accelerated Immunotherapy Approvals Without Confirmatory Benefit

Targeted Therapies in Oncology, April 2, 2021, Volume 10, Issue 6
Pages: 104

The FDA has been leading an industry-wide evaluation of accelerated approvals of oncology drugs for which the clinical benefit was not verified in confirmatory trials.

The FDA has been leading an industry-wide evaluation of accelerated approvals of oncology drugs for which the clinical benefit was not verified in confirmatory trials. Already 10 indications have been called into question, with some resulting in voluntary withdrawal or planned withdrawal from the market in the United States by the developers. But many more have yet to be resolved and will be the topic of discussion at the upcoming Oncologic Drugs Advisory Committee (ODAC) meeting, taking place April 27 to April 29.1

The FDA’s accelerated approval program was put into place in 1992 to expedite the approval of drugs that treat serious conditions and fill areas of unmet medical needs.2 These approvals were granted based on surrogate or intermediate end points—such as progression-free survival (PFS), disease-free survival, and response rate—that suggest clinical benefit without requiring the time necessary to demonstrate clinical benefit with a standard end point, such as overall survival (OS). However, all agents granted accelerated approval are required to show confirmation of clinical benefit in a confirmatory trial for an accelerated approval to be converted into a full approval.

According to the FDA, an indication can be withdrawn or changed if a confirmatory trial fails to verify clinical benefit or justify the associated risks with sufficient benefit.

An investigation published in JAMA Internal Medicine in 2019 suggested that 9% of confirmatory trials for cancer drugs that were granted accelerated approvals through the FDA program did not confirm benefit.3 The FDA, however, has not typically made a comment when a confirmatory trial failed to meet its primary end point.

In the announcement of the upcoming ODAC meeting, the FDA noted that only 6% of accelerated oncology approvals have ever been withdrawn from the market since the accelerated approval program first began, which included 4 recent actions.1

Yet with 4 drugs being voluntarily withdrawn from the market or in the process of being withdrawn and 6 more indications up for discussion for potential removal, the FDA is now clearly taking a stand against a number of these trials that failed to validate benefit for an indication.

The First 4 to Go

Nivolumab

The first signs of a change in the water with the confirmatory trials that failed to show benefit came in late December 2020 when Bristol Myers Squibb announced it had decided to withdraw the indication for nivolumab (Opdivo), an anti– PD-1 antibody, as a treatment for patients with small cell lung cancer (SCLC) whose disease has progressed after platinum-based chemotherapy and at least 1 other line of therapy.4

Accelerated approval for nivolumab in this setting was granted in August 2018 based on the demonstration of benefit in terms of durable overall response rate as seen in the multicenter, multiarm, open-label phase 1/2 CheckMate 032 trial (NCT01928394).5 The trial looked at the use of nivolumab monotherapy or nivolumab in combination with ipilimumab (Yervoy) in 245 patients with limited- or extensive-stage SCLC who had disease progression after at least 1 prior platinum-containing regimen and showed an overall response rate of 12% (95% CI, 6.5%-19.5%).5,6 Responses lasted 6 months or more in 77% of responding patients, 12 months or more in 62%, and 18 months or more in 39%.

CheckMate 451 (NCT02538666) and CheckMate331 (NCT02481830), both phase 3 trials, were supposed to verify the clinical benefit of nivolumab in this setting; however, neither trial met its primary end point of OS.

CheckMate 451 was a randomized, double-blind study of maintenance therapy with nivolumab and ipilimumab versus nivolumab monotherapy versus placebo in 834 patients with extensive-stage SCLC who did not progress on first-line platinum-based chemotherapy. OS was not significantly improved for nivolumab monotherapy versus placebo (HR, 0.84; 95% CI, 0.69-1.02) or the combination versus placebo (HR, 0.92; 95% CI, 0.75-1.12; P = .3693).7

Further, the open-label, randomized CheckMate331 study enrolled 569 patients with SCLC who had relapsed after first-line platinum-based chemotherapy to receive either nivolumab or standard chemotherapy. The median OS with nivolumab was 7.5 months versus 8.4 months with chemotherapy (HR, 0.86; 95% CI, 0.72- 1.04; P = .11). OS was similar between the arms regardless of PD-L1 expression levels.8

Durvalumab

Next, on February 22, AstraZeneca announced in a press release that the company was voluntarily removing from the US market the indication for durvalumab (Imfinzi), a PD-L1 immune checkpoint inhibitor, as treatment of adult patients with previously treated locally advanced or metastatic bladder cancer.9

Durvalumab was granted an accelerated approval in May 2017 based on findings from a phase 1/2 study (NCT01693562).10 The openlabel trial explored the use of durvalumab in patients with advanced solid tumors, and among a group of 191 patients with locally advanced or metastatic urothelial carcinoma, the objective response rate (ORR) was 17.8%, with complete responses (CRs) in 7 patients.11

The median PFS in the cohort was 1.5 months (95% CI, 1.4-1.9), and the median OS was 18.2 months (95% CI, 8.1-not estimable).

The open-label, multicenter, randomized, controlled DANUBE study (NCT02516241) was planned to be the confirmatory trial for the durvalumab indication. It enrolled 1032 patients who were randomized to receive durvalumab monotherapy, durvalumab plus tremelimumab with durvalumab maintenance, or chemotherapy in the first-line setting. The primary end points of the study were OS in the durvalumab monotherapy arm versus chemotherapy in patients with high PD-L1 expression (≥25% of tumor or immune cells) and OS of the combination regimen versus chemotherapy in the overall population.

In patients with high PD-L1 expression, the median OS was 14.4 months (95% CI, 10.4-17.3) in the durvalumab monotherapy arm versus 12.1 months (95% CI, 10.4-15.0) in the chemotherapy arm (HR, 0.89; 95% CI, 0.71-1.11; 2-sided P=.30). In the overall population, the median OS was 15.1 months (95% CI, 13.1-18.0) in the durvalumab/ tremelimumab arm versus 12.1 months (95% CI, 10.9-14.0) in the chemotherapy arm (HR, 0.85; 95% CI, 0.72-1.02; 2-sided P=.075).12

Pembrolizumab

On March 2, Merck announced that the pembrolizumab (Keytruda) was being voluntarily withdrawn from the US market as a treatment for patients with metastatic SCLC with disease progression on or after platinum-based chemotherapy and at least 1 other prior line of therapy.13 The company’s press release noted that the withdrawal process for the PD-1 inhibitor would take several weeks to complete.

When pembrolizumab was granted accelerated approval for this indication in June 2019, it was based on findings from 83 patients pooled from individual cohorts from the KEYNOTE-158 (NCT02628067) and KEYNOTE-28 (NCT02054806) trials.14

The evaluated patient population comprised those with SCLC who had disease progression on or after 2 or more prior lines of therapy and were treated with intravenous pembrolizumab at either 200 mg every 3 weeks (cohort G of the phase 2 KEYNOTE-158 trial; n = 64) or 10 mg/kg every 2 weeks (cohort C1 of the phase 1b KEYNOTE-28 trial; n= 19) for up to 2 years. The primary end point was ORR by independent review per RECIST. At a median of 7.7-months follow-up (range, 0.5-48.7), the ORR was 19.3% (95% CI, 11.4%-29.4%), with 2 patients achieving a CR. The median duration of response (DOR) was not reached, but 61% of responders had responses lasting at least 18 months.15

The randomized, double-blind phase 3 KEYNOTE-604 study (NCT03066778) served as the confirmatory trial for the approval; however, it met only 1 of its dual primary end points. The trial compared pembrolizumab plus etoposide and platinum chemotherapy with etoposide/ platinum chemotherapy alone in patients with previously untreated extensive-stage SCLC. A total of 453 patients were enrolled and treated with 200 mg intravenous pembrolizumab every 3 weeks up to 35 cycles, plus 4 cycles of etoposide/platinum or chemotherapy alone. The primary end points were PFS by blinded central review and OS in the intention-totreat population.

The median PFS with pembrolizumab and etoposide/platinum was 4.5 months (95% CI, 4.3-5.4) and 4.3 months (95% CI, 4.2-4.4) with etoposide/platinum alone; at 1 year, the PFS rates were 13.6% and 3.1%, respectively. The HR for PFS benefit at the second interim analysis was 0.75 (95% CI, 0.61-0.91; P = .0023).16

The median OS was 10.8 months (95% CI, 9.2-12.9) in the pembrolizumab arm versus 9.7 months (95% CI, 8.6-10.7) in the chemotherapy arm. At 12 months, the OS rate in the pembrolizumab group was 45.1% and 39.6% in the chemotherapy group; at 24 months, the OS rates were 22.5% and 11.2%, respectively. The HR for OS was 0.80, and the significance threshold was not reached (95% CI, 0.64-0.98; P = .0164).

Atezolizumab Roche announced on March 8 that the indication for the PD-L1 inhibitor atezolizumab (Tecentriq) as treatment of patients with metastatic urothelial carcinoma previously treated with platinum was being voluntarily withdrawn in the United States.17 The 10 indications undergoing review are listed in the TABLE. 1,4,9,13,17

The indication was granted accelerated approval in May 2016, marking the first immune checkpoint inhibitor to be FDA approved to treat bladder cancer.18 Accelerated approval was granted based on findings from 310 patients with inoperable locally advanced or metastatic urothelial carcinoma whose disease had progressed after previous platinum-based chemotherapy who were treated in the second cohort of the single-arm, 2-cohort phase 2 IMvigor210 trial (NCT02108652). The coprimary end points of the trial were facility-assessed ORR by RECIST v1.1 and investigator-assessed ORR by immune-modified RECIST criteria.

The ORR by RECIST v1.1 was 15% (95% CI, 11%-20%; P = .0058) in all patients and 37% (95% CI, 19%-37%; P < .0001) in patients with high PD-L1 expression on immune cells (IC2/3). By independent review, the ORR was 15% (95% CI, 11%-19%) in all patients and 26% (95% CI, 18%- 36%) in high PD-L1 expressors. Responses were ongoing after a median of 11.7-months follow-up (95% CI, 11.4-12.2) in 84% of responders.19

However, continued approval was to be based on findings from the randomized phase 3 IMvigor211 confirmatory trial (NCT02302807). This study enrolled 931 patients with metastatic urothelial carcinoma who had progressed after platinum-based chemotherapy to receive either atezolizumab or physician’s choice of vinflunine, paclitaxel, or docetaxel chemotherapy. The primary end point was OS in patients with high PD-L1 expression of IC2/3.

Median OS in the IC2/3 group (n = 234) was 11.1 months (95% CI, 8.6-15.5) with atezolizumab versus 10.6 months (95% CI, 8.4-12.2) with chemotherapy (stratified HR, 0.87; 95% CI, 0.63-1.21; P=.41).

Objective response rates showed a similar lack of difference between the arms at 23% versus 22% in the pembrolizumab and chemotherapy arms, respectively. However, DOR was increased in the immunotherapy arm with a median of 15.9 months (95% CI, 10.4-not estimable) versus 8.3 months (95% CI, 5.6-13.2) with chemotherapy (HR, 0.57; 95% CI, 0.26-1.26).20

Arjun V. Balar, MD, cophysician editor in chief of Targeted Therapies in Oncology, explained in an interview that this failure was particularly troubling because the IMvigor211 trial was conducted in the same patient population as the earlier study, unlike in some of the other indications, but the primary end point still could not be met.

Common Themes

All 4 announcements from the 4 companies included similar messaging that explained the decision to withdraw the indication was done in consultation with the FDA as part of a “broader industry-wide evaluation” of accelerated approvals that did not meet their postmarketing requirements. In addition, each press release suggested that patients consult their health care providers about continued treatment if they were receiving the agent in the related setting.

“My sense is that these companies are offering these withdrawal of approvals as... an offering to the FDA so that it kind of levels the field, saying, ‘This is our...sacrifice to the FDA gods,’ so to speak, but others are under scrutiny, and so the FDA is holding the ODAC [meeting] to allow the companies to provide justification to defend their existing labels,” said Balar, director of the Genitourinary Medical Oncology Program and medical director of the Clinical Trials Office at NYU Langone Perlmutter Cancer Center and associate professor in the Department of Medicine at NYU Grossman School of Medicine, suggesting that the companies withdrew the indication before the FDA was forced to do so itself.

6 Indications Undergo Scrutiny

Atezolizumab in Breast Cancer

The first product to be reviewed during the FDA ODAC meeting will be atezolizumab when used in combination with nab-paclitaxel (Abraxane) for the treatment of adult patients with unresectable locally advanced or metastatic triple-negative breast cancer (TNBC) whose tumors express PD-L1 (PD-L1 staining ≥ 1% on tumor-infiltrating immune cells).1

This indication was first granted accelerated approval by the FDA on March 8, 2019, based on findings from the phase 3 IMpassion130 trial (NCT02425891).21 The double-blind, randomized study included 902 patients with unresectable locally advanced or metastatic TNBC who had not received prior chemotherapy for metastatic disease to receive either atezolizumab and nab-paclitaxel or nab-paclitaxel alone.

In the overall population, the median PFS was 7.2 months with the combination versus 5.5 months with nab-paclitaxel alone (HR, 0.80; 95% CI, 0.69-0.92; P=.002). Among PD-L1–positive patients (n = 369), the median PFS was 7.5 months versus 5.0 months in the combination and monotherapy arms, respectively (HR, 0.62; 95% CI, 0.49-0.78; P < .001).22

Although this was a phase 3 trial, the accelerated approval still required further proof of clinical benefit with the combination in a confirmatory trial, which was supposed to be the phase 3 IMpassion131 trial (NCT03125902).

IMpassion131 was a multicenter, randomized, double-blind study that explored the combination of atezolizumab and paclitaxel compared with paclitaxel alone in 651 patients with previously untreated, inoperable locally advanced or metastatic TNBC. The primary end point was PFS in PD-L1–positive patients, but this end point could not meet statistical significance, according to a press release from Roche. Data for the secondary end point of OS also did not seem to favor the combination.23

In September 2020, the FDA released a statement that alerted health care professionals to efficacy and potential safety concerns for treatment substitutions in patients with previously untreated, inoperable locally advanced or metastatic TNBC in the trial. In the alert, the FDA cautioned that health care professionals should not replace nab-paclitaxel with paclitaxel in clinical practice when used in combination with atezolizumab.24

Pembrolizumab in Bladder Cancer

On the second day of the ODAC meeting, the FDA committee will discuss the potential continued approval for pembrolizumab as treatment of patients with locally advanced or metastatic urothelial carcinoma who are not eligible for cisplatin-containing chemotherapy.

Accelerated approval for this indication was granted on May 18, 2017, and the agent was also given a second-line full indication on the same date for patients with locally advanced or metastatic urothelial carcinoma who have disease progression during or following platinum-containing chemotherapy or within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy.25

The first-line accelerated indication was granted based on findings from the single-arm phase 2 KEYNOTE-052 trial (NCT02335424), which demonstrated significant activity with pembrolizumab in patients with cisplatin-ineligible urothelial cancer. Patients showed an ORR of 28% (95% CI, 20%-29%) and a CR rate of 5% with pembrolizumab treatment. The median DOR was not yet reached.26

Of note, in patients with high PD-L1 expression (combined positive score [CPS] ≥ 10%; n = 110), the ORR was 47.3% (95% CI, 37.7%-57.0%).

Patients with a CPS between 1% and 10% had an ORR of 20% (95% CI, 14%-28%).

KEYNOTE-361 (NCT02853305), a randomized, open-label phase 3 study, was intended to be the confirmatory trial. It explored the use of pembrolizumab in combination with chemotherapy versus pembrolizumab monotherapy or chemotherapy alone as frontline treatment for patients with advanced or metastatic urothelial cancer, and it had dual primary end points of OS and PFS in the combination arm compared with chemotherapy alone. Although benefit was seen for the combination of pembrolizumab and chemotherapy over chemotherapy alone, the benefits did not meet statistical significance, according to a press release from Merck.27

Balar explained that although high PD-L1 expressors had a greater benefit in the KEYNOTE-052 trial, in KEYNOTE-361, high expressors had a similar ORR to the overall study population of approximately 30%, so the benefit was not replicated.

Additionally, as the study was underway, the FDA issued a warning based on an early assessment of the study that suggested pembrolizumab monotherapy was not effective in patients with cisplatin-ineligible locally advanced or metastatic urothelial cancer who have low PD-L1 expression.28

Atezolizumab in Bladder Cancer

The atezolizumab indication for patients with locally advanced or metastatic urothelial carcinoma who are not eligible for cisplatin-containing chemotherapy suffered a similar fate as the pembrolizumab urothelial cancer indication.

Approval for this indication was granted on April 18, 2017, and was also based on findings from a separate cohort (cohort 1) of the IMvigor210 trial.29 In this cohort, the ORR was 24% (95% CI, 16%-32%) with CRs in 8%, and the median DOR was not yet reached. The median OS in this population was 16.3 months (95% CI, 10.4-24.5), with a 1-year OS rate of 58% (95% CI, 49%-67%) and a 2-year OS rate of 41% (95% CI, 32%-50%).30

The phase 3 IMvigor130 trial (NCT02807636) of atezolizumab with chemotherapy, atezolizumab monotherapy, or chemotherapy monotherapy in patients with untreated locally advanced or metastatic urothelial cancer was the confirmatory trial for this indication. However, the FDA warning for single-agent immune checkpoint inhibitors administered in the first-line setting for patients with platinum-ineligible urothelial cancer issued about pembrolizumab also extended to atezolizumab.24 The warning noted that the trial showed a decrease in OS outcomes for patients with low PD-L1 expression receiving atezolizumab monotherapy compared with chemotherapy. As such, the trial was changed so that patients with low expression could no longer be enrolled into the immunotherapy monotherapy arm.

Primary end points for the IMvigor130 trial focused on PFS and OS for the immunotherapy/ chemotherapy combination arm compared with the chemotherapy-alone arm. OS for atezolizumab monotherapy versus chemotherapy alone was only formally tested if the OS was positive for the other comparison.

The immunotherapy/chemotherapy combination actually showed improved outcomes over chemotherapy, leading to a positive trial. Median PFS was 8.2 months (95% CI, 6.5-8.3) with atezolizumab and chemotherapy versus 6.3 months (95% CI, 6.2-7.0) with chemotherapy alone (HR, 0.82; 95% CI, 0.70-0.96; 1-sided P=.007). Median OS was 16.0 months (95% CI, 13.9-18.9) with the combination versus 13.4 months (95% CI, 12.0- 15.2) with chemotherapy alone (HR, 0.83; 95% CI, 0.69-1.00; 1-sided P =.027).31

However, the benefit of the combination did not reflect the approval granted to the monotherapy.

Additionally, Balar commented that unlike in the pembrolizumab situation, patients with high PD-L1 expression in the confirmatory trial had a higher ORR than in the IMvigor210 trial. “PD-L1 is extremely inconsistent,” he stressed.

Pembrolizumab in Gastric Cancer

Three gastrointestinal immunotherapy indications will be reviewed during the third day of the ODAC meeting.

The FDA granted accelerated approval on September 22, 2017, to pembrolizumab for patients with recurrent locally advanced or metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma whose tumors express PD-L1 who experienced disease progression on or after 2 or more prior lines of therapy, including fluoropyrimidine- and platinum-containing chemotherapy and, if appropriate, HER2-targeted therapy.32

Approval was based on findings from KEYNOTE-059 trial (NCT02335411) that explored the use of pembrolizumab in 259 patients with gastric/GEJ adenocarcinoma who had progressive disease after 2 or more prior lines of therapy. Among patients with PD-L1–positive tumors, the ORR was 13.3% (95% CI, 8.2%-20.0%) with a response duration ranging from 2.8+ to 19.4+ months.33

However, the confirmatory randomized, open-label phase 3 KEYNOTE-061 trial (NCT02370498) did not show a benefit for pembrolizumab compared with paclitaxel in patients with PD-L1–positive (CPS ≥ 1) advanced gastric/GEJ cancer that had progressed on first-line chemotherapy with a platinum and fluoropyrimidine. The median OS in the pembrolizumab arm was 9.1 months (95% CI, 6.2- 10.7) versus 8.3 months (95% CI, 7.6-9.0) with paclitaxel (HR, 0.82; 95% CI, 0.66-1.03; 1-sided P = .0421). In terms of PFS, another primary end point of the trial, the medians were 1.5 months (95% CI, 1.4-2.0) with pembrolizumab and 4.1 months (95% CI, 3.1-4.2) with paclitaxel (HR, 1.27; 95% CI, 1.03-1.57).34

The developers then tried to use KEYNOTE-062 (NCT02494583), a randomized, partially blinded phase 3 trial as a new confirmatory trial for the accelerated approval.35 This study randomized 763 patients with untreated, locally advanced, unresectable, or metastatic gastric/GEJ cancer with PD-L1–positive (CPS≥ 1) expression to either pembrolizumab monotherapy, pembrolizumab with chemotherapy, or chemotherapy alone. Pembrolizumab monotherapy showed a similar but noninferior OS to chemotherapy (10.6 vs 11.1 months; HR, 0.91; 99.2% CI, 0.69-1.18) in patients with a CPS of 1 or more. The combination regimen showed a slight improvement over chemotherapy alone in terms of median OS (12.5 vs 11.1 months; HR, 0.85; 95% CI, 0.70-1.03; P = .05).36

Pembrolizumab in Liver Cancer

Pembrolizumab for the treatment of patients with hepatocellular carcinoma (HCC) who have been previously treated with sorafenib (Nexavar) was granted accelerated approval by the FDA on November 9, 2018.37

This indication was supported by findings from the nonrandomized, open-label phase 2 KEYNOTE-224 trial (NCT02702414) of patients with HCC who were previously treated with sorafenib and were either intolerant of the tyrosine kinase inhibitor or had progressed after treatment. The ORR was 17% (95% CI, 11%-26%) among 104 eligible patients, and 1 patient had a CR.38

The pivotal randomized, double-blind phase 3 KEYNOTE-240 trial (NCT02702401), which acted as the confirmatory trial for the accelerated approval, looked at a similar patient population and showed similar response rates to the KEYNOTE-224 trial.

However, the trial did not meet its primary end points of PFS and OS benefit for pembrolizumab and best supportive care (BSC) versus BSC alone, as neither met the threshold for statistical significance.

Median OS in the pembrolizumab arm was 13.9 months (95% CI, 11.6-16.0) versus 10.6 months (95% CI, 8.3-13.5) in the BSC-alone arm (HR, 0.781; 95% CI, 0.611-0.998; P=.0238). The median PFS was 3.0 months (95% CI, 2.8-4.1) and 2.8 months (95% CI, 2.5-4.1) in the pembrolizumab/BSC and BSC arms, respectively (HR, 0.775; 95% CI, 0.609-0.987; P=.0186) at first analysis.39

“The study really did confirm the activity of pembrolizumab. We saw a response rate of 18%, which was very durable,” said lead author Richard S. Finn, MD, on the results of the KEYNOTE-240 trial in an interview with Targeted Therapies in Oncology. “This study clearly showed that pembrolizumab helps a subset of patients and is well tolerated, confirming the safety data. The ‘near miss,’ so to speak, statistically suggests that had the study been designed differently from a statistical standpoint, either [if it had been] larger or not included as many interim analyses or coprimary end points, that very likely we could have hit that statistical end point.”

Finn is professor of medicine in the Department of Medicine, Division of Hematology/ Oncology, at the Geffen School of Medicine and director of the Signal Transduction and Therapeutics Program at the Jonsson Comprehensive Cancer Center at UCLA.

Nivolumab in Liver Cancer

The nivolumab indication was granted accelerated approval by the FDA on September 22, 2017, as a single-agent treatment for patients with HCC previously treated with sorafenib.40

Approval was based on findings from CheckMate040 (NCT01658878), which enrolled 154 patients with HCC and Child-Pugh A cirrhosis who had progressed on or were intolerant to sorafenib. The confirmed ORR was 14.3% (95% CI, 9.2%-20.8%), and 55% of responders had a response that lasted a year or more.

CheckMate 459 (NCT02576509) was intended to be the confirmatory trial, but the primary end point of OS benefit was not met.

The randomized, multicenter phase 3 trial enrolled 743 patients with unresectable, advanced HCC and randomized them to receive either nivolumab or sorafenib as a first-line treatment. The median OS was 16.4 months (95% CI, 13.9-18.4) with nivolumab versus 14.7 months (95% CI, 11.9-17.2) with sorafenib, which did not meet the prespecified threshold for statistical significance (P = .0752).41

However, the ORR was more than double in the nivolumab arm compared with the sorafenib arm, especially among patients with positive PD-L1 expression.

“I would say [the results] confirmed the activity of [nivolumab] in liver cancer. The challenge with CheckMate 459 is that the accelerated approval was given in the second-line setting, but it wasn’t studied in a phase 3 study in the second-line setting,” Finn said.

What This Could Mean for the Future

The 4 indications being voluntarily withdrawn from the market and the 6 other indications with fates yet to be decided encompass 10 indications for immune checkpoint inhibitors to treat patients with solid tumors in first-line through third-line settings. How did this happen?

According to Balar, it was because “we didn’t understand how best to judge the benefits of immunotherapy” at the time.

“I think we had a lot of enthusiasm that [immunotherapy] was going to somehow replace chemotherapy,” he said. “But it was never supposed [to replace chemotherapy]. It is different. It’s fundamentally different. And I think ODACs like this remind us that it is fundamentally very different from chemotherapy.”

Balar compared the difference to a tortoise and hare, with the hare being chemotherapy that shows initial benefit in OS Kaplan-Meier curves but then that benefit slows over time. With immunotherapy, the slow-and-steady tortoise, the benefit is sustained, resulting in a significant tail of the curve and more people showing durable benefit over time compared with chemotherapy.

“I think the general take-home message is: Don’t view these ODACs as an indictment against immunotherapy. It is not. It’s, rather, an opportunity for us to reset our expectations about it,” he said.

Balar said he does not expect any more immunotherapy accelerated approvals to be on the chopping block; however, he does think that as a result of these actions, the design of immunotherapy clinical trials will change going forward. “I think, though, that in terms of future trials, there will no longer be immunotherapy monotherapy in randomized trials in metastatic first line…It’s always going to be combination based,” he said.

Regarding the 6 indications that will be discussed at the upcoming ODAC meeting, both Finn and Balar expressed that they hope immunotherapy will still be available to patients in some of these settings to provide them with more options.

“It’s been really valuable to have [these] options for patients, and from personal experience, our patients are certainly alive today because they’ve had access to those drugs,” said Finn. “Pembrolizumab and nivolumab have accelerated approvals in the second-line setting as does ipilimumab/nivolumab, and I think those will remain options for patients who have not received immunotherapy in the frontline setting. However, there will be an asterisk in the guidelines, so to speak, that they have not met their end points in phase 3 trials.

“Some guidelines might remove [pembrolizumab and nivolumab] completely. Currently, in European guidelines, [pembrolizumab and nivolumab] don’t have high-level recommendations because they’re not approved there, but in the United States, hopefully [these agents] will remain options for patients.”

As to the FDA’s accelerated approval, Balar does not think that this will lead to any significant changes for the program.

“I think the accelerated approval pathway is important, I think we need to maintain it. Personally, I believe that maintaining access to treatment options for patients is important. And I still believe, more broadly, that immunotherapy is still biologically and therapeutically an extremely important advancement in bladder cancer. In that, if you rescind a first-line label, then you’re essentially requiring all patients to have to go through chemotherapy to eventually get access to therapy. And I think if we were to do that, then that would be a major, major step back,” Balar commented.

References:

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2. Accelerated approval. FDA. Updated January 4, 2018. Accessed March 22, 2021. https://bit.ly/3vO6hCZ

3. Gyawali B, Hey SP, Kesselheim AS. Assessment of the clinical benefit of cancer drugs receiving accelerated approval. JAMA Intern Med. 2019;179(7):906-913. doi:10.1001/jamainternmed.2019.0462

4. Bristol Myers Squibb statement on Opdivo (nivolumab) small cell lung cancer US indication. News release. Bristol Myers Squibb. December 29, 2020. Accessed March 22, 2021. https://bit.ly/2X5PVFK

5. FDA grants nivolumab accelerated approval for third-line treatment of metastatic small cell lung cancer. FDA. Updated August 20, 2018. Accessed March 22, 2021. https://bit.ly/3lGENdP

6. Antonia SJ, López-Martin JA, Bendell JC, et al. Nivolumab alone and nivolumab plus ipilimumab in recurrent small-cell lung cancer (CheckMate 032): a multicentre, open-label, phase 1/2 trial. Lancet Oncol. 2016;17(7):883-895. doi:10.1016/S1470-2045(16)30098-5

7. Owonikoko T, Kim HR, Govindan R, et al. Nivolumab (nivo) plus ipilimumab (ipi), nivo, or placebo (pbo) as maintenance therapy in patients (pts) with extensive disease small cell lung cancer (ED-SCLC) after first-line (1L) platinum-based chemotherapy (chemo): Results from the double-blind, randomized phase III CheckMate 451 study. Ann Oncol. 2019;30(suppl 2):II77. doi:10.1093/annonc/mdz094

8. Spigel DR, Vicente D, Ciuleanu TE, et al. Second-line nivolumab in relapsed small-cell lung cancer: CheckMate 331. Ann Oncol. Published online February 1, 2021. doi:10.1016/j.annonc.2021.01.071


9. Voluntary withdrawal of Imfinzi indication in advanced bladder cancer in the US. News release. AstraZeneca. February 22, 2021. Accessed March 22, 2021. https://bit.ly/3dPZimL

10. AstraZeneca’s Imfinzi (durvalumab) receives US FDA accelerated approval for previously treated patients with advanced bladder cancer. News release. AstraZeneca. May 1, 2017. Accessed March 22, 2017. https:// bit.ly/3lI0CtF

11. Powles T, O’Donnell PH, Massard C, et al. Efficacy and safety of durvalumab in locally advanced or metastatic urothelial carcinoma: updated results from a phase 1/2 open-label study. JAMA Oncol. 2017;3(9):e172411. doi:10.1001/jamaoncol.2017.2411

12. Powles T, van der Heijden MS, Castellano D, et al; DANUBE study investigators. Durvalumab alone and durvalumab plus tremelimumab versus chemotherapy in previously untreated patients with unresectable, locally advanced or metastatic urothelial carcinoma (DANUBE): a randomised,open-label, multicentre, phase 3 trial. Lancet Oncol. 2020;21(12):1574- 1588. doi:10.1016/S1470-2045(20)30541-6

13. Merck provides update on Keytruda (pembrolizumab) Indication in metastatic small cell lung cancer in the US. News release. Merck. March 1, 2021. Accessed March 22, 2021. https://bit.ly/3e1ct4j

14. FDA approves pembrolizumab for metastatic small cell lung cancer. FDA. Updated June 18, 2019. Accessed March 22, 2021. https://bit. ly/305roSH

15. Chung HC, Piha-Paul SA, Lopez-Martin J, et al. Pembrolizumab after two or more lines of previous therapy in patients with recurrent or metastatic SCLC: results from the KEYNOTE-028 and KEYNOTE-158 studies. J Thorac Oncol. 2020;15(4):618-627. doi:10.1016/j.jtho.2019.12.109

16. Rudin CM, Awad MM, Navarro A, et al. KEYNOTE-604: Pembrolizumab (pembro) or placebo plus etoposide and platinum (EP) as first-line therapy for extensive-stage (ES) small-cell lung cancer (SCLC). J Clin Oncol. 2020;38(suppl 15):9001. doi:10.1200/JCO.2020.38.15_suppl.9001

17. Roche provides update on Tecentriq US indication in prior-platinum treated metastatic bladder cancer. News release. Roche. March 8, 2021. Accessed March 22, 2021. https://bit.ly/3d5kwe2

18. FDA approves new, targeted treatment for bladder cancer. News release. FDA. May 18, 2016. March 22, 2021. https://bit.ly/3cTSamU

19. Rosenberg JE, Hoffman-Censits J, Powles T, et al. Atezolizumab in patients with locally advanced and metastatic urothelial carcinoma who have progressed following treatment with platinum-based chemotherapy: a single-arm, multicentre, phase 2 trial. Lancet. 2016;387(10031):1909-1920. doi:10.1016/S0140-6736(16)00561-4

20. Powles T, Durán I, van der Heijden MS, et al. Atezolizumab versus chemotherapy in patients with platinum-treated locally advanced or metastatic urothelial carcinoma (IMvigor211): a multicentre, open-label, phase 3 randomised controlled trial. Lancet. 2018;391(10122):748-757. doi:10.1016/S0140-6736(17)33297-X

21. FDA approves atezolizumab for PD-L1 positive unresectable locally advanced or metastatic triple-negative breast cancer. FDA. Updated March 18, 2019. Accessed March 31, 2021. https://bit.ly/2Pq5w2A

22. Schmid P, Adams S, Rugo HS, et al; IMpassion130 Trial Investigators. Atezolizumab and nab-paclitaxel in advanced triple-negative breast cancer. N Engl J Med. 2018;379(22):2108-2121. doi:10.1056/NEJMoa1809615

23. Roche provides update on phase III study of Tecentriq in combination with paclitaxel for people with metastatic triple-negative breast cancer. News release. Roche. August 6, 2020. Accessed March 31, 2021. https:// bit.ly/31GviSM

24. FDA alerts health care professionals and oncology clinical investigators about efficacy and potential safety concerns with atezolizumab in combination with paclitaxel for treatment of breast cancer. FDA. September 8, 2020. Accessed March 31, 2021. https://bit.ly/31CRm0v

25. FDA approves Merck’s Keytruda (pembrolizumab) for certain patients with locally advanced or metastatic urothelial carcinoma, a type of bladder cancer. News release. Merck. May 18, 2017. Accessed March 31, 2021. https://bit.ly/31LSOO9

26. Balar AV, Castellano D, O’Donnell PH, et al. First-line pembrolizumab in cisplatin-ineligible patients with locally advanced and unresectable or metastatic urothelial cancer (KEYNOTE-052): a multicentre, single-arm, phase 2 study. Lancet Oncol. 2017;18(11):1483-1492. doi:10.1016/ s1470-2045(17)30616-2

27. Merck provides update on phase 3 KEYNOTE-361 trial evaluating Keytruda (pembrolizumab) as monotherapy and in combination with chemotherapy in patients with advanced or metastatic urothelial carcinoma. News release. Merck. June 9, 2020. Accessed March 31, 2021. https:// bit.ly/2Pq9Tuw

28. FDA limits the use of Tecentriq and Keytruda for some urothelial cancer patients. FDA. Updated July 5, 2018. Accessed March 31, 2021. https://bit.ly/3cJP3PL

29. FDA grants Roche’s Tecentriq (atezolizumab) accelerated approval as initial treatment for certain people with advanced bladder cancer. News release. Roche. April 18, 2017. Accessed March 31, 2021. https://bit. ly/3cHXQ4z

30. Balar AV, Dreicer R, Loriot Y, et al. Atezolizumab (atezo) in first-line cisplatin-ineligible or platinum-treated locally advanced or metastatic urothelial cancer (mUC): long-term efficacy from phase 2 study IMvigor210. J Clin Oncol. 2018;36(suppl 15):4523. doi:10.1200/JCO.2018.36.15_suppl.4523

31. Galsky MD, Arija JÁA, Bamias A, et al; IMvigor130 Study Group. Atezolizumab with or without chemotherapy in metastatic urothelial cancer (IMvigor130): a multicentre, randomised, placebo-controlled phase 3 trial. Lancet. 2020;395(10236):1547-1557. doi:10.1016/S0140- 6736(20)30230-0

32. FDA grants accelerated approval to pembrolizumab for advanced gastric cancer. FDA. Updated September 22, 2017. Accessed March 31, 2021. https://bit.ly/2OhI07B

33. Fuchs CS, Doi T, Jang RW, et al. Safety and efficacy of pembrolizumab monotherapy in patients with previously treated advanced gastric and gastroesophageal junction cancer: phase 2 clinical KEYNOTE-059 trial. JAMA Oncol. 2018;4(5):e180013. doi:10.1001/jamaoncol.2018.0013

34. Shitara K, Özgüroğlu M, Bang YJ, et al; KEYNOTE-061 Investigators. Pembrolizumab versus paclitaxel for previously treated, advanced gastric or gastro-oesophageal junction cancer (KEYNOTE-061): a randomised, open-label, controlled, phase 3 trial. Lancet. 2018;392(10142):123-133. doi:10.1016/S0140-6736(18)31257-1

35. Merck provides update on phase 3 KEYNOTE-062 trial evaluating Keytruda (pembrolizumab) as monotherapy and in combination with chemotherapy for first-line treatment of patients with advanced gastric or gastroesophageal junction adenocarcinoma. News release. Merck. April 25, 2019. Accessed March 31, 2021. https://bit.ly/3sLJCpd

36. Shitara K, Van Cutsem E, Bang YJ, et al. Efficacy and safety of pembrolizumab or pembrolizumab plus chemotherapy vs chemotherapy alone for patients with first-line, advanced gastric cancer: the KEYNOTE-062 phase 3 randomized clinical trial. JAMA Oncol. 2020;6(10):1571-1580. doi:10.1001/jamaoncol.2020.3370

37. FDA grants accelerated approval to pembrolizumab for hepatocellular carcinoma. FDA. Updated December 14, 2018. Accessed April 1, 2021. https://bit.ly/3sYzYiM

38. Zhu AX, Finn RS, Edeline J, et al; KEYNOTE-224 investigators. Pembrolizumab in patients with advanced hepatocellular carcinoma previously treated with sorafenib (KEYNOTE-224): a non-randomised, open-label phase 2 trial. Lancet Oncol. 2018;19(7):940-952. doi:10.1016/S1470- 2045(18)30351-6

39. Finn RS, Ryoo BY, Merle P, et al; KEYNOTE-240 investigators. Pembrolizumab as second-line therapy in patients with advanced hepatocellular carcinoma in KEYNOTE-240: a randomized, double-blind, phase III trial. J Clin Oncol. 2020;38(3):193-202. doi:10.1200/JCO.19.01307

40. FDA grants accelerated approval to nivolumab for HCC previously treated with sorafenib. FDA. Updated September 25, 2017. Accessed April 1, 2021. https://bit.ly/31IHPVI

41. Yau T, Park JW, Finn RS, et al. CheckMate 459: a randomized, multi-center phase III study of nivolumab (NIVO) vs sorafenib (SOR) as first-line (1L) treatment in patients (pts) with advanced hepatocellular carcinoma (aHCC). Ann Oncol. 2019;30(suppl 5):v874-v875. doi:10.1093/ annonc/mdz394.029 annonc/mdz394.029