ODAC Committee Votes Against Upholding 3 Indications in Lung and Hematologic Malignancies

On September 22 and 23, 2022, the FDA’s Oncologic Drugs Advisory Committee (ODAC) convened for a hearing to assess the risk-benefit ratio of 3 agents.

On September 22 and 23, 2022, the FDA’s Oncologic Drugs Advisory Committee (ODAC) convened for a hearing to assess the risk-benefit ratio of 3 agents. First, data supporting the new drug application (NDA) for poziotinib tablets was evaluated against available agents. Second, confirmatory and requested post marketing data for the continued approval of indications for melphalan flufenamide (Pepaxto) and duvelisib (Copiktra), respectively, were assessed. After deliberation, the participants on each of the ODAC panels voted against indications for all 3 treatments.

Poziotinib for HER2 Exon 20 Insertion–Mutated NSCLC

In a 9 to 4 vote, ODAC voted that the benefits of poziotinib do not outweigh its risks for the treatment of patients with HER2 exon 20 insertion–mutated non–small cell lung cancer (NSCLC).1

In explaining his decision, mirroring many of those who also voted no, Scott Waldman, MD, PhD, of Thomas Jefferson University, in Philadelphia, Pennsylvania said, “Clearly there’s a clinical unmet need for the drug, and the drug has activity, but I don’t know that it has a meaningful improvement over other drugs that, in the real world, are available to patients right now.

Waldman added that the agent has a high level of toxicities associated with it which can be managed, but it is complicated by the fact that the dose of the drug has not been adequately optimized. “That uncertainty is going to be carried through into the potential confirmatory trial, which has an end point that is far away,” he said. “[Moreover,] these patients are at risk for toxicity and [the trial] isn’t studying the same dose that’s seeking approval right now.” Waldman is the Samuel M.V. Hamilton Professor of Medicine, a professor in the Department of Biochemistry and Molecular Biology, chair of the Department of Pharmacology & Experimental Therapeutics, and director of the MD/PhD program at Jefferson.

On February 14, 2022, the FDA accepted for review an NDA seeking the approval of poziotinib in previously treated patients with locally advanced or metastatic NSCLC with HER2 exon 20 insertion mutations.2

The NDA was based on findings from cohort 2 of the phase 2 ZENITH20 trial (NCT03318939), in which poziotinib, given at a once-daily dose of 16 mg, led to an objective response rate (ORR) of 27.8% (95% CI, 18.9%-38.2%) in this population (n = 90).The median duration of response (DOR) was 5.1 months (95% CI, 4.2-5.5), and the median progression-free survival (PFS) was 5.5 months (95% CI, 3.9-5.8).

ODAC reviewed efficacy results that failed to show improvements over current therapy, a high rate of toxicity, inadequate dosage optimization, and delayed confirmation of benefit with the tyrosine kinase inhibitor (TKI).

In their rebuttal, the sponsor stated that the confirmatory phase 3 PINNACLE trial (NCT05378763) is ongoing. However, committee members emphasized concern that the availability of other agents, including docetaxel with or without ramucirumab (Cyramza), pembrolizumab (Keytruda)/nivolumab (Opdivo), and off-label fam-trastuzumab deruxtecan-nxki (Enhertu) could negatively affect enrollment. The sponsor acknowledged that the study has yet to enroll any patients, and primary results are not expected until 2026.1

Regarding safety, all patients experienced adverse effects (AEs); 81% were treatment related and grade 3 or greater in severity (grade ≥ 3 rash, 49%; grade ≥ 3 diarrhea, 26%). Fatal AEs occurred in 10% of patients, and drug interruption and dose reduction occurred in 87% and 77% of patients, respectively.3

Members in support of the approval argued that clinicians have experience and are comfortable managing the AEs associated with TKIs.

Continued Approval of Melphalan Flufenamide in Relapsed/Refractory Multiple Myeloma

In a 14 to 2 vote, ODAC voted that the benefit-risk profile of melphalan flufenamide is not favorable for the approved indicated population of patients with relapsed/refractory multiple myeloma.4

Committee member Christopher Lieu, MD, said, “I voted no. Post hoc analysis really should be used for hypothesis generation as opposed to labeling and indication for use. There’s certainly a need for better drugs…but we shouldn’t be using drugs that might be harming patients. To me, the answer is simple. You have an analysis which may support the use in a specified patient population that could show a benefit, and a confirmatory study should be performed in this population, but the data do not support the use of this agent.” Lieu is an associate professor, associate director for clinical research, and codirector of Gastrointestinal Medical Oncology at the University of Colorado Cancer Center.

The agent received accelerated approval for use in combination with dexamethasone in 2021;5 however, data from the confirmatory phase 3 OCEAN trial (NCT03151811) did not meet the primary or secondary end points of improved PFS and overall survival (OS) vs pomalidomide (Pomalyst) and dexamethasone according to FDA standards.

In the meeting, committee members reviewed the benefit-risk ratio of melphalan flufenamide for patients with relapsed or refractory multiple myeloma who have received at least 4 prior lines of therapy and whose disease is refractory to at least 1 proteasome inhibitor, 1 immunomodulatory agent, and 1 CD38-directed monoclonal antibody.

The regulatory agency based its concerns for continued approval on the potential detriment in OS, failure to demonstrate PFS improvement, and lack of an appropriate dose with the alkylating cytotoxic agent.

Preliminary results from the trial showed that the median OS was 19.7 months (95% CI, 15.1-25.6) with melphalan flufenamide/dexamethasone vs 25.0 months (95% CI, 18.1-31.9) with pomalidomide/dexamethasone (HR, 1.104; 95% CI, 0.846-1.441), highlighting a detriment in survival in the investigative arm vs the control arm.

Updated results showed a continued detriment in OS, with a median OS of 20.2 months (95% CI, 15.8-24.3) with melphalan flufenamide vs 24.0 months (95% CI, 19.1-28.7) with pomalidomide (HR, 1.144; 95% CI, 0.913-1.435).

Although the drug developer, Oncopeptides, showed data illustrating that the OS results could have been adversely affected by patients with a time to progression within 36 months of transplant, the FDA contended that subgroups were not prospectively included in the statistical analysis plan with control of Type I error, and subgroup analyses cannot be used to conclude a treatment benefit in a subpopulation––in this case, patients without autologous stem cell transplant (ASCT) or post-ASCT progression after 36 months.

Notably, the FDA encouraged Oncopeptides to pursue a prospective trial in this population to confirm the potential benefit therein.

Additionally, the FDA showed that the median PFS in the primary analysis was 6.9 months (95% CI, 5.1-8.5) with melphalan flufenamide/dexamethasone vs 4.9 months (95% CI, 4.2-5.9) with pomalidomide/dexamethasone, failing to demonstrate statistical superiority (HR, 0.817; 95% CI, 0.659-1.012; P = .0644). Oncopeptides asserted that updated findings showed that treatment with melphalan flufenamide was superior to pomalidomide regarding PFS in this population (HR, 0.792; 95% CI, 0.640-0.979; P = .0311). The analysis was conducted by a blinded independent review committee after determining that data from 29 patients needed to be reassessed.4

However, the FDA maintained that the trial failed to demonstrate PFS benefit and further emphasized that worse OS negates any real or perceived PFS improvement.

The final point was that the fixed 40-mg dose evaluated in the trial was poorly tolerated and led to high rates of dose modification. Specifically, 78% of patients experienced at least 1 dose modification, 47% experienced at least 1 AE leading to dose reduction, and 26% experienced at least 1 AE leading to drug discontinuation.

Weight or body-sized based dosing may be more appropriate, according to the FDA. “A lower dose may be more tolerable.”

Duvelisib Loses Support for CLL/SLL Indication

In an 8 to 4 vote, ODAC voted that the final OS data submitted did not demonstrate a strong enough benefit-risk ratio to support the continued approval of duvelisib for the treatment of adult patients with relapsed or refractory chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) after at least 2 prior therapies.1

Top concerns addressed for the continued approval for the highlighted long-term OS data from the phase 3 DUO trial (NCT02004522), which showed a higher rate of deaths with duvelisib vs ofatumumab (Kesimpta), a higher rate of fatal AEs attributed to infection, and an OS detriment in the setting of PFS and ORR.

“All of us feel that this is a complex situation just by virtue of the design of the clinical trial,” Jorge A. Garcia, MD, FACP, chair of the ODAC meeting said prior to the vote. “Some of the themes of our discussion relate to our inability to use the clinical trial design to really determine the true detrimental outcome of patients receiving duvelisib and that related to the compounding effect of crossover.” Garcia is a professor of medicine and urology at Case Western Reserve University School of Medicine in Cleland, Ohio. He is also the George and Edith Richman Distinguished Scientist Chair and chair of the Solid Tumor Oncology Division at University Hospitals Seidman Cancer Center.

He added that it is hard to look at these data in the absence of the clinical data available for other PI3K inhibitors and the class effects in the diseases which are chronic in nature that have a long natural history.

Commenting on his vote no, Christopher Lieu, MD, said, “I thought these data were extremely difficult to interpret, but in agreement with [other no votes] I have concerns about this class of medication. If we are not clearly improving OS in our patients but we are increasing toxicity and treatment-associated death, I’m not sure that we are truly helping patients.”

The initial application, submitted by Secura Bio Inc, was approved in 2018 based on data DUO, which evaluated duvelisib vs ofatumumab in 319 adults with CLL or SLL after at least 1 prior therapy. In data supporting the application, the median PFS in the intention-to-treat (ITT) population was 13.3 months (95% CI, 12.1-16.8) vs 9.9 months (95% CI, 9.2, 11.3) with duvelisib and ofatumumab, respectively (HR, 0.52; 95% CI, 0.39-0.69, P < .0001). The ORR in the duvelisib arm (n = 160) was 73.8% (95% CI, 66.9%-80.6%) vs 45.3% (95% CI, 37.5%-53.0%) in the ofatumumab arm (n = 159).6

At the time of approval, the median OS data were immature with a median of 24 months of follow-up, and the OS was not reached in either arm in the indicated population (HR, 0.82; 95% CI, 0.49-1.37).6

Reports of substantial toxicity including fatal AEs led the FDA to issue a box warning to address the toxicities and a postmarketing requirement was issued to Secura Bio Inc requesting 5-year follow-up data for OS. The identified safety concerns included serious or fatal infections, diarrhea or colitis, rash, pneumonitis, hepatotoxicity, and neutropenia.7,8

Five-year OS follow-up data from the DUO trial were submitted in June 2021 with a data cutoff of January 22, 2021.

The median OS in the ITT population was 52.3 months (95% CI, 41.8-68.0) in the duvelisib arm vs 63.3 months (95% CI, 41.2–not estimable) in the ofatumumab arm (HR, 1.09; 95% CI, 0.79-1.51). This detriment extended to the indicated population with a median OS of 43.9 months (95% CI, 32.4-56.5) among patients who received duvelisib after 2 or more prior lines of therapy (n = 95) vs 46.8 (95% CI, 28.6-74.9) among those who received ofatumumab (n = 101; HR, 1.06; 95% CI, 0.71-1.58).

The updated median PFS in the ITT duvelisib arm was 17.85 months (95% CI, 15.16-22.59) vs 9.47 months (95% CI, 9.14-11.14) in the ofatumumab arm (HR, 0.40; 95% CI, 0.27-0.59).

Safety data also signaled a higher rate of death in duvelisib-treated population vs ofatumumab-treated population. In the ITT analysis 23 deaths were reported, 13 of which were among patients with 2 or more prior lines of therapy in the duvelisib cohort. In the ofatumumab population, 5 deaths occurred overall and 4 were in the indicated population. Infection was the primary cause of death in the duvelisib arm accounting for 14 events. One patient died of infection due to ofatumumab treatment.7

Following this analysis, the FDA issued a safety alert in June 2022 intended to alert patients and health care providers of the potential risk of continued use of duvelisib.

Of note, crossover upon disease progression was permitted in the DUO trial. Ninety patients (57%) crossed over from the ofatumumab arm to the duvelisib arm compared with 9 patients (6%) from duvelisib to ofatumumab upon disease progression.

A sensitivity analysis was performed and demonstrated consistent potential OS detriment with the primary analysis. Further, most subgroups also reported an OS detriment with duvelisib, but for those that did not (ie, those who were refractory or had early relapse to purine treatment) would require more substantial analysis.


  1. Oncologic Drugs Advisory Committee (ODAC) Meeting. FDA. September 22, 2022. Accessed September 22, 2022. bit.ly/3dFRtlU
  2. Spectrum Pharmaceuticals announces acceptance of new drug application filing for poziotinib. News release. Spectrum Pharmaceuticals; February 11, 2022. Accessed September 22, 2022. bit.ly/3gGReox
  3. Le X, Cornelissen R, Garrassino M, et al. Poziotinib in non–small-cell lung cancer harboring HER2 exon 20 insertion mutations after prior therapies: ZENITH20-2 trial. J Clin Oncol. 2022;40(7):710-718. doi:10.1200/JCO.21.01323
  4. Oncologic Drugs Advisory Committee (ODAC) Meeting. FDA. September 22, 2022. Accessed September 22, 2022. bit.ly/3dFRtlU
  5. FDA grants accelerated approval to melphalan flufenamide for relapsed or refractory multiple myeloma. FDA. Updated March 1, 2022. Accessed September 22, 2022. bit.ly/3OZIxEz
  6. Oncologic Drugs Advisory Committee (ODAC) Meeting. FDA. September 23, 2022. Accessed September 23, 2022. bit.ly/3BN1SnC
  7. Briefing document. FDA. Accessed September 23, 2022. bit.ly/3DP2jk5
  8. Meeting of the Oncologic Drugs Advisory Committee (ODAC) day 1. FDA. April 21, 2022. Accessed September 23, 2022. bit.ly/3C9lqE2