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.

In a 9 to 4 vote, ODAC voted that the benefits of poziotinib do not outweigh its risks for the treatment of patients with 

 exon 20 insertion–mutated non–small cell lung cancer (NSCLC).

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 

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.

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.

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.

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;

 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; 

 = .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; 

 = .0311). The analysis was conducted by a blinded independent review committee after determining that data from 29 patients needed to be reassessed.

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.

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, 

 < .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).

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).

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.

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.

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.

Oncologic Drugs Advisory Committee (ODAC) Meeting. FDA. September 22, 2022. Accessed September 22, 2022. bit.ly/3dFRtlU

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

Le X, Cornelissen R, Garrassino M, et al. Poziotinib in non–small-cell lung cancer harboring 

 exon 20 insertion mutations after prior therapies: ZENITH20-2 trial. 

. 2022;40(7):710-718. doi:10.1200/JCO.21.01323

Oncologic Drugs Advisory Committee (ODAC) Meeting. FDA. September 22, 2022. Accessed September 22, 2022. bit.ly/3dFRtlU

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

Oncologic Drugs Advisory Committee (ODAC) Meeting. FDA. September 23, 2022. Accessed September 23, 2022. bit.ly/3BN1SnC

Briefing document. FDA. Accessed September 23, 2022. bit.ly/3DP2jk5

Meeting of the Oncologic Drugs Advisory Committee (ODAC) day 1. FDA. April 21, 2022. Accessed September 23, 2022. bit.ly/3C9lqE2

Articles

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. 

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

Selpercatinib (Retevmo) was recently approved for 2 new solid tumor indications. The kinase inhibitor was granted regular approval for locally advanced or metastatic 

 fusion–positive non–small cell lung cancer (NSCLC).

 It was also granted accelerated approval for patients with solid tumor harboring a 

Selpercatinib had previously received accelerated for 

-fused NSCLC approval based on initial findings from the phase 1/2 LIBRETTO-001 trial (NCT03157128). Confirmatory data from an additional 172 patients and 18 months of extended follow-up secured the agent’s full approval. Updated findings showed that patients with 

-positive NSCLC achieved a 61% overall response rate (ORR), a complete response rate (CR) 7.3% and a partial response (PR) rate of 54%. In addition, the median duration of response was 28.6 months (95% CI, 20–not estimable [NE]) and 63% achieved a response which lasted for 12 months or longer.

The accelerated approval was supported by findings from the phase 1/2 LIBRETTO-001 trial (NCT03157128), which showed that that the targeted therapy yielded an ORR of 44% (95% CI, 28%-60%) in patients with 

-fusion solid tumors, as well as a 4.9% complete response, and a 39% partial response rate. In this trial, the median duration of responses was 24.5 months (95% CI, 9.2-NE), and 67% of patients achieved a response that lasted for at least 6 months.

Patients who achieved responses included those with pancreatic adenocarcinoma, colorectal cancer, salivary, unknown primary, breast, soft tissue sarcoma, bronchial carcinoid, ovarian, small intestine, and cholangiocarcinoma.

In terms of testing, in the population of patients with NSCLC, 94% of 

-fusions were identified with next-generation sequencing (NGS), 84.6% were confirmed with a tumor sample, 9.3% were found with a blood or plasma sample, 4.0% were detected with FISH, and 1.6% through PCR. In addition, 0.4% had their mutation tested through another method. In solid tumors, 97.6% of 

-fusions were detected via NGS, and 2.4% of these fusions were detected through FISH.

Selpercatinib comes in 40 mg and 80 mg capsules. For patients weighing less than 50 kg, the recommended dose is 120 mg twice a day. For those who are greater than 50 kg, the recommended dose is 160 mg twice a day. If a patient has severe hepatic impairment, they should receive a reduced dose.

Providers should avoid coadministering with acid-reducing agents, strong and moderate CYP3A inhibitors or inducers, CYP2C8 and CYP3A substrates, and certain P-gp substrates. If acid-reducing agents are necessary, then selpercatinib should be taken with food and the administration time should be modified. If strong or moderate CYP3A inhibitors cannot be avoided, the selpercatinib dose should be reduced. If a patient required CYP2C8 and CYP3A substrates, or P-gp substrates, the substrate dosages should be reduced, as recommended in their product labeling.

There are no contraindications, however, the agent comes with warnings for hepatotoxicity, interstitial lung disease (ILD), hypertension, hemorrhagic events, hypersensitivity, tumor lysis syndrome, hypothyroidism, and risk of impaired wound healing. The drug also increases the risk for embryo-fetal toxicities.

For hepatotoxicity risk, the label advice monitoring alanine aminotransferase (ALT) and aspartate aminotransferase (AST), prior to initiation selpercatinib and monitoring every 2 weeks during the first 3 months, followed by monthly monitoring as necessary.

Patients with uncontrolled hypertension should not initiate selpercatinib. All patients should have their blood pressure optimized prior to starting treatment and should be monitored at their first week of treatment and monthly thereafter. Thyroid function should also be assessed at baseline and periodically throughout treatment.

Patients should be evaluated for QT interval, electrolytes and thyroid stimulating hormone at baseline, and periodically throughout treatment. If patients require concomitant treatment with strong and moderate CYP3A inhibitors, minoring should be even more frequent.

Because selpercatinib increases the risk of impaired wound healing, it should be withheld for at least 7 days prior to elective surgery. Following major surgery, patients should not receive this agent for at least 2 weeks and until their wounds have adequately healed. The safety of agent resumption following wound healing complications are not yet established.

In addition, if a patient developed hypersensitivity, the agent should be withheld, and corticosteroids should be initiated. Upon resolution, treatment should be resumed at a reduce dose and increased by 1 dose level each week until the dose is the same as it was prior to the onset of the reaction. Once the target dose has been reached, tapering can begin.

Based on the severity of possible hepatotoxicity, ILD, hypertension, or QT interval prolongation, the agent should be withheld, dose reduced, or permanently; discontinued.

The most common any-grade adverse events associated with selpercatinib include edema, diarrhea, fatigue, dry mouth, hypertension, abdominal pain, constipation, rash, nausea, and headache. The most common grade 3 or 4 laboratory abnormalities include decreased lymphocytes, increased ALT, increased AST, decreased sodium, and decreased calcium.

FDA approves selpercatinib for locally advanced or metastatic RET fusion-positive non-small cell lung cancer. News release. FDA. September 21, 2022. Accessed September 21, 2022. 

FDA approves first therapy for patients with lung and thyroid cancers with a certain genetic mutation or fusion. News release. FDA. May 8, 2020. Accessed September 21, 2022. 

FDA approves selpercatinib for locally advanced or metastatic RET fusion-positive solid tumors. News release. FDA. September 21, 2022. Accessed September 21, 2022. 

Retevmo. Prescribing information. Eli Lilly and Company; 2022. Accessed September 21, 2022. 

Selpercatinib was approved by the FDA for RET fusion–positive non–small cell lung cancer and locally advanced or metastatic RET fusion–positive solid tumors. 

Selpercatinib Is Approved for 2 RET Fusion–Positive Solid Tumors, Non–Small Cell Lung Cancer

Progression-free survival (PFS) rates were doubled in patients receiving sotorasib (Lumakras) for 

 G12C–mutated non–small cell lung cancer (NSCLC) compared with patients receiving docetaxel. In addition, patients receiving sotorasib also experienced a significant reduction in the risk of progression or death, according to data from the phase 3 CodeBreak 200 trial (NCT04303780), presented at the 2022 ESMO Congress.

At a median follow-up of 17.7 months, the 12-month PFS rate was 24.8% with sotorasib compared with 10.1% with docetaxel. Median PFS was 5.6 months (95% CI, 4.3-7.8) with sotorasib vs 4.5 months (95% CI, 3.0-5.7) with docetaxel (HR, 0.66; 95% CI, 0.51-0.86; 

 = .002). There were fewer grade 3 or greater treatment-related adverse effects (TRAEs) with the KRAS G12C inhibitor compared with chemotherapy (33.1% vs 40.4%, respectively). Additionally, serious adverse events were less common with sotorasib vs docetaxel (10.7% vs 22.5%).

“The PFS rate doubled and the PFS benefit was seen across all subgroups tested. Likewise, the secondary end points of objective response rate [ORR], disease control rate [DCR], time to response, and duration of response were all significantly improved in favor of sotorasib,” said study author Melissa L. Johnson, MD, director, Lung Cancer Research Program, Sarah Cannon Research Institute. “In my opinion, this supports sotorasib as a new second-line standard for patients with 

 (NCT03600883), the FDA granted sotorasib an 

 G12C–mutated locally advanced or metastatic NSCLC. In this study, the ORR was 36% (95% CI, 28%-45%) for a median duration of 10 months.

The global phase 3 CodeBreaK 200 study enrolled 345 patients with locally advanced, unresectable, or metastatic 

 G12C–mutated NSCLC. The study was originally designed to enroll 650 participants but was reduced to approximately 330, based on guidance from the FDA. The agency requested that patients on the docetaxel arm be able to crossover to receive sotorasib following disease progression. This shift maintained the statistical power for the primary end point of PFS but underpowered the trial to show a statistical difference in overall survival, which was a secondary end point.

“The trial was initially twice as big and when the CodeBreaK 100 data read out the FDA suggested strongly that the trial be amended to reduce the number of patients enrolled by half, so it would decrease the number of patients randomized to docetaxel,” Johnson said.

For the study, patients were randomized to receive either oral sotorasib at 960 mg per day (n = 171) or intravenous (IV) docetaxel at 75 mg/m2 every 3 weeks (n = 174). All patients had received prior platinum-based chemotherapy and a checkpoint inhibitor either concurrently or sequentially. Patients with active brain metastases were excluded from the study, although a history of brain metastases was allowed, Johnson noted.

The ORR with sotorasib was 28.1% (95% CI, 21.5%-35.4%) compared with 13.2% (95% CI, 8.6%-19.2%) with docetaxel (

 <.001). When also considering patients with stable disease, the overall DCR was 82.5% for sotorasib compared with 60.3% with docetaxel.

“Secondary end points were all significantly improved in favor of sotorasib,” said Johnson. “Response, disease control, time to response, and duration were all positive in favor of sotorasib.”

TRAEs leading to discontinuation were experienced by 9.5% of patients in the sotorasib arm compared with 11.3% with docetaxel. The most common any-grade TRAEs between sotorasib and docetaxel, respectively, were diarrhea (33.7% vs 18.5%), nausea (14.2% vs 19.9%), alanine aminotransferase (ALT) increase (10.1% vs 0%), aspartate aminotransferase (AST) increase (10.1% vs 0%), and fatigue (6.5% vs 25.2%). The most common grade 3 or greater TRAEs with sotorasib were diarrhea (11.8%), ALT increase (7.7%), and AST increase (5.3%).

“In CodeBreaK 100 as well as 200, the safety signals are pretty similar,” Johnson said. “There were 10% to 20% of patients who hit grade 3 [liver toxicity] but it was amenable to dose reduction and dose hold followed by restarting.”

Patient-reported outcomes were improved with sotorasib vs docetaxel, including time to deterioration in global health status, physical function, and cancer-related symptoms. For quality of life, global health status ratings were 6.6 with docetaxel vs 9.3 with sotorasib, representing a 31% reduction in the risk of quality-of-life deterioration with the targeted therapy (HR, 0.69; 95% CI, 0.53-0.91; 

 = .005). Sotorasib also delayed physical functioning deterioration by 31% vs docetaxel (9.4 vs 15.1; HR, 0.69; 95% CI, 0.52-0.92; 

 were also delayed significantly with sotorasib vs docetaxel. There was a 37% reduction in the risk of dyspnea (HR, 0.63; 95% CI, 0.48-0.83; 

 <.001) and the risk of cough worsening was delayed by 45% with sotorasib (HR, 0.55; 95% CI, 0.38-0.80;

 <.001). Chest pain deterioration was numerically delayed with sotorasib, with lower scores seen with docetaxel (27.3 vs 34.9); however, this finding was not statistically significant (HR, 0.84; 95% CI, 0.60-1.18; 

“Sotorasib is oral daily vs IV for docetaxel every 3 weeks. You lose your hair with docetaxel. Patients don’t lose their hair with sotorasib, for example,” Johnson said. “There are a lot of subtle ways this data shows how much better quality of life is for patients [with sotorasib vs docetaxel] and the patient-reported outcomes also show that.”

The phase 1/2 CodeBreaK 101 trial (NCT04185883) continues to enroll patients to explore potential sotorasib combination therapies for solid tumors with 

 G12C mutations. There are also several phase 1/2 studies exploring various sotorasib combinations across settings. Additionally, the phase 3 CodeBreaK 300 trial (NCT05198934) is exploring sotorasib with panitumumab (Vectibix) for patients with 

“We look at [CodeBreaK 200] as the first step. There are more studies ongoing adding other drugs to it,” Johnson said. “It is well tolerated, so it will pair nicely with other drugs inhibiting MAP kinase, EGFR, even PD-L1.”

Johnson ML, de Langen AJ, Waterhouse DM, et al. Sotorasib versus docetaxel for previously treated non-small cell lung cancer with KRAS G12C mutation: CodeBreaK 200 phase III study. 

. 2022;33(suppl 7):LBA10. doi:10.1016/j.annonc.2022.08.051

FDA grants accelerated approval to sotorasib for KRAS G12C mutated NSCLC. FDA. May 28, 2021. Accessed September 12, 2022. https://bit.ly/3De4CwM

Sotorasib doubled the progression-free survival rate in patients with KRAS G12C–mutated non–small cell lung cancer. 

Phase 3 Findings Showcase PFS Benefit with Sotorasib for Patients With KRAS G12C+ NSCLC

A saturated fatty acid diet, but not a high-fiber diet, may be linked to superior outcomes in patients with non–small cell lung cancer (NSCLC) receiving immunotherapy checkpoint blockade (ICB), according to Julie Malo, CCRP.

However, the mechanisms between colon epithelial integrity and immune responses are not well understood and further strategies to use the microbiome as adjuvant therapy are warranted, she added.

Malo, who is a research nurse at the University of Montreal, presented findings from a nurse-led dietary intervention at the 

European Society of Medical Oncology Congress 2022

. Immunotherapy is changing the treatment landscape across oncology, Malo said, adding that this treatment modality has had a particularly significant effect on the treatment of patients with melanoma and NSCLC.

“ICBs are now the standard therapy for a wide variety of [cancers] but are the backbone therapy for patients with NSCLC or melanoma,” she said. “We can see a significant improvement in the survival rate in patients treated with immunotherapy vs those treated with chemotherapy alone.”

For example, findings from Robert et al showed that treatment with nivolumab (Opdivo) prolonged the median survival of patients with melanoma compared with dacarbazine. At a follow-up of 18 months, the median overall survival (OS) with the immunotherapy (n = 210) was not reached compared with 10.8 months (95% CI, 9.3-12.1) with dacarbazine (n = 208). The hazard ratio was 0.42 (99.79% CI, 0.25-0.73; 

Moreover, Reck et al demonstrated that pembrolizumab improved OS for patients with lung cancer. At a follow-up of 72 months, the median OS with immunotherapy was 26.3 months (95% CI, 13.3 to 40.4) vs 13.4 months (95% CI, 9.4-18.3) with chemotherapy. The number of events associated with pembrolizumab (n = 154) was 103 (66.9%) vs 123 (81.5%) with chemotherapy (n = 151; HR, 0.62; 95% CI, 0.48-0.81).

“Despite these improvements in outcomes with ICB, resistance to these treatments is universal,” Malo explained. “Therefore, finding new strategies to increase ICB efficacy or [challenge] ICB resistance is an unmet clinical need.”

According to Malo, literature suggest that the microbiome plays a 

key role in the efficacy of immunotherapy treatments

The intestinal microbiome is the most populated of the different microbiomes in the human body, it is situated in the small intestine and the colon. Here, bacterial colonization occurs in a very gradual and specific way: the intestinal bacteria absorb oxygen and uses it to multiply and promote bacteria growth in anaerobic environment.6

Multiple factors affect the diversity of the microbiome, including where an individual was born, their current geographical location, and genetics. The microbiome increases its diversity through the first 3 to 5 years of an individual’s life, but, once established, remains relatively stable throughout adult life. Only major changes in lifestyle or diet, including the introduction of an antibiotic treatment, will upset the microbiome once it has been established. However, certain changes in the microbial composition can induce the production of toxics and create chronic inflammation. This process is called dysbiosis and it can affect the efficacy of ICB.4

Findings from Derosa et al showed that in a cohort of patients with NSCLC receiving ICB, the median OS among those who were receiving antibiotic therapy was 7.9 months, whereas, among those who were not receiving antibiotic therapy, the median OS was 24.6 months (HR, 4.4; 95% CI, 2.6-7.6;

“In light of all this information, it is important to find ways to modulate the microbiome in order to use it as an adjuvant to ICB treatment,” Malo explained.

Investigators sought to influence the gut microbiome in a noninvasive and natural way. To that end, a team of oncologists, oncology nurses, and nutritionists designed a questionnaire to ask patients about their different dietary habits, including their intake of fruits, vegetables, meat, and alcohol, as well as information about their geographical living environment. The questionnaire therefore offered a global view of their lifestyle habits.

The questionnaire was presented to patients (n = 105) with advanced NSCLC prior to their initiation of their ICB treatment. A 1-hour interview with a research nurse and a 47-question assessment captured information on the intake of 30 different nutrients. Examples of patient questions included if they ate 3 meals per day, if they fasted, if they consumed fresh or canned fruit, salad, vegetables, potatoes, chips, eggs or egg-based recipes, legumes, nuts and seeks, high-fiber breakfast cereals, whole wheat bread, other bread options, or rice.

“Our first finding was that our patients had a fairly homogeneous and relatively poor diet that was lacking variety,” Malo noted, adding that most patients reported that they do not eat bran cereal, oatmeal, or other grains, but almost all of them consume coffee.

Malo J. Impact of diet on immune checkpoint blockade; nurse-directed dietary intervention. Poster presented at: European Society for Medical Oncology Congress 2022; September 9-13, 2022; Paris, France.

Reck M, Rodríguez-Abreu D, Robinson AG, et al. Five-year outcomes with pembrolizumab versus chemotherapy for metastatic non-small-cell lung cancer with PD-L1 tumor proportion score ≥ 50. 

. 2021;39(21):2339-2349. doi:10.1200/JCO.21.00174

Robert C, Long GV, Brady B, et al. Nivolumab in previously untreated melanoma without BRAF mutation. 

. 2015;372(4):320-330. doi:10.1056/NEJMoa1412082

Derosa L, Hellmann MD, Spaziano M, et al. Negative association of antibiotics on clinical activity of immune checkpoint inhibitors in patients with advanced renal cell and non-small-cell lung cancer. 

. 2018;29(6):1437-1444. doi:10.1093/annonc/mdy103

Hanahan D. Hallmarks of cancer: new dimensions. 

. 2022;12(1):31-46. doi:10.1158/2159-8290.CD-21-1059

Clarke G, Sandhu KV, Griffin BT, Dinan TG, Cryan JF, Hyland NP. Gut reactions: breaking down xenobiotic-microbiome interactions. 

. 2019;71(2):198-224. doi:10.1124/pr.118.015768

Julie Malo, CCRP, a research nurse with the University of Montreal, discusses a nurse-directed initiative examining how the gut microbiome affects immune checkpoint blockade responses in patients with non–small cell lung cancer. 

Nurse-Led Research Links Saturate Fatty Acids to Improved Immunotherapy Responses in NSCLC

Cannabinoids are becoming more popular for patients with cancer as a pain management strategy. However, with inconsistent laws across states and federal bodies, it can be difficult for nurses and patients to comfortably discuss cannabinoids and cannabinoid use.

As the public perception and patient success stories with unconventional, alternative, and natural therapeutics shift consumer attitudes, it is important for nurses and their patients to understand the differences in the products and the adverse effects associated with each. According to a study by Butler et al in 2021, nearly half of individuals who participated in a survey who had consumed cannabidiol (CBD) did not disclose use to their health care provider.

“We see a lot of patients who have been trying to talk to us about CBD [cannabidiol], and cannabinoids and THC, [tetrahydrocannabinol]” Karen Hande, PhD(c), DNP, ANP-BC, CNE, FAANP, ANEF, a professor of nursing at Vanderbilt University School of Nursing, said in a presentation during the Oncology Nursing Society Bridge.

Although Hande stated in her presentation that she was no expert in cannabinoids or medical cannabis, her clinical research primarily focuses on helping patients effectively manage their cancer-related pain. Therefore, she has become very interested in cannabis and has dedicated a lot of time and research to best understand the evidence-based data that exists for these products. In her presentation, “Cannabinoids for Patients With Cancer,” Hande discussed the available evidence on CBD and the possible risks, particularly in vulnerable populations.

“I think it’s just important for under us to understand a kind of broad overview about cannabinoids and THC and CBD, because this gives us a better understanding of where the laws come into play,” Hande said. She added, “It took me quite some time to try to understand all the differences and trying to make sure I give the correct information to my patients.”

A key concept for oncology nurses to understand, according to Hande, is the variations of cannabinoids.

Cannabinoids are compounds found in the cannabis plant. These compounds interact with the human endocannabinoid system. The exact relationship still required further understanding.

“Cannabis has many names for [many] strains, and hemp and marijuana are under this big umbrella of cannabis plants; they are all considered to be 1 species: the cannabis sativa plant,” she said. “This is a genus of flowering plants. And these can contain about over 100 phytocannabinoids, [and] they have a wide range of effects on the body in the brain.”

The following products are derived from cannabis: marijuana, hemp, THC, and CBD. In addition, there are man-made synthetic cannabinoids (K2/Spice); however, these agents are designed to mimic the mind-altering effects of illicit drugs. For her talk, Hande chose to focus on the products derived from the plant itself, as oncology nurses are more likely to encounter patients using plant-derived products.

If a patient reports marijuana use, this means they are using the dried flowers, leaves, stems, and seeds of the cannabis plant. Marijuana is also known as cannabis, weed, pot, or dope. Specifically, it can be defined as a plant with at least 0.3% delta-9 THC by weight. It is consumed by smoking (joints, blunts, bongs), vaping (vaporizing electronics devices), or by mixing or infusing it into foods or drinks (edibles).

“This is an important differentiating factor that I’ll be highlighting regularly through this talk,” Hande said during her presentation. “Marijuana is more than 0.3% of THC by weight.”

Marijuana is the most used federally illegal drug in the United States, with approximately 18% of Americans reported using it at least once in 2019 (~48.2 million Americans).1

Because marijuana has THC, it is associated with the following health risks: alterations in memory, learning, attention, decision-making, coordination, emotion, and reaction times.2 In terms of long-term health, marijuana has been linked to an increased risk of psychosis and schizophrenia,3 and, like other drugs, it’s use during pregnancy may increase the risk of embryo-toxicities.4 Moreover, this drug, depending on where it is sourced, may be laced with other substances. Consumers may or may not be aware of other substances in their product.

Using marijuana in combination with other agents may also result in impairment and can increase the risk of overdose.

Federally, marijuana is illegal as a recreational drug. It is classified as a schedule 1 drug, per the Drug Enforcement Agency. Although it is legal in some states for medical for nonmedical adult use, this does not mean that is safe, Hande noted. Specifically, smoking marijuana can expose users to harmful chemicals, and insufficient evidence exists to document the safest method for consuming.

Legally, hemp must contain a THC concentration of less than 0.3% by dry wright. It is the same species of plant as the cannabis plant and, along with bamboo, it is one of the fastest growing plants on Earth. There are almost no restrictions on hundreds of compounds made by the plant. Industrial hemp is cannabis sativa plant grown specifically for industrial or medicinal use.

“Many states across the country have hemp cultivation,” Hande said. “This allows cultivation of hemp from commercial or research or pilot programs. There are only a few states that do not allow cultivation of hemp.”

In 2018, the farm bill legalized the production and sale of hemp and its extracts, removing the product from the controlled substance act. Of note, per federal law, hemp cannot contain greater than 0.3% THC. If the concentration of THC surpasses this measurement, it is classified as marijuana.

As of September 2022, 47 states have enacted legislation to establish hemp production programs or cultivation research.

THC is a compound of the cannabis plant. This psychoactive agent causes, what is known as a high. It is consumed via dabbing—a specific method for inhaling THC concentrates.

Unfortunately, the concentrated forms of THC mean that there is an increased risk of additives or contaminating substances existing in the product.

CBD is another active cannabinoid found in the cannabis plant. This agent is not psychoactive and consequently does not cause a high.

CBD can be derived either directly from the cannabis plant or from a hemp product. The key difference between cannabis- and hemp-derived CBD is the concentration of THC. Hemp-derived CBD must have a THC concentration less than 0.3% to be federally legal. CBD products containing greater concentrations are federally illegal but are legal under some states.

“The main difference between cannabis and hemp-derived CBD is the amount of THC that it can contain,” Hande stressed. “Hemp-derived CBD includes less than 0.3% of the THC. [Therefore,] it’s federally legal to use hemp-derived CBD, but CBD products that contain more than 0.3% of THC are federally illegal. This is where the conflict between the state and the federal laws [can arise].”

The extraction process for CBD and THC are similar; farmers harvest the hemp and it is sent to an extractor. If the extraction is not performed with pharmaceutical grade standards, the CBD may become contaminated with THC, chemical solvents, or even pesticides. This is compounded by the fact that the US does not hold CBD supplies to a standard, and federal enforcement is lacking.

CBD can be converted into delta-8-THC, delta-9 THC, and other THC isomers through a solvent, acid, and heat. These products end up with higher concentrations of delta-8 THC than those which occur naturally in the cannabis plant. Consequently, these products may create harmful by-products that presently are not well-characterized.

Delta-8 THC products are increasing in popularity, in both marijuana- and hemp-based markets. It is appearing in markets that are operating legally under state, territorial, or tribal laws.

As of 2022, most states and territories permit full and restricted marketplaces where consumers can purchase hemp and hemp-derived CBD products.

According to Hande, there are a wide variety of delta-8 THC-containing products in the market. For example, vapes, smokable hemp sprayed with delta-8 THC extract, distillates, tinctures, gummies, chocolates, and even infused beverages can fit into this category. Moreover, the testing method for these products are still under development. This means that Delta-8 THC products may not be systematically tested for contaminants such as heavy metals, solvents, or pesticides which can cause adverse health effects.

How to Talk to Your Patient About Cannabinoid Use

Nurses hold a key role in discussing not only the risks of cannabinoid use but providing educational information for the safe consumption. Should a patient be interested in trying CBD products, counsel on the lack of evidence, contaminants, misleading labels, and legal issues of surrounding use. One approach to counter the “buyer beware” notion is to provide evidence-based patient education and to screen for any drug/drug interactions that may occur should the patient consume CBD products.

Additionally, assessing the patient’s baseline knowledge base before use will be beneficial and open communication may help establish trust and increase reported use between the patient and the health care provider. Finally, addressing the topic early on in care may remove the barrier of the stigma surrounding cannabinoid use.

Hande concluded by adding that many trials are ongoing in the cannabinoid arena and that results are expected to be published over the next several years. She noted that the oncology nurses should be up-to-date on the latest findings to provide guidance.

Marijuana and public health data and statistics. Centers for Disease Control and Prevention. June 8, 2021. Accessed September 14, 2022. bit.ly/3ROqaoi

Testai FD, Gorelick PB, Aparicio HJ, et al. Use of marijuana: effect on brain health: a scientific statement from the American Heart Association. 

. 2022;53(4):e176-e187. doi:10.1161/STR.0000000000000396

Di Forti M, Quattrone D, Freeman TP, et al. The contribution of cannabis use to variation in the incidence of psychotic disorder across Europe (EU-GEI): a multicentre case-control study. 

. 2019;6(5):427-436. doi:10.1016/S2215-0366(19)30048-3

Health effects of marijuana and cannabis-derived products presented in new report. National Academies. January 12, 2017. Accessed September 14, 2022. 

Karen Hande, PhD(c), DNP, ANP-BC, CNE, FAANP, ANEF, explains the difference between some of the popular cannabinoid products that patients with cancer may be taking.

Oncology Nurses: What Cannabinoid Is Your Patient Taking?

® spoke with Christine Miaskowski, PhD, RN

professor in the Department of Physiological Nursing and Anesthesia at UCSF School of Nursing. Miaskowski discusses results from research which showcases an increased risk of hearing loss among patients who received platinum- or taxane-based cancer treatments. She also discusses the importance of including hearing assessments as a standard of care for survivors.

Top takeaways from the discussion include:

“When we did audio metrically confirmed hearing loss [assessments], we found that between 50% to 70% of survivors had confirmed hearing loss.” 

“It’s really, very surprising because it is a group of patients with very common cancers: breast, lung, gynecologic and GI [gastrointestinal] malignancies.” 

“The good news is that the type of hearing loss these patients experience is amenable to a hearing aid. So, if we can get people tested, and they demonstrate this kind of hearing loss, we can improve their quality of life.” 

“Nurses care about interactions with other people, people’s quality of life, [their] social function… if you've got hearing loss, and you're sitting at a table with people, and you can't hear them, you're not going to be likely to participate.” 

“We don’t even think about [some of] these consequences; in terms of occupation, social gatherings, safety for a child… We really, as nurses, need to be doing something about this.” 

Episode 33: Balancing the Benefit and Toxicity of Cisplatin in Young Children with Cancer

Episode 45: Key Advances in Cancer Survivorship Toxicity Management

Audiological Assessments May Be Vital Component of Cancer Survivorship Care Following Chemotherapy

Hearing Loss Found in Testicular Cancer Survivors After Cisplatin Therapy

In this episode of “The Vitals,” Christine Miaskowski, PhD, RN, discusses research showcasing that adult patients receiving either a platinum-based chemotherapy, taxane alone, or a combined regimen of platinum- and taxane-based treatment may be at risk of hearing loss. 

Lung Cancer

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

Selpercatinib Is Approved for 2 RET Fusion–Positive Solid Tumors, Non–Small Cell Lung Cancer

Phase 3 Findings Showcase PFS Benefit with Sotorasib for Patients With KRAS G12C+ NSCLC

Nurse-Led Research Links Saturate Fatty Acids to Improved Immunotherapy Responses in NSCLC

Oncology Nurses: What Cannabinoid Is Your Patient Taking?

Are Hearing Tests Necessary For Adult Cancer Survivors?

Goodwin Provides Nursing Perspective on Recent FDA Approvals in NSCLC

Better End-of-Life Options Are Needed for AYA Patients With Advanced Cancer

Integration of Sexual Health Considerations Into Thoracic Oncology Care Is Critical

Gefitinib Plus Chemotherapy Proves Effective in EGFR-Mutated Non–Small Cell Lung Cancer