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Cytotoxic chemotherapy can cause significant and sometimes prolonged neutropenia, often increasing the risk of hospitalization and life-threatening infections. To reduce the risk of these complications, which can lead to poor outcomes, prophylactic granulocyte colony-stimulating factors (G-CSFs) are used, but these agents can be burdensome to administer and have toxicities such as bone pain that can affect patients’ quality of life. A novel agent has emerged that shows promise in addressing these challenges: a selective immunomodulating microtubule-binding agent (SIMBA) called plinabulin. “Not only does it affect progenitors that can affect the blood counts, but it may also have an anticancer effect,” William J. Gradishar, MD, said during a recent 

Gradishar was joined by a panel of breast cancer experts who discussed plinabulin, including some promising data from several clinical trials, including the pivotal phase 3 PROTECTIVE-2 trial (NCT03294577).

 “It would be nice to give all the medication on the same day and have good control without worrying about a drug not working or how many doses of short-acting growth factor to give and when,” said Hope S. Rugo, MD, FASCO. Based on the positive data, plinabulin was under review with the FDA at the time of the Peer Exchange; however, the FDA recently issued a complete response letter (CRL) requesting an additional trial before the agent could be approved for chemotherapy-induced neutropenia (CIN).

In addition to reviewing plinabulin, the panelists briefly discussed several other novel chemoprotective therapies under exploration, including trilaciclib (Cosela), which was recently approved to reduce chemotherapy-induced bone marrow suppression in patients with extensive-stage small cell lung cancer (SCLS).

On December 1, 2021, the FDA issued a CRL to BeyondSpring Pharmaceuticals’ new drug application (NDA) for approval of plinabulin in combination with G-CSF to prevent CIN.

The CRL indicated that the results of PROTECTIVE-2 were “not sufficiently robust to demonstrate benefit and that a second well-controlled trial would be required to satisfy the substantial evidence requirement to support the CIN indication.” The rejection was surprising and it has been reported that it may have resulted from an early miscommunication between BeyondSpring and the FDA.

 Although the NDA focused on data from the phase 3 PROTECTIVE-2 trial, it also included data from 5 supportive trials that collectively enrolled over 1200 patients; however, the FDA considered only the phase 3 data and deemed it insufficient. In contrast, BeyondSpring anticipated that all included data would be considered.

In a news release announcing the FDA’s decision, BeyondSpring did not commit to a second study but said it “expects to work closely with the FDA to consider the possible future clinical pathway for CIN, which may include a second study.”

 Analysts anticipate that a meeting between BeyondSpring and the FDA will occur early next year.

 Discussions to file a new application for approval in non–small cell lung cancer (NSCLC) are also planned based on data from the DUBLIN-3 trial (NCT02504489).

Plinabulin is a SIMBA, which is a potent antigen-presenting cell inducer.

 “Not only is it capable of potentially preventing the deep neutropenia that we see in some patients, but it also may have an effect on the immune system,” Gradishar said. He explained that plinabulin binds to microtubules and releases the protein GEF-H1, activating the signaling pathway. Once that pathway is activated, there is a maturation of dendritic cells, which then present the antigen to the T cells, leading to their activation.

“Before we had the acronym SIMBA, we were focusing more on the properties that affected blood counts, specifically, the intensity and depth of neutropenia. In one of the clinical trials [it was] suggested that there was indeed an antitumor effect, which broadened the acronym to take that into account,” he said.

Because of plinabulin’s dual action in prevent-ing neutropenia and potentially exerting antitumor effects, the panelists expressed interest in learning how this agent may interact with certain anticancer treatments down the road, particularly checkpoint inhibitors. “It’s so fascinating that a drug that’s been developed for neutropenia could also have other effects that could potentially affect the efficacy of the agents that we’re using by helping the immune system recognize tumor cells,” Rita Nanda, MD, said.

Plinabulin is given as a single dose per chemo-therapy cycle via a 30-minute intravenous (IV) infusion. It is administered on the same day, 30 minutes after the chemotherapy dose.

The panelists’ discussion focused on 3 trials that evaluated plinabulin: the phase 2/3 PROTECTIVE-1 trial (NCT03102606),

PROTECTIVE-1 is a global, multicenter, double-blind trial that randomly assigned 105 patients with breast, lung (NSCLC), or hormone-refractory prostate cancer 1:1 to receive 4 cycles of docetaxel 75 mg/m

 plus placebo on day 1 and pegfilgrastim 6 mg on day 2 (n = 53) or docetaxel 75 mg/m

 plus plinabulin 40 mg on day 1 and placebo on day 2 (n = 52).

 “The small study was designed as a noninferiority trial to look at days of severe neutropenia, and built into the trial were almost daily CBCs [complete blood counts] and tracking of the neutrophil count,” Tiffany A. Traina, MD, said.

The study met its primary end point, with significantly fewer days of neutropenia in the plinabulin arm vs the pegfilgrastim arm. Severe neutropenia was defined as absolute neutrophil count of less than 0.5 cells × 109/L. The mean duration of severe neutropenia (DSN) in cycle 1 was 0.246 days in the pegfilgrastim arm (95% CI, 0.205-0.287), compared with 0.770 in the plinabulin arm (95% CI, 0.682-0.857).

 Several secondary end points also favored plinabulin.

Traina said another advantage in the plinabulin arm was significantly less bone pain and less thrombocytopenia. “I don’t know if that was anticipated, but it was observed,” she added. Overall, plinabulin was well tolerated, with a comparable safety profile to pegfilgrastim. Traina noted that the most common adverse effects (AEs) included low-grade infusion reactions and gastrointestinal toxicity, including nausea, diarrhea, and fatigue. “It can be potentially hard to tease out what is related to docetaxel, given that both arms are receiving backbone chemotherapy, but it did appear well tolerated,” Traina said.

Nanda and Gradishar pointed out that the PROTECTIVE-1 study shows several benefits of single-agent plinabulin over single-agent pegfilgrastim. These include its ease of use and reduced risk of thrombocytopenia, which is another major concern with chemotherapy, particularly platinum agents, and a reduction in patients experiencing bone pain. “When we talk about effects of these drugs, we’re usually worried about the pleiotropic effect or the off-target effect, Gradishar said. “What we’re describing here is a drug that is pretty well tolerated, easy to give, and the off-target effects are favorable for the patient regarding neutropenia and a potential anticancer effect. Right now, it looks like a very favorable kind of drug to be using.”

The PROTECTIVE-2 study assessed whether combining plinabulin with pegfilgrastim could be beneficial. “One rationale for putting these 2 agents together, plinabulin plus pegfilgrastim, would be more of the continuous protection against neutropenia throughout that intercycle duration,” Traina said. Data show that plinabulin mainly exerts its CIN preventive effects in week 1 of the cycle when more than 75% of clinical complications occur.

 In contrast, G-CSFs such as pegfilgrastim primarily exert their CIN-preventive effects during week 2 of the cycle.

 “We still get that [absolute neutrophil count] nadir, and then we get quicker recovery,” she said.

PROTECTIVE-2 is a global, multicenter, double-blind trial that randomly assigned 221 patients with ECOG scores of 0 or 1 who were receiving docetaxel 75 mg/m

), a regimen known as TAC, to receive either plinabulin (40 mg) plus pegfilgrastim (6 mg) or pegfilgrastim (6 mg) plus placebo.

 “Lack of grade 4 neutropenia was the primary end point,” Trina said.

She noted that PROTECTIVE-2 met its primary end point. In data presented that the 2021 American Society of Clinical Oncology Annual Meeting, investigators showed that among the 110 patients in the plinabulin/pegfilgrastim arm 31.53% were protected from grade 4 neutropenia vs 13.64% of those treated with pegfilgrastim alone (n = 111) in cycle 1 (

 = .0015). As in PROTECTIVE-1, several secondary end points were clinically meaningful. Febrile neutropenia was observed in 3.60% of patients treated with the combination vs 6.36% of patients treated with pegfilgrastim alone through cycle 4 (

Additionally, when considering cases of profound neutropenia, measured as an absolute neutrophil count of 100 per μL, the combination treatment improved clinical benefit by close to 50%. The median duration of febrile neutropenia with the combination was 1.25 days, compared with 2.28 days with pegfilgrastim alone. The rates of hospitalization were 75% with the combination vs 100% with pegfilgrastim alone and the median duration of hospitalization was 3.75 days vs 7.14 days, respectively. The administration of plinabulin/pegfilgrastim resulted in 2.7% of patients adjusting the chemotherapy dose and/or regimen in later cycles, compared with 6.3% of patients who received pegfilgrastim alone.

Traina said bone pain was also reduced with the combination. Patients who received the combination experienced bone pain at a frequency of 18%, compared with 30% among those who received pegfilgrastim alone (

 “It’s certainly more comfortable for our patients,” Traina said.

Another exciting finding Traina highlighted was that overall incidence of grade 4 events was significantly lower in the combination arm. “Plinabulin plus pegfilgrastim had 20% lower grade 4 adverse events with TAC compared with TAC plus pegfilgrastim. It seems to be having an effect beyond just affecting the neutrophil count,” she said.

Nanda said she has not used TAC in many years, noting that it is a challenging regimen for patients, making any agent that can help with tolerability welcomed. “I think an improvement in quality of life in addition to the reduction of AEs and chemotherapy-induced neutropenia and febrile neutropenia is a home run,” she said, adding that she is interested in seeing whether plinabulin may have benefit in the setting of other difficult-to-tolerate chemotherapy regimens, particularly those used in patients with early-stage triple-negative breast cancer.

DUBLIN-3 is a phase 3, global, randomized, single-blind, active-controlled trial that included 559 patients with epidermal growth factor receptor wild type NSCLC with measurable lung lesions being treated in the second and third line. Patients were treated on a 21-day cycle with docetaxel 75 mg/m

 on days 1 and 8 or with docetaxel alone.

 Unlike PROTECTIVE-1 and PROTECTIVE-2, the primary end point was overall survival (OS).

The mean and median OS rates were significantly improved in the plinabulin arm. Additionally, OS rates doubled with plinabulin/docetaxel vs docetaxel alone at 24 months (22.13% vs 12.51%; 

 value not determinable). Secondary end points favoring plinabulin/docetaxel over docetaxel alone included investigator-assessed overall response rate (12.23% vs 6.76%, respectively; 

 = .0275) and mean progression-free survival (6.0 vs 4.4 months, respectively; 

“The differences that were presented were modest, but to see an agent that not only prevents neutropenia but also has anticancer properties is pretty exciting,” Nanda said. “It is certainly worthy of additional investigation, particularly as we’re moving immunotherapy into the early-stage setting.”

A variety of other agents are being explored as prophylaxis against CIN. One such agent, trilaciclib, received FDA approval on February 12, 2021, to reduce the frequency of CIN in patients with small cell lung cancer.

 Approval was based on data from 3 randomized phase 2 trials that showed that use of G-CSFs, erythropoiesis-stimulating agents (ESAs), and red blood cell (RBC) transfusions on or after week 5 was significantly lower among patients receiving trilaciclib vs placebo (28.5% vs 56.3%, 

 Additionally, when severe neutropenia occurred, the duration was reduced in patients who received trilaciclib.

The panelists noted that trilaciclib is also being explored for breast cancer. “It did not show the same [benefit in reducing neutropenia] in breast cancer with a different chemotherapy backbone,” Rugo said. “It’s intriguing that these drugs may work differently based on the kind of chemotherapy backbone we have as well.”

Although the primary end point of a reduction in grade 4 neutropenia was not met in the trial, Rugo mentioned that in results from an ongoing phase 2 trial (NCT02978716) assessing the addition of trilaciclib to gemcitabine/carboplatin in women with triple-negative breast cancer, there was an unexpected positive finding.

 The investigators observed a 63% reduction in the risk of death (

 < .0001) with the addition of trilaciclib.

"Other compounds are being investigated, including one that goes by the acronym ALRN-6924, which is a peptide that may also have a similar effect on preventing neutropenia,” Gradishar said. A phase 1b trial (NCT04022876) is assessing ALRN-06924 in preventing chemotherapy-induced AEs in patients with small cell lung cancer or NSCLC treated with carboplatin/pemetrexed. The trial is currently recruiting patients.

Blayney DW, Shi Y, Adamchuck H, et al. Clinical trial testing superiority of combination plinabulin (Plin) and pegfilgrastim (Peg) versus peg alone in breast cancer treated with high-risk febrile neutropenia risk chemotherapy (chemo): final results of the phase 3 protective-2 in chemo-induced neutropenia (CIN) prevention. 

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BeyondSpring Pharmaceuticals receives complete response letter from the FDA for plinabulin new drug application for prevention of chemotherapy-induced neutropenia (CIN). News release. Beyond-Spring Pharmaceuticals. December 1, 2021. Accessed December 6, 2021. bit.ly/3o9Y0ro

FDA approves drug to reduce bone marrow suppression caused by chemotherapy. News release. FDA. February 12, 2021. Accessed December 6, 2021. bit.ly/31pO6cH

Taylor NP. BeyondSpring lurches down as FDA rejects plinabulin, raising questions about lung cancer prospects. Fierce Biotech. December 3, 2021. Accessed December 6, 2021. bit.ly/3or3Api

Han B, Shi YK, Feinstein T, et al. DUBLIN-3 (BPI-2358-103): a global phase (Ph) III trial with the plinabulin/docetaxel (Plin/Doc) combination vs. Doc in 2nd/3rd Line NSCLC patients (pts) with EGFR-wild type (wt) progressing on a prior platinum-based regimen. 

. 2021;32(suppl 5):S1218-S1346. doi:10.1016/j.annonc.2021.08.2127

Blayney DW, Shi Y, Bondarenko I, et al. Head-to-head comparison of single agent (SA) plinabulin (Plin) versus pegfilgrastim (Peg) for the prevention of chemotherapy-induced neutropenia (CIN) in the phase 3 trial PROTECTIVE-1. 

. 2021;39(suppl 15):547. doi:10.1200/JCO.2021.39.15_suppl.547

BeyondSpring announces positive topline results from its DUBLIN-3 registrational trial of plinabulin in combination with docetaxel for the treatment of 2nd/3rd line non-small cell lung cancer (NSCLC) with EGFR wild type. News release. BeyondSpring Pharmaceuticals. August 4, 2021. Accessed December 6, 2021. bit.ly/331tHuJ

Ferrarotto R, Anderson I, Medgyasszay B, et al. Trilaciclib prior to chemotherapy reduces the usage of supportive care interventions for chemotherapy-induced myelosuppression in patients with small cell lung cancer: pooled analysis of three randomized phase 2 trials. 

. 2021;10(17):5748-5756. doi:10.1002/cam4.4089

O’Shaughnessy J, Wright GS, Thummala AR, et al. Trilaciclib improves overall survival when given with gemcitabine/carboplatin in patients with metastatic triple-negative breast cancer: final analysis of a randomized phase 2 trial. 

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A study of ALRN-6924 for the prevention of chemotherapy-induced side effects (chemoprotection). ClinicalTrials.gov. Updated July 1, 2021. Accessed December 6, 2021. https://clinicaltrials.gov/ct2/show/NCT04022876

Articles

Hope S. Rugo, MD, FASCO, Rita Nanda, MD, William J. Gradishar, MD, and Tiffany A. Traina, MD discuss the selective immunomodulating microtubule-binding agent plinabulin, plus several other novel chemoprotective therapies under exploration, including trilaciclib.

SIMBA Therapy Encounters Barriers But Holds Promise for Neutropenia and Beyond

The recent approval of sotorasib (Lumakras) for the treatment of patients with advanced 

 G12C–mutant non–small cell lung cancer (NSCLC) marks a milestone for cancer therapy. After 4 decades of research into the oncogenic implications of 

 mutations in human cancers, the FDA’s May 2021 accelerated approval of the KRAS G12C inhibitor represents the first successful therapy directed at a target long considered 

Having finally made some headway in 1 cohort of patients, investigators are focused on finding ways to broaden the impact of KRAS inhibition. They are describing mechanisms of resistance to these drugs and offering a number of potential paths forward, including exploring coinhibitory targets (

Figure. Potential Pathway Partners for KRAS G12C Inhibitors

Many mechanisms of resistance hinge on reactivation of the RAS/MAPK pathway. Combinations of KRAS G12C inhibitors with drugs targeting upstream and downstream components of related signaling networks are showing promise in NSCLC and colorectal cancer (CRC).

 Novel drug designs, such as RAS(ON) inhibitors, which target the active form of KRAS, could help tackle particularly challenging acquired resistance mutations that drive cross-resistance to KRAS G12C inhibitors.

This year is shaping up to a busy one for KRAS research. Mirati Therapeutics’ adagrasib (MRTX849) is hot on the heels of sotorasib. The company expects to file a new drug application for the agent as a second-line treatment of patients with 

A number of other companies are developing KRAS G12C inhibitors and vying for potential best-in-class status.

 These drugs are being tested as monotherapy and in combination with a range of targeted therapies in KRAS G12C–mutant solid tumors (

). Amgen is continuing its development of trend-setting sotorasib, notably in the CodeBreaK 101 trial (NCT04185883), a master protocol that currently includes 15 substudies.

Table. Select Clinical Trials of Combination Therapies in 

Investigators aim to recruit more than 1000 participants with 

 G12C–mutant advanced solid tumors, NSCLC, or CRC. 

Meanwhile, clinical testing is expected to start on the first KRAS(ON) agent and on drugs targeting other KRAS variants that are more common in malignancies other than NSCLC.

Although KRAS G12C inhibitors offer an important new therapeutic option for a subset of patients with NSCLC, clinical trial experience suggests that fewer than half of patients respond and responses can be short-lived.

 Furthermore, these drugs have modest activity as single agents in patients with CRC.

 In the phase 2 CodeBreaK 100 trial (NCT03600883), sotorasib monotherapy demonstrated an objective response rate (ORR) of 9.7% in 6 of 62 patients, all partial responses (PRs), according to peer-reviewing findings detailed in 

 in December 2021. At the European Society for Medical Oncology (ESMO) Congress 2021, investigators reported that adagrasib monotherapy resulted in a 22% response rate, including 1 unconfirmed PR, among 45 patients treated during the phase 1/2 KRYSTAL-1 (NCT03785249) study.

Even preclinical studies have shown indications of variable degrees of sensitivity to KRAS G12C inhibitors.

 Experience with other targeted therapies suggests that resistance to KRAS G12C inhibitors inevitably arises, and investigators have begun to unravel the underlying molecular mechanisms.

Studies indicate that rapid, adaptive RAS pathway reactivation is a key mechanism of resistance to KRAS G12C inhibitors, although it remains an open question whether this is mediated by activation of alternative wild-type RAS proteins (NRAS and HRAS), production of mutant KRAS G12C in the active guanosine triphosphate–bound state, or both.

In nonmutant cells, KRAS is maintained in the active state (which is not targetable by current KRAS G12C inhibitors) by the activity of upstream receptor tyrosine kinases (RTKs) and SHP2, a phosphatase that activates RAS signaling downstream of multiple RTKs.

 Coinhibition of these targets may enhance the activity of KRAS G12C inhibitors.

Potential mechanisms of acquired resistance to KRAS G12C inhibitors were outlined by Pasi A. Jänne, MD, PhD, at the American Association for Cancer Research-National Cancer InstituteEuropean Organisation for Research and Treatment of Cancer (AACR-NCI-EORTC) Virtual International Conference on Molecular Targets and Cancer Therapeutics in October 2021.

 award winner in the lung cancer category, is director of the Lowe Center for Thoracic Oncology, the Belfer Center for Applied Cancer Science, and the Chen-Huang Center for EGFR Mutant Lung Cancers at Dana-Farber Cancer Institute in Boston, Massachusetts.

During his presentation, Jänne noted that investigators are just beginning to understand these processes, with much of what is known having emerged over only the past several months.

He highlighted 2 key studies. In the first, investigators conducted molecular analyses of tumor tissue and circulating tumor DNA from plasma samples from 38 patients (27 with NSCLC, 10 with CRC, and 1 with cancer of the appendix) who exhibited acquired resistance following treatment with adagrasib in the KRYSTAL-1 study.

A potential underlying cause of resistance was identified in 17 of the 38 patients. Seven of these patients displayed multiple concurrent mechanisms of resistance, which appeared to be more common in patients with CRC. Secondary alterations of the KRAS gene were identified in 9 of the 17 patients and included G12D/R/V/W, Q61H, R68S, H95D/Q/R, and Y96C mutations in addition to amplification of the KRAS G12C allele.

 genes involved in other RTK/RAS/ MAPK signaling pathways were observed in 12 of the 17 patients and included activating mutations in 

. Transformation from adenocarcinoma to squamous cell histology also was observed in 2 patients with NSCLC.

In the second study, investigators used the chemical mutagen N-ethyl-N-nitrosourea to induce mutations in the KRAS gene, transduce the mutated genes into cell lines, and then study their impact on KRAS G12C inhibitor activity.

Among clones resistant to sotorasib (n = 68), 52 harbored secondary 

 mutations, most commonly A59T, R68M, and Y96D following high doses (≥ 1000 nM) of the drug, and G13D, A59S, R68M, and Q61L after lower doses (100nM-500 nM). Clones resistant to adagrasib (n = 74), 72 of which involved secondary 

 mutations, most commonly harbored Y96D mutations after a high dose (≥ 200 nM) of adagrasib and Q99L, R68S, V8E, M72I, and A59S variants after low doses (20-100 nM).

Investigators also evaluated the degree of resistance associated with each 

 mutation. G13D, A59S/T, R68M, and Y96D/S mutations were all identified as highly resistant to sotorasib, whereas Y96D/S and Q99L conferred strong resistance to adagrasib. Some variants, such as V8E, G13D, A59S/T, and R68M that were resistant to sotorasib remained sensitive to adagrasib; the reverse was true for the Q99L mutation, which was resistant to adagrasib but remained sensitive to sotorasib. Notably, the Y96D/S mutations were identified as a mechanism of cross-resistance to both KRAS G12C inhibitors.

Insights from these and other studies are already facilitating the design of novel therapeutic strategies and drugs that might prevent or delay the development of resistance.

Ongoing clinical trials of KRAS G12C inhibitors are largely focused on evaluating rational combinations based on positive preclinical results, including drug regimens cotargeting upstream components of the RAS pathway, including RTKs such as EGFR and HER, and downstream components such as MEK.

Following Jänne’s presentation at the 2021 AACR-NCI-EORTC conference were 2 reports of data from the ongoing phase 1b/2 CodeBreaK 101 trial, a multiarm study evaluating numerous sotorasib combinations. At the time of presentation, 41 patients (18 with CRC, 18 with NSCLC, and 5 with other solid tumors) had received treatment with sotorasib 960 mg daily in combination with the MEK inhibitor trametinib (Mekinist) at 1 mg or 2 mg daily in 1 arm of this study.

Among patients with CRC, the objective response rate (ORR) was 14.3% (95% CI, 0.4%57.9%) in those previously treated with a KRAS G12C inhibitor (n = 7) and 9.1% (95% CI, 0.2%-41.3%) for KRAS G12C inhibitor–naïve patients (n = 11). Among patients with NSCLC, ORRs were 0% in 3 patients and 20% in 15 patients (95% CI, 4.3%-48.1%), respectively. The disease control rates (DCRs) were 85.7% and 66.7% in patients with CRC and NSCLC who had previously received KRAS G12C inhibitors and 81.8% and 86.7%, respectively, among those who had not.

The combination was well tolerated, with no unexpected or new toxicities and no fatal treatment-related adverse effects (TRAEs). The most common any-grade TRAEs were diarrhea, rash, dermatitis, nausea, vomiting, peripheral edema, decreased ejection fraction, and increased blood creatine phosphokinase. There was 1 dose- limiting toxicity (DLT): trametinib-related grade 3 maculopapular rash at the 2-mg dose.

In a separate arm of the study, 33 patients were treated with sotorasib 960 mg daily in combination with the pan-ERBB inhibitor afatinib (Gilotrif) at 20 mg or 30 mg once daily (dose exploration) and afatinib 30 mg once daily (dose expansion), including patients who had previously received sotorasib.

Overall, the ORR was 30.3% (95% CI, 15.6%48.7%), consisting of all partial responses (PRs), and the DCR was 75.8%. ORRs were 20.0% (95% CI, 2.5%-55.6%) at the 20-mg dose and 34.8% (95% CI, 16.4%-57.3%) at the 30-mg dose. Among patients who had received prior sotorasib, 3 had stable disease (SD), 1 had progressive disease, and 1 withdrew due to an adverse effect.

The most common any-grade TRAEs included diarrhea, nausea, and vomiting. Diarrhea was also the most common TRAE of grade 3 or higher. One fatal TRAE, respiratory failure attributed to sotorasib, was reported in the 30-mg dose- exploration group.

At the 2021 ESMO Congress, investigators reported results from a third arm of CodeBreaK 101 in which the combination of sotorasib and EGFR-targeted antibody panitumumab (Vectibix) was evaluated.

The dose-exploration group (part 1 cohort A) comprised 8 patients who received sotorasib 960 mg daily plus panitumumab 6 mg/kg every 2 weeks, including 5 participants previously treated with sotorasib. In this cohort of 8 patients, there was 1 confirmed PR and 5 patients experienced SD. In the dose-expansion phase (part 2 cohort A), results were reported for 18 patients who were naïve to KRAS G12C inhibitor therapy and received the sotorasib/panitumumab combination at the recommended dose. There were 3 confirmed and 3 unconfirmed PRs plus 12 participants with SDs, for a DCR of 83.3%. Among the 41 enrolled patients, there were no DLTs or grade 4 or higher TRAEs.

In another presentation at the 2021 ESMO Congress, investigators described data from a cohort of patients with CRC receiving adagrasib in combination with the EGFR antibody cetuximab (Erbitux) in the KRYSTAL-1 study. Among the 28 patients evaluable for response, the ORR was 43% including 2 unconfirmed PRs and the DCR was 100%. Grade 3/4 TRAEs were reported in 16% of patients, but there were no fatal events.

 The phase 3 KRYSTAL-10 trial (NCT04793958) of this combination in 

Given the apparent complexity of KRAS G12C inhibitor resistance, in which alterations in multiple different RTKs are implicated,

 the SHP2 protein, a central node in the RAS pathway that lies downstream of multiple different RTKs, has emerged as an attractive therapeutic target.

 A number of SHP2 inhibitors are in development, several of which are being evaluated in combination with KRAS G12C inhibitors. BBP-398, a SHP2 inhibitor, is being evaluated in a phase 1 trial (NCT04528836) as monotherapy in patients with advanced solid tumors harboring 

 G12C mutations or MAPK pathway alterations, excluding 

Findings from studies of the mechanisms of acquired resistance to KRAS G12C inhibitors suggest that switching between these inhibitors upon progression could be effective against some 

 resistance mutations. On the other hand, the Y96D/S variants appear to mediate cross- resistance to both drugs and present a particular therapeutic challenge.

In the preclinical setting, combining KRAS G12C inhibitors with an inhibitor of the guanine nucleotide exchange factor SOS1 or with a SHP2 inhibitor was found to be active against the Y96D/S mutant.

 Several ongoing clinical trials are evaluating the combination of the SOS1 inhibitor BI 1701963 with KRAS G12C inhibitors. 

The Y96D mutation also was shown to be susceptible to a new type of KRAS inhibitor that targets the GTP-bound form of the protein.

 Steve Kelsey, MD, MB ChB, FRCP, FRCPath, president of research and development at Revolution Medicines, which is developing these new drugs, described these KRAS(ON) inhibitors during a presentation at the 2021 AACR-NCI-EORTC conference.

Based on the company’s proprietary tricomplex inhibitor technology, these drugs exploit cyclophilin A, a chaperone protein, to create a binding pocket for the RAS inhibitor on the smooth surface of the GTP-bound KRAS G12C protein. In addition, binding of the cyclophilin A protein to the active mutant protein blocks it from interacting with downstream effectors.

A first-in-class KRAS G12C(ON) inhibitor, RMC-6291, is in preclinical development. The agent demonstrated a superior response rate compared with adagrasib in NSCLC KRAS G12C xenografts with an ORR per mouse RECIST of 68% (13 of 19 xenografts) vs 42% (8 of 19 xenografts), respectively.

Revolution Medicines also is using its tricomplex technology to develop RAS(ON) inhibitors that target all 

 variants. Although these pan-RAS(ON) inhibitors also have activity against wild-type RAS isoforms, meaning that they are likely to cause more toxicity than KRAS G12C inhibitors, they may offer another strategy for overcoming resistance.

Lead candidate RMC-6236 has demonstrated antitumor activity in G12D-, G12V-, and G12Rmutant preclinical models, with notable activity against variants implicated in resistance to KRAS G12C inhibitors, according to Kelsey. Revolution Medicines plans to advance both RMC-6291 and RMC-6236 into clinical trials.

Meanwhile, Mirati Therapeutics is developing MRTX1133, a KRAS G12D inhibitor with high affinity for both the active and inactive forms of the KRAS G12D–mutant protein. MRTX1133 has demonstrated potent antitumor activity in KRAS G12D–mutant xenograft models, with tumor regression in 60% of models and response in 73% of pancreatic cancer and 25% of CRC models.

 Mirati expects to file an investigational new drug application for MRTX1133 in 2022.

Jane de Lartigue, PhD, is a freelance medical writer based in Gainesville, Florida.

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Weiss J, Yaeger RD, Johnson ML, et al. KRYSTAL-1: adagrasib (MRTX849) as monotherapy or combined with cetuximab (Cetux) in patients (Pts) with colorectal cancer (CRC) harboring a KRASG12C mutation. 

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Gandara D, Marrone K, Govindan R, Skoulidis F, Durm G. A phase 1b study evaluating the combination of sotorasib, a KRASG12C inhibitor, and afatinib, a pan-ErbB tyrosine kinase inhibitor, in advanced KRAS p.G12C mutated non-small cell lung cancer (NSCLC).Presented at:AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; October 7-10, 2021; virtual. Abstract P05-02.

Kelsey S. Discovery and development of RAS(ON) inhibitors beyond KRAS G12C.Presented at:AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; October 7-10, 2021; virtual.

Mirati Therapeutics. Targeting the genetic and immunological drivers of cancer. November 8, 2021. Accessed December 9, 2021. https://ir.mirati.com/events-and-presentations/default.aspx

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The recent approval of sotorasib for the treatment of patients with advanced  KRAS G12C–mutant non–small cell lung cancer marks a milestone for cancer therapy.

Next Steps for KRAS Inhibitors Focus on Tackling Resistance

Patient education in oncology can often be daunting and complicated for clinicians and patients. Traditional patient education methods such as videos, handouts, and reviewing standard medical imaging often fall short in conveying complex information. As a result, 3-dimensional (3D) virtual reality (VR) experiences are increasingly being explored as an appealing alternative method of imaging review for patients with cancer.

“Patients struggle to know what’s happening within their own bodies,” said Douglas E. Holt, MD, a radiation oncologist at Gamma West Cancer Services in Idaho Falls, Idaho, in an interview with 

. “They’re making decisions being somewhat or quite uninformed about what’s going on. VR [provides an] opportunity to help patients be engaged in their own disease process and on decisions of the future of their cancer [journey].”

Holt developed and implemented a program to demonstrate how VR can improve patient education.

He received the 2021 Association of Community Cancer Centers (ACCC) Innovator Award for his work and presented the findings at the ACCC 38th (Virtual) National Oncology Conference in November 2021.

Although most patients want to be as informed as possible about their condition, studies have found that up to 80% of information presented to patients by clinicians is forgotten almost immediately. As much as 50% of the information that is remembered by patients is retained inaccurately, and patient recall tends to be poorer as greater amounts of information are presented. These issues can be worsened by factors including poor health literacy among patients, the amount and complexity of information presented, language barriers, and the stress a patient is feeling because of the diagnosis.

By itself, verbal discussion between patient and clinician has been found to be the least effective educational method. Standard medical imaging contains most of the information patients need to understand their condition but is difficult to interpret without years of training. Because of the shortcomings of current patient education strategies, patients often lack the context and understanding to participate in discussions about their condition and to make decisions concerning their care.

“Medical imaging has a lot of the information right there; it’s just in a form [that] patients can’t understand,” Holt said. “VR is a way that clinicians can intuitively show someone their own body, where the problem is with their tumor, and the extent of their disease. [Clinicians] can show patients why they are having the symptoms they’re having and then help them understand what their treatment would look like.”

Holt sought to address the disconnect in patient education in oncology by using VR in a proofof-concept study. The goal of the trial was to identify and address the technical challenges of implementing VR in the clinic and to objectively measure subjective patient experiences with the technology. Holt partnered with clinical psychology professionals and a psychometrician utilizing a mixed-methods approach consisting of quantitative surveys and qualitative semistructured interviews. A qualitative analysis was also performed to identify commonly shared themes among patients.

The median age of the 25-patient population was 59 years (range, 11-95). The population included patients with tumor sites in the central nervous system, head and neck, breast, thorax, gastrointestinal tract, and pelvis. The median time from diagnosis to the VR education experience was 5 months (interquartile range, 3-19). Each VR session lasted approximately 5 to 7 minutes and included patients and their caregivers.

During the session, patients wore a VR headset and used 2 hand controls to navigate the experience. The system combined individual slices of medical images to create a 3D rendering of the patient’s tumor site that could be viewed from a third-person perspective. Patients could freely move about, rotate, and zoom in and out on their tumor to get a better understanding of its size, location, and potential impact on neighboring organs.

After the VR session, patients rated their understanding of their tumor/disease at a mean level of 9.2 out of 10, with a 10 being full understanding, compared with 5.6 before the session (P < .0001). 

Patients were also asked to identify their preferred method for medical imaging review; 96.9% of patients chose VR vs 3.1% who selected imaging review via a standard computer screen. Members of the study population ranked what they considered the top educational tool for understanding their disease after the VR session. VR received the top ranking 83.3% of the time, followed by verbal discussion (8.3%), self-research (5.6%), and drawings (2.8%).

VR also outperformed imaging review via a standard computer screen in an understanding of disease and treatment analysis on a scale of 1 to 3, with 3 being full understanding. The mean patient rating with the VR experience was higher than that for the computer screen in every category surveyed: tumor appearance (2.8 vs 1.3, respectively), tumor size (2.8 vs 1.4), tumor location (2.9 vs 1.5), organs adjacent to tumor (2.9 vs 1.2), tumor- related symptoms (2.7 vs 1.6), treatment rationale (2.9 vs 2.0), radiation target (3.0 vs 2.0), and radiation toxicity (2.8 vs 1.3). On the same 3-point scale, VR also outperformed the computer screen when patients rated the experience for reduction in anxiety (2.2 vs 1.1), feeling of engagement in health care (2.8 vs 1.5), and satisfaction (2.9 vs 1.6). Investigators asked patients to rate the level of importance of VR in viewing their tumor/disease. The method attained a mean score of 9.1 out of 10. 

Patients gave additional feedback on the VR imaging review on a 5-point scale from “strongly disagree” to “strongly agree.” Most patients strongly agreed (78.9%) or agreed (18.4%) that they were comfortable with VR for medical imaging review; 2.7% strongly disagreed. 

The statement, “important for VR experience to be shared via multiuser platform” was strongly agreed with by 64.9% of patients and agreed with by 32.4% of patients. Most patients also strongly agreed with the statements “VR increased trust in physician and treatment team” (75.0%), “want VR to be used in own healthcare in future” (81.6%), and “VR should become standard-ofcare in imaging review” (78.9%). Patients did not strongly disagree or disagree with any of the other statement options.

“The general response [to VR education] was amazingly positive,” Holt said. “A lot of patients would say something [such as], ‘that was incredible,’ or ‘that was amazing.’ With cancer consultations, those are not words you usually hear.”

Patient education in oncology can often be daunting and complicated for clinicians and patients.

Vol. 23/No. 1 | Oncology Live®

SIMBA Therapy Encounters Barriers But Holds Promise for Neutropenia and Beyond

Next Steps for KRAS Inhibitors Focus on Tackling Resistance

3D Virtual Reality Poised to Offer Superior Patient Education in Oncology

Overcoming Barriers to Clinical Access in Oncology Care Delivery Requires Multilevel Interventions

Targeting CD166 Represents a New Avenue of Attack for Breast Cancer

Triplet and Quadruplet Regimens Set a New Course for Myeloma

Implications of FDA Approval of Alzheimer Drug May Extend to Novel Anticancer Therapies