Silas Inman

A doubled the rate of progression-free survival (PFS) at 12 months and reduced the risk of progression or death by 34% was seen with the KRAS G12C inhibitor sotorasib (Lumakras) vs docetaxel in patients with previously treated non–small cell lung cancer (NSCLC) harboring a 

 G12C mutation, according to findings from the phase 3 CodeBreaK 200 trial (NCT04303780) presented at the ESMO Congress 2022.

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 

Based on findings from the earlier phase 1/2 CodeBreaK 100 trial (NCT03600883), the FDA granted sotorasib an accelerated approval in May 2021 for patients with 

 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; 

The worsening of key cancer-related symptoms 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):S808-S869. 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

Articles

Significant improvements in progression-free survival were seen with sotorasib compared with docetaxel in patients with KRAS G12C–mutated non–small cell lung cancer.

Sotorasib Doubles PFS Rates vs Docetaxel in KRAS G12C–Mutated NSCLC

Updated findings from the phase 3 CLEAR study (NCT02811861) showed that even with an additional 7 months of follow-up, lenvatinib (Lenvima) in combination with pembrolizumab (Keytruda) led to a continued overall survival (OS) and progression-free survival (PFS) benefit over sunitinib (Sutent) monotherapy in patients with advanced clear cell renal cell carcinoma (RCC).

At a median follow-up of approximately 33 months, a 28% reduction in the risk of death was seen with lenvatinib plus pembrolizumab compared with sunitinib (HR, 0.72; 95% CI, 0.55-0.93). The 24-month OS rate with the combination was 80.2% (95% CI, 75.5%-84.1%) compared with 69.7% (95% CI, 64.4%-74.3%) for sunitinib. Median OS was not estimable for either treatment. Median PFS was 23.3 months (95% CI, 20.8-27.7) with the combination vs 9.2 months (95% CI, 6.0-11.0) with sunitinib (HR, 0.42; 95% CI, 0.34-0.52).

“These data clearly show that the efficacy benefit observed at the primary analysis was robust and maintained with longer follow-up, once again supporting lenvatinib and pembrolizumab as a standard of care in first-line advanced RCC,” lead author Camillo G. Porta, MD, Interdisciplinary Department of Medicine, University of Bari Aldo Moro, said during a presentation of the data at the 2022 ESMO Congress. “With longer follow up, at around 33 months, lenvatinib and pembrolizumab continued to show a clinically meaningful benefit in PFS, OS, and ORR vs sunitinib, consistent with primary analysis.”

In the 3-arm study, patients were evenly randomized to receive lenvatinib at 20 mg orally per day plus intravenous pembrolizumab at 200 mg every 3 weeks (n = 355), lenvatinib at 18 mg per day plus oral everolimus at 5 mg per day (n = 357), or oral sunitinib at 50 mg per day for 4 weeks on and 2 weeks off (n = 357). Updated findings for the everolimus arm were not presented at the ESMO meeting.

In the combination arm, the median age of patients was 64 years with 54.6% less than age 65. In the sunitinib group, the median age was 61 years and 63% of patients were below the age of 65. MSKCC prognostic risk was similar between arms. In the combination arm, 27% of patients had favorable risk, 63.9% had intermediate, and 9% had poor risk disease. By IMDC, 59.2% had intermediate risk, 31% favorable, 9.3% poor, and 0.6% could not be evaluated. The PD-L1 combined positive score was ≥1 for a third of patients and <1 for a third of patients. It was not available for the remaining patients. The most common site of metastases was the lung (70.1%) and nearly three-fourths had received a prior nephrectomy.

The objective response rate (ORR) was 71% with lenvatinib plus pembrolizumab (95% CI, 66.3%-75.7%) compared with 36.1% (95% CI, 31.2%-41.1%) for sunitinib (relative risk, 1.97; 95% CI, 1.69-2.29). The rate of complete responses was 17.2% with the combination compared with 4.2% for sunitinib. The median duration of response was 26.0 months (95% CI, 22.2-41.4) with lenvatinib/pembrolizumab compared with 14.7 months (95% CI, 9.4-16.8) with sunitinib.

Initial findings from the study were published in the 

 At this point the median follow-up was 26.6 months and the hazard ratio for OS was 0.66 favoring lenvatinib and pembrolizumab (95% CI, 0.49-0.88; 

 = .005). The median PFS was 23.9 vs 9.2 months, for the combination and sunitinib, respectively (HR, 0.39 95% CI, 0.52-0.80; 

The most dramatic differences between the 2 data sets were seen in the complete response rates, which increased from 16.1% in the initial presentation to 17.2% at the update. “These are the highest complete responses ever observed have seen in kidney cancer,” Porta said.

The PFS hazard ratio (HR) for lenvatinib plus pembrolizumab vs sunitinib was reported by risk group. By MSKCC criteria, the HRs were 0.18 (95% CI, 0.08-0.42), 0.46 (95% CI, 0.35-0.60), and 0.43 (95% CI, 0.29-0.64) for those with poor, intermediate, and favorable risk, respectively. By IMDC criteria, the HRs were 0.30 (95% CI, 0.14-0.62), 0.41 (95% CI, 0.30-0.54), and 0.47 (95% CI, 0.32-0.69), respectively.

The OS HRs were also described by risk criteria for the combination vs single agent. By MSKCC criteria, the OS HRs were 0.50 (95% CI, 0.25-1.02), 0.71 (95% CI, 0.52-0.97), and 1.00 (95% CI, 0.51-1.96) for poor, intermediate, and favorable risk, respectively. By IMDC criteria, the HRs were 0.39 (95% CI, 0.20-0.77), 0.72 (95% CI, 0.52-1.00), and 1.22 (95% CI, 0.55-2.26).

“PFS for patients across all MSKCC and IMDC risk groups and OS for patients across poor and intermediate risk groups favored lenvatinib and pembrolizumab,” Porta noted. “Medians for favorable risk groups were not reached. There were too few events in these groups to form conclusions.”

After 2 years, 101 of 355 patients stopped treatment with pembrolizumab and continued on single-agent lenvatinib alone. In this group, the OS rate at 36 months was 94.5%. Patients who completed 2 years of pembrolizumab had a similar disease risk as the full study population, with 65 having IMDC intermediate or poor risk disease and 36 having favorable risk.

Invited discussant Kate Young, MD, noted that in the absence of head-to-head data that outcomes with the combination of lenvatinib and pembrolizumab looked "slightly better" than other frontline options for RCC, making it an appealing choice. Although, she cautioned against cross trial comparisons.

“Outcome data continues to show clinically meaningful benefit in PFS, OS, and ORR supporting lenvatinib and pembrolizumab as a first-line treatment option in clear cell RCC for all risk groups,” said Young, Locum Medical Oncology Consultant (Renal/Melanoma) at The Royal Marsden NHS Foundation Trust. “The depth of response remains impressive, and this is another good first-line option.”

In August 2021, based on the earlier data from the CLEAR study, the FDA approved the combination of lenvatinib and pembrolizumab as a first-line therapy for patients with advanced RCC.

1. Porta CG, Eto M, Motzer RJ, et al. Updated efficacy of lenvatinib (LEN) + pembrolizumab (PEMBRO) vs sunitinib (SUN) in patients (pts) with advanced renal cell carcinoma (aRCC) in the CLEAR study. 

 2022;33(suppl 7):1449MO. doi:10.1016/j.annonc.2022.07.1552.

2. Motzer RJ, Alekseev B, Rha S-Y, et al. Lenvatinib plus Pembrolizumab or Everolimus for Advanced Renal Cell Carcinoma. 

. 2021;384:1289-1300. doi:10.1056/NEJMoa2035716.

3. FDA approves lenvatinib plus pembrolizumab for advanced renal cell carcinoma. News Release. FDA. August 11, 2021. Accessed September 11, 2022. https://bit.ly/3B5MvGA

Even after additional follow-up, the CLEAR trial showed a benefit for the combination of lenvatinib and pembrolizumab over sunitinib in patients with advanced clear cell renal cell carcinoma. 

Additional Follow-up for CLEAR Trial Shows Maintained Lenvatinib/Pembrolizumab Benefit in RCC

Positive signals from a blood-based multi-cancer early detection (MCED) test led to cancer diagnosis in 35 individuals using standard diagnostic tools after the test indicated potential cancers in 1.4% of individuals from an otherwise healthy cohort of 6621 participants aged 50 years or older in the the prospective PATHFINDER study (NCT04241796), according to data presented at the 2022 ESMO Congress.

Based on these findings, the specificity of the test was determined to be 99.1%, with a positive predictive value of 38.0% (95% CI, 28.8%-48.3%). In most cases (97.1%) the test was able to indicate where the tumor was located, which helped to guide diagnostic procedures (95% CI, 85.1%-99.8%). Overall, there were 19 solid tumors and 17 hematologic cancers diagnosed, many of which do not currently have standard screening tests available, according to lead investigator Deb Schrag, MD, MPH.

“The exciting thing about this approach is that it detected solid tumors and liquid tumors. It's really a pan-tumor assay,” Schrag, chair, Department of Medicine, Memorial Sloan Kettering Cancer Center, said when presenting the results. “MCED screening was safely implemented in adults over 50 years of age. When the blood tests were positive, workups were typically completed in less than 3 months. I think this is really a new concept. It shows it is feasible to detect cancers using blood tests."

The test utilizes both next-generation sequencing and machine learning algorithms to analyze methylation patterns in cell-free DNA from whole blood specimens. The MCED test results indicate whether a cancer signal is detected and, if positive, the test provides a suspected tissue of origin, based on the type of methyl group identified.

In the PATHFINDER study, blood collection and ordering of the test was added to standard cancer screening. Test results were returned to the investigators to discuss with the participant. There were 2 cohorts of patients. Cohort A included those at elevated risk of cancer, defined as a previous history of cancer more than 3 years prior to the study, history of smoking >100 cigarettes in their lifetime, or a genetic cancer predisposition or hereditary syndrome. Cohort B contained other patients who did not meet these criteria. Regular guideline-recommended cancer screenings were also continued.

If a test was negative, no additional steps were taken until follow up at 12 months. In the case of a positive test, the diagnostic approach selected was left to the investigator's discretion. Most patients (90.9%) with a true positive test (n = 35) received more than 1 imaging test and 81.8% underwent more than 1 invasive diagnostic procedure. In those with false-positive results (n = 57), 93.0% of patients received more than 1 imaging test and 29.8% received more than 1 invasive procedure.

The median time from a positive test to resolution was 79 days across all 92 patients. This varied between the true-positive and the false-positive group. For those in the true-positive group, a diagnosis was made in a median of 57 days compared with a median time to resolution of 162 days in those with a false-positive result.

There were 36 cancers detected in the 35 people, with 24 in the high-risk group and 11 in the non–high-risk group. Of those detected, 14 were stage I or II disease and 7 were found in individuals with a known history of cancer. Overall, there were 26 cancers identified in groups lacking a standard screening test.

The types of cancers detected were lymphoma (n = 12), breast (n = 5), colon/rectum (n = 2), prostate (n = 2), lymphoid leukemia (n = 2), Waldenström macroglobulinemia (n = 2), oropharyngeal (n = 2), liver (n = 1), intrahepatic bile ducts (n = 1), lung (n = 1), pancreas (n = 1), small intestine (n = 1), ovary (n = 1), uterus (n = 1), bone (n = 1), and plasma cell myeloma disorders (n = 1).

“We had 1 patient who had both a breast and an endometrial cancer,” Schrag said. “I think what's exciting about this new paradigm, in concept, is that many of these are cancers for which we do not have any standard screening.”

A prespecified retrospective analysis was conducted using an updated version of the MCED test, known as Galleri, on banked blood samples from the study. With this test, a positive signal was indicated in 0.9% of patients, bringing the specificity up to 99.5%. The positive predictive value for the refined MCED test was 43.1%. The tissue of origin was detected in 88% of patients. For the refined test, 263 patients would need to be screened to identify 1 patient with cancer compared with 189 with the standard test definition.

Anxiety surrounding the screening process was collected using the Patient Reported Outcomes Measurement Information System (PROMIS).

 The baseline anxiety score across patients was approximately 47. In those with a positive signal detected, there was a mean 3.6-point increase in anxiety levels when the results were returned, compared with an increase of only 0.7 for those with a negative signal. At the time of diagnostic resolution, there was a 2.5-point increase over baseline in anxiety. By the end of the study, however, anxiety levels returned to similar levels as baseline.

Overall, 5749 patients completed a satisfaction survey, with most (~97%) indicating some level of satisfaction with the test. Overall, 48.5% were extremely satisfied, 33.3% were very satisfied, and 15.3% were satisfied.

“This study was a prelude to a larger study. We needed to see how physicians would approach workup, what diagnostic odysseys we'd send patients down, and whether they'd be upset,” said Schrag. “People were a little anxious, but it was manageable, and it was transient. People understood the ramifications of this test and they were a little anxious, but they managed very well.”

In July, GRAIL, the developer of the Galleri test, announced it had completed enrollment in a large randomized, controlled study to further examine the refined MCED test.

 The trial, which is being conducted in collaboration with the National Health Service England, enrolled 140,000 healthy individuals aged 50 to 77 years. In this study, the test will be used at baseline and then annually for 2 additional years. Patients were randomized 1:1 to the MCED test or control. Results are expected in 2026 (ISRCTN91431511).

1. Schrag D, McDonnell III CH, Nadauld L, et al. A prospective study of a multi-cancer early detection blood test. 

. 2022;33(suppl 7).DOI:10.1016/j.annonc.2022.07.1029.

2. Schrag D, Beer TM, McDonnell III CH, et al. Evaluation of anxiety, distress and satisfaction with a multi-cancer early detection test. 

. 2022;33(suppl 7).DOI:10.1016/j.annonc.2022.07.1034.

3. GRAIL News Release. Grail and National Health Service (NHS) England Complete Enrollment of 140,000 Participants in Largest Study of Multi-Cancer Early Detection Test. Published: July 18, 2022. 

Positive signals from a blood-based multi-cancer early detection test led to cancer diagnoses after the test indicated potential cancers in 1.4% of individuals from an otherwise healthy cohort of participants in the the prospective PATHFINDER study.

Promising Results Demonstrated With Blood Tests for Early Cancer Detection

The use of oncolytic virus T-VEC (talimogene laherparepvec; Imlygic) as a neoadjuvant treatment demonstrated consistent efficacy improvements at 5 years vs surgery alone for patients with stage IIIB to IVM1a melanoma, according to long-term results from a phase 2 study (NCT02211131) presented at 

At the final 5-year analysis of the open-label study, the 5-year relapse-free survival (RFS) rate was 22.3% with T-VEC prior to surgery, compared with 15.2% for surgery alone (HR, 0.76; 80% CI, 0.60-0.97). At 5 years, 77.3% of patients treated with T-VEC prior to surgery were alive compared with 62.7% with surgery alone (HR, 0.54; 80% CI, 0.36-0.81). The event-free survival (EFS) rate at 5 years was 43.7% with T-VEC vs 62.7% with surgery alone (HR, 0.57; 80% CI, 0.43-0.76).

“The primary end point was relapse-free survival, and this was not the conventional relapse-free survival. It does not only count all the local, regional, and distant recurrences, [but] it also counts all the patients who withdrew to go to surgery and all the R1 and R2 resections,” lead investigator Reinhard Dummer, MD, University Hospital Zurich, Switzerland, said during a presentation of the results. “If the surgeon failed to completely resect the melanoma lesion, this is already counted as a relapse event.”

T-VEC is administered as a local injection directly to the tumor site. The therapy consists of herpes simplex 1 virus that has been genetically modified to secrete the cytokine GM-CSF, which causes cell lysis. Additionally, the lysis results in the release of tumor-derived antigens resulting in activation of an immune response. “There is both activation of T cells and natural killer cells with T-VEC,” Dummer said.

In the study, patients were randomized to surgery (n = 75) or 6 doses of intralesional T-VEC followed by surgery. Surgery was completed over a span of 6 weeks. T-VEC was administered as ≤4 ml x 106 plaque-forming units (PCU)/ml at week 1. After 3 weeks, it was administered at ≤4 ml x 108 PCU/ml over 2 weeks. Surgical resection in the T-VEC arm was completed from week 13 to week 18.

The baseline characteristics were balanced between arms for T-VEC plus surgery and surgery alone. In the T-VEC arm, the median age was 63.5 years and nearly two-thirds were male (64.5%). The most common ECOG score was 0 (88.2%) and the disease stages were well balanced, with the most common stage being IIIC. Most patients had received a prior surgery for melanoma (93.4%) and a minority had received radiotherapy (5.3%).

There were more patients enrolled in this study with in-transit melanoma than other neoadjuvant studies, Dummer said. There were 21.1% of patients in the combination arm with in-transit disease and 23% in the surgery arm. Additionally, there were patients with nodal involvement and in-transit disease (22.4% vs 23%, respectively).

“One patient that I treated had extensive in-transit disease with multiple lesions, and there was a pronounced response in all of them and by histology this patient shows a complete remission,” said Dummer.

Following surgery, adjuvant therapy was determined by investigator's choice. In the T-VEC arm, 13.7% of patients received adjuvant therapy (n = 10), which most often consisted of immunotherapy (n = 8). More patients received adjuvant therapy in the surgery alone group (31.9%; n = 22), with immunotherapy being the top choice half of the time (n = 11). Approximately half of patients in the T-VEC arm received a subsequent therapy in any setting (54.8%) compared with over three-fourths in the surgery group (78.3%).

“In this final readout of the largest randomized neoadjuvant trial for an oncolytic virus in advanced melanoma, we report durable improvements in RFS, EFS, and overall survival at 5 years with neoadjuvant T-VEC plus surgery vs standard surgery,” said Dummer. “These results suggest that an intratumorally-administered oncolytic agent can elicit a meaningful long-term systemic effect and support neoadjuvant T-VEC plus surgery in advanced resectable melanoma.”

Caroline Robert, MD, PhD, head of the Dermatology Unit at Gustave Roussy, discussed the findings during the session at the ESMO meeting. She noted the results of the study favored T-VEC and that the low toxicity profile associated with the oncolytic virus gave it an advantage against more active but also more toxic regimens, like nivolumab (Opdivo) plus ipilimumab (Yervoy). However, she questioned the statistical plan used for the trial.

“There was potential bias in the randomization, a gap between the 2 arms in treatment timing, and an absence of visibility of the timing of events, especially in the combination arm,” she said. “The relaxed alpha error of 80% confidence interval means there's a 20% risk to conclude that the result is positive, whereas it is not, with the upper end of the confidence interval close to 1. Results may not have been significant if a more standard 95% CI had been chosen.”

Additional studies continue to assess T-VEC in the neoadjuvant setting for patients with melanoma, either as a single agent or in combination with other therapies. A study in the Netherlands is looking at T-VEC with nivolumab (NCT04330430) and another conducted at the University of California, Davis, is assessing it as a single agent (NCT04427306). Both studies are in phase 2 and currently recruiting participants.

Dummer R, Gyorki D, Hyngstrom J, et al. Final 5-year results of the phase II, multicenter, randomized, open-label trial of talimogene laherparepvec (T-VEC) neoadjuvant treatment (Tx) plus surgery vs immediate surgery in patients (pts) with resectable stage IIIB-IVM1a melanoma (MEL). 

. 2022;33(suppl 7).DOI:10.1016/j.annonc.2022.08.037

The oncolytic virus T-VEC showed consistent improvements at 5 years for patients with stage IIIB to IVM1a melanoma.

Neoadjuvant T-VEC Demonstrates Consistent Efficacy Improvements in Resectable Melanoma at 5 Years

A tumor-infiltrating lymphocyte (TIL) therapy showed a 50% reduction in the risk of disease progression or death compared with ipilimumab (Yervoy) in patients with stage IIIC/IV unresectable, treatment-refractory melanoma, according to findings from the randomized phase 3 M14TIL trial (NCT02278887) presented at 

The TIL therapy was manufactured at various centers in the Netherlands Cancer Institute, and after a median follow-up of 33.0 months, median progression-free survival (PFS) was 7.2 months (95% CI, 4.2-13.1) compared with 3.1 months for ipilimumab (95% CI, 3.0-4.3), which was statistically significant (HR, 0.50; 95% CI, 0.35-0.72; 

 < .001). The 6-month PFS rate was 52.7% with the TIL therapy compared with 21.4% for ipilimumab.

“This is the first multicenter, randomized, controlled trial studying a T-cell therapy in solid cancer, in this case comparing TIL to ipilimumab as more or less a second-line treatment for metastatic melanoma. TIL significantly improved PFS,” lead investigator John Haanen, MD, PhD, Netherlands Cancer Institute in Amsterdam, said in a press conference at the meeting.

In the open-label study, which was initiated in 2014, 168 patients were randomized to receive TILs (n = 84) or ipilimumab (n = 84). Most patients were refractory to a prior anti-PD-1 therapy (86%). Patients were evenly stratified by 

 status, treatment line, and treatment center. LDH was ≤ 2 times the upper limit of normal, and all patients had a WHO performance status between 0 and 1.

For those in the TIL arm, the adoptive cell therapy was manufactured from a resected lesion of 2 to 3 cm in size. TILs were collected from the resected tissue and then expanded ex vivo using anti-CD3, feeder cells, and interleuken-2 (IL-2) until they reached ≥5 x 109 cells per infusion.

“The patients undergo surgery and the [TILs are grown] in the time needed for patients to recover from that, because we need a metastatic lesion to grow the TIL. If it is a subcutaneous nodule, it is easy, but if it is a lung nodule, it can be a bigger surgery. The time to grow the cells takes 5 to 6 weeks,” he said. “The total period of treatment consists of 8 weeks, more or less.”

Prior to infusion of the autologous T-cell product, patients received lymphodepleting cyclophosphamide for 2 days at 60 mg/kg/day and 5 days of fludarabine at 25 mg/m2/day. High-dose IL-2 (600,000 IU/kg/dose) was administered every 8 hours following infusion with the TILs to support proliferation. Hospitalization was required throughout this process. In the ipilimumab arm, the CTLA-4 inhibitor was administered at 3 mg/kg every 3 weeks for up to 4 doses.

The overall response rate was 48.8% with the TIL therapy (95% CI, 38%-60%) compared with 21.4% for ipilimumab (95% CI, 13%-32%). The complete response rate was 20.2% for patients treated with the TIL therapy (95% CI, 12%-30%) compared with 7.1% for ipilimumab (95% CI, 3%-15%). An additional 19.1% of patients experienced stable disease in the TIL arm compared with 17.9% in the ipilimumab group, bringing the clinical benefit rates to 67.9% and 39.3% in each arm, respectively.

The median OS was 25.8 months with TILs (95% CI, 18.2-not reached) vs 18.9 months with ipilimumab (95% CI, 13.8-32.6); however, these data were not yet statistically significant with follow-up ongoing (HR, 0.83; 95% CI, 0.54-1.27; 

Grade ≥3 treatment-related adverse events were experienced by all patients in the TIL arm compared with 57% of patients in the ipilimumab group. Most of these events were related to IL-2 and the conditioning regimen, Haanen noted.

“There were no new safety concerns with TIL beyond what is known for this treatment. All of these toxicities are driven by the lymphodepleting regimen and the high-dose IL-2. Most of these side effects were already completely gone by the time the patients were released from the hospital and there were no long-term sequelae in patients treated with TILs,” he said. “There was also better health-related quality of life scores in patients treated with TIL.”

The study was conducted in collaboration with the Ministry of Health, Welfare, and Sport in the Netherlands. With this collaboration, it was agreed that if the study was positive, the treatment would become a standard of care in the Netherlands by January 2023, according to Haanen. Beyond that, EMA and FDA registration would be required, he said, which they are currently considering.

“If it gets EMA approval, the next question is how to roll it out,” he said. “At this point, you could involve pharma to do this or train other centers on the protocol to do point-of-care productions.”

Haanen JBAG, Rohaan M, Borch TH, et al. Treatment with tumor-infiltrating lymphocytes (TIL) versus ipilimumab for advanced melanoma: Results from a multicenter, randomized phase III trial. 

. 2022;33(suppl 7):S808-S869. doi:10.1016/j.annonc.2022.08.036.

A novel tumor-infiltrating lymphocyte therapy showed a 50% reduction in  the risk of death for patients with stage IIIC/IV unresectable, treatment-refractory melanoma.

Tumor-Infiltrating Lymphocyte Therapy Shows Better PFS vs Ipilimumab in Unresectable Melanoma

The combination use of the PD-1 inhibitor camrelizumab and the VEGFR2 TKI rivoceranib significantly improved both progression-free (PFS) and overall survival (OS) compared with sorafenib (Nexavar) for patients with unresectable hepatocellular carcinoma (HCC), according to findings from a phase 3 study (NCT03764293) presented at the ESMO Congress 2022.

The median OS with camrelizumab and rivoceranib was 22.1 months (95% CI, 19.1-27.2) compared with 15.2 months with sorafenib (95% CI, 13.0-18.5), which equated to a 38% reduction in the risk of death (HR, 0.62; 95% CI, 0.49-0.80; 

 < .0001). Median PFS with camrelizumab and rivoceranib was 5.6 months (95% CI, 5.5-6.3) compared with 3.7 months for sorafenib (95% CI, 2.8-3.7), which was a 48% reduction in the risk of progression or death (HR, 0.52; 95% CI, 0.41-0.65; 

“This is the first positive international phase 3 study to report significant PFS and OS benefits with the combination of an immunotherapy and a small-molecule TKI over sorafenib for unresectable HCC,” lead investigator Shukui Qin, MD, Department of Medical Oncology, Cancer Center of Jinling Hospital, in Nanjing China, said during a presentation of the results. “Moreover, camrelizumab plus rivoceranib provides the longest OS, at 22.1 months, seen in a front-line pivotal phase 3 study in advanced HCC to date.”

In the phase 3 study, patients were evenly randomized between camrelizumab at 200 mg intravenously every 2 weeks plus oral daily rivoceranib at 250 mg (n = 272) or oral sorafenib at 400 mg twice daily (n = 271). The median age of patients in the combination arm was 58 years compared with 56 years in the sorafenib arm. Most patients across both groups were enrolled in Asia (82.7%), with 47 patients in each arm being non-Asian.

Baseline characteristics were similar across arms. In the camrelizumab plus rivoceranib arm, most patients had BCLC stage C disease (86.8%), a majority had an ECOG performance status of 1 (55.9%), and the AFP was 400 ng/ml or greater for 35.3%. Macroscopic vascular invasion and extrahepatic spread were seen in 73.5% of patients and the most common etiology was hepatitis B virus infection (76.5%). Slightly more than half of patients had received a local therapy (59.2%) before entering the study.

The confirmed objective response rate (ORR) by blinded independent review committee and RECIST v1.1 criteria was 25.4% with camrelizumab plus rivoceranib compared with 5.9% for sorafenib, representing superiority for the combination (

 < .0001). These findings were similar for modified RECIST criteria-determined ORR, at 33.1% for the combination vs 10.0% for sorafenib (

 < .0001). The median duration of response per RECIST v1.1 was 14.8 months with camrelizumab plus rivoceranib and 9.2 months for sorafenib.

By RECIST v1.1 criteria, there were 3 complete responses (CR) with camrelizumab plus rivoceranib compared with 1 CR for sorafenib. Using the modified RECIST criteria, there were 14 CRs with the combination compared with 3 for the single agent. When including stable disease, the disease control rate (DCR) by RECIST v1.1 with the combination was 78.3%, compared with 53.9% for the single agent. These rates were similar by the modified criteria.

The 6-month PFS rate with camrelizumab plus rivoceranib was 44.6% compared with 22.7% for sorafenib. For OS, there were 76.5% of patients alive at 12 months in the camrelizumab plus rivoceranib arm, compared with 60.8% with sorafenib. At month 18, the OS rate was 60.9% with the combination vs 45.2% with monotherapy.

These benefits were seen across subgroups, Qin said. By geographic region, the hazard ratio for OS was 0.55 favoring the combination in non-Asian patients. The small size of the population, however, limited statistical analyses, with a very broad confidence interval observed (95% CI, 0.29-1.02). “PFS and OS generally favored camrelizumab plus rivoceranib across subgroups,” Qin noted.

Grade 3/4 treatment-related adverse events (TRAE) were experienced by 80.5% of patients in the camrelizumab plus rivoceranib arm vs 52% in the sorafenib group. There was 1 grade 5 TRAE in each treatment group. Serious TRAEs were experienced by 24.3% of patients treated with the combination compared with 5.9% in the single agent arm. Dose modifications or interruptions for TRAEs were required for 80.5% in the combination group vs 50.2% in the monotherapy arm; however, treatment discontinuation of all treatment components was similar between groups at 3.7% for camrelizumab plus rivoceranib vs 4.5% for sorafenib.

The most frequently observed TRAEs of grade ≥3 in severity with the camrelizumab plus rivoceranib combination were hypertension (37.5%), AST increase (16.5%), ALT increase (12.9%), palmar-plantar erythrodysesthesia (PPE; 12.1%), and platelet count decrease (11.8%). For sorafenib, the most common grade ≥3 TRAEs were PPE (15.2%) and hypertension (14.9%).

“The combination of camrelizumab plus rivoceranib was generally well-tolerated, with a safety profile in line with each individual agent and the underlying disease,” Qin said. “These findings support that camrelizumab plus rivoceranib represents another new first-line treatment option for unresectable HCC.”

During a discussion of the findings, R. Katie Kelley, MD, from the Helen Diller Family Comprehensive Cancer Center at the University of California, San Francisco, described potential advantages with the use of an oral angiogenesis inhibitor, but also cautioned that careful patient selection was required, given the hepatotoxicity seen with the combination. Moreover, she noted challenges with extrapolating the data to a non-Asian population, particularly given the high rates of hepatitis B virus infection seen in the underlying etiology.

“The advent of multiple first- and later-line treatment options marks enormous progress in HCC and provides new opportunity to individualize treatment decisions,” said Kelley. “Region and etiology may impact outcomes in HCC trials involving immune checkpoint inhibitor therapies. Global trials require advanced planning with regulatory agencies to define minimum subpopulation thresholds.”

With the presentation, Elavar Therapeutics, the company developing the combination, announced plans to work with the FDA on a potential route to approval. Additionally, the company is planning to submit rivoceranib to the FDA for the treatment of recurrent or metastatic adenoid cystic carcinoma (ACC). Findings for this indication were presented at the 2022 ASCO Annual Meeting, showing an ORR by investigator-assessed RECIST 1.1 criteria of 15.1% (95% CI, 7.8%-25.4%) with rivoceranib and a DCR rate of 64.4% (95% CI, 52.3%-75.3%).

“Based on the positive results of the combination study, Elevar plans to work closely with the US Food & Drug Administration for submission of a new drug application [NDA] for rivoceranib in combination with camrelizumab as a treatment option for HCC,” Saeho Chong, chief executive officer of Elevar, said in a statement. “In addition, Elevar anticipates submission of a [new drug application] to the US Food & Drug Administration for rivoceranib as a treatment option for ACC by the end of 2022.”

1) Qin S, Chan SL, Gu S, et al. Camrelizumab (C) plus rivoceranib (R) vs. sorafenib (S) as first-line therapy for unresectable hepatocellular carcinoma (uHCC): a randomized, phase III trial. 

. 2022;33(suppl 7). doi:10.1016/j.annomnc.2022.08.032.

2) Kang H, Ahn M-J, Muzaffar J, et al. A phase 2 study of the oral vascular endothelial growth factor receptor 2 (VEGFR2) inhibitor, rivoceranib, for recurrent or metastatic (R/M) adenoid cystic carcinoma (ACC). 

. 2022;40 (suppl 16):abstr 6020. doi:10.1200/JCO.2022.40.16_suppl.6020.

Findings presented at ESMO 2022 show the survival benefits of camrelizumab plus rivoceranib in patients with unresectable HCC.