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Sotorasib versus docetaxel for previously treated non-small cell lung cancer with 

 G12C mutation: CodeBreaK 200 phase III study (Abstract LBA 10) 

The KRAS G12C inhibitor sotorasib (Lumakras) doubled the rate of progression-free survival (PFS) at 12 months and reduced the risk of progression or death by 34% compared with docetaxel for patients with previously treated non–small cell lung cancer (NSCLC) with 

G12C mutations, according to findings from the phase 3 CodeBreaK 200 trial (NCT04303780). 

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 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 median overall survival was 10.6 months (95% CI, 8.9-14.0) with sotorasib compared with 11.3 months (95% CI, 9.0-14.9) with docetaxel (HR, 1.01; 95% CI, 0.77-1.33;

 = .53). Thirty-six percent of patients in the sotorasib arm received a subsequent therapy at crossover compared with 42% in the docetaxel arm. A subsequent KRAS G12C inhibitor was received by 34% of patients in the docetaxel arm. The most common treatment at crossover for those in the sotorasib arm was chemotherapy (21%). 

For the study, patients were randomly assigned to receive either oral sotorasib at 960 mg per day (n = 171) or intravenous (IV) docetaxel at 75 mg/m

 every 3 weeks (n = 174). All patients had received prior platinum-based chemotherapy and a checkpoint inhibitor either concurrently or sequentially. 

The objective response rate 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 disease control rate was 82.5% for sotorasib compared with 60.3% with docetaxel. Any degree of tumor shrinkage was seen in 80.4% of patients treated with sotorasib compared with 62.8% of those treated with docetaxel. 

"In my opinion, this supports sotorasib as a new second-line standard for patients with 

 G12C–mutated NSCLC. We look at [CodeBreaK 200] as the first step. There are more studies ongoing adding other drugs to it. It is well tolerated, so it will pair nicely with other drugs inhibiting MAP kinase, EGFR, and even PD-L1.”

Primary results of the phase 3 KEYNOTE-412 study: Pembrolizumab plus chemoradiation therapy (CRT) vs placebo plus CRT for locally advanced head and neck squamous cell carcinoma (Abstract LBA 5) 

Pembrolizumab (Keytruda) plus chemoradiation failed to demonstrate a statistically significant improvement in event-free survival (EFS) vs chemoradiation alone in patients with locally advanced head and neck squamous cell carcinoma, according to findings from the phase 3 KEYNOTE-412 trial (NCT03040999). 

The results showed that median EFS was not reached (NR; 95% CI, 44.7-NR) with pembrolizumab plus chemoradiation vs 46.6 months (95% CI, 27.5-NR) with chemoradiation alone, failing to meet the superiority threshold of a 1-sided alpha of 0.0242 (HR, 0.83; 95% CI, 0.68-1.03; 

 = .0429). The 24-month EFS rate was 63.2% with pembrolizumab/chemoradiation vs 56.2% with chemoradiation alone; the 36-month EFS rates were 57.4% and 52.1%, respectively. 

The median overall survival (OS) was NR in either arm (HR, 0.90; 95% CI, 0.71-1.15). The 24-month OS rates in the pembrolizumab/ chemoradiation and chemoradiation-alone arms, respectively, were 77.9% and 76.8%; the 36-month OS rates were 71.9% and 70.1%. 

In a post hoc analysis of EFS and OS in patients with a PD-L1 CPS of at least 20, the addition of pembrolizumab to chemoradiation appeared to result in greater benefit compared with chemoradiation alone. Here the median EFS was NR in either arm but demonstrated a 24-month EFS rate of 71.2% with pembrolizumab/chemoradiation vs 62.6% with chemoradiation alone; the 36-month EFS rates were 66.7% and 57.2%, respectively (HR, 0.73; 95% CI, 0.49-1.06). The median OS was also NR in either arm, but indicated a 24-month OS rate of 83.3% with pembrolizumab/chemoradiation vs 79.9% with chemoradiation alone; the 36-month OS rates were 79.1% and 73.0%, respectively (HR, 0.67; 95% CI, 0.43-1.04). 

"In this study, pembrolizumab given as a lead-in dose, concomitantly with chemoradiotherapy and then adjuvantly for 1 year, failed to deliver a statistically significant improvement in EFS as a primary end point when compared with placebo. Even though there was a trend in favor of the pembrolizumab arm in the intention-to-treat and PD-L1–positive populations, the current study [data] cannot be interpreted as an indication for were 0.41 (95% CI, 0.23-0.69), 0.34 (95% CI, 0.230.52), and 0.20 (95% CI, 0.14-0.29), respectively. This update was good, as we try to use of anti–PD-1 therapy in combination with chemoradiotherapy in any patient group. Indeed, in light of the recent presentations of negative findings from the JAVELIN Head and Neck 100 [NCT02952586], REACH [NCT02999087], and PembroRad [NCT02707588] studies, these data should signal the need for a change in thinking in how to design optimal combination regimens. Focus is now likely to shift to neoadjuvant and true adjuvant therapy approaches.”

Osimertinib as adjuvant therapy in patients (pts) with resected 

-mutated (EGFRm) stage IB-IIIA non–small cell lung cancer (NSCLC): Updated results from ADAURA (Abstract LBA 47) 

Adjuvant osimertinib (Tagrisso) resulted in a 77% reduction in the risk of disease recurrence or death in patients with 

-mutated, stage II to IIIA non–small cell lung cancer (NSCLC), with a disease-free survival (DFS) improvement observed irrespective of prior adjuvant chemotherapy or disease stage, according to updated findings from the phase 3 ADAURA trial (NCT02511106). 

At a median follow-up of 44.2 months (range, 0-67) with osimertinib (n = 233) and 19.6 months (range, 0-70) with placebo (n = 237), the median DFS was 65.8 months (95% CI, 54.4-not calculable [NC]) vs 21.9 months (95% CI, 16.6-27.5), respectively, in the population of patients with stage II/ IIIA disease (HR, 0.23; 95% CI, 0.18-0.30). 

In the overall population, osimertinib (n = 339) resulted in a median DFS of 65.8 months (95% CI, 61.7-NC) vs 28.1 months (95% CI, 22.1-35.0) with placebo (n = 343), translating to a 73% reduction in the risk of disease recurrence or death (HR, 0.27; 95% CI, 0.21-0.34). In this group, the median follow-up for those who received osimertinib was 44.2 months (range, 0-69) and 27.7 months (range, 0-70) for those given placebo. 

Notably, the DFS benefit provided by osimertinib over placebo was observed across all predefined subgroups. In those who received prior adjuvant chemotherapy (n = 410), the HR for DFS was 0.29 (95% CI, 0.21-0.39); the HR was 0.36 (95% CI, 0.24-0.55) in those who did not (n = 272). The HRs for those with stage IB (n = 212), stage II (n = 236), and stage IIIA (n = 234) disease, per criteria according to the AJCC Cancer Staging Manual, 7th edition (American Joint Committee on Cancer/Union for International Cancer Control), were 0.41 (95% CI, 0.23-0.69), 0.34 (95% CI, 0.230.52), and 0.20 (95% CI, 0.14-0.29), respectively.

"This update was good, as we try to anticipate what the long-term observation of the Kaplan-Meier curves will have us conclude. The DFS curve is the anticipated [marker] and simulation of the survival. The more [follow-up we have], the more we see the separation of the curves remain and an overall survival benefit is anticipated.

The [presentation] confirms the magnitude of osimertinib vs placebo across stages. Discussants noted that [patients with] stage II and stage III [disease] start to benefit less than the stage I, so the patients with less risk of relapsing look like they are starting to benefit more. This may be the topic of a dedicated trial, but it looks like even when the lymph nodes are not affected by the disease, osimertinib might change the DFS and maybe the survival. It is quite interesting to see how much these data confirm the role of osimertinib in the adjuvant setting. 

The challenge is more the biomarker assessment than the interpretation of the data. Does this mean we are just going to use a pCR for EGFR or are we going to an NGS 50 to 400 gene panel? At the time being we are trying to advocate that this trial will be continues across biomarkers to assess the same panel of genes you in this setting that you would do in the metastatic setting."

Trastuzumab deruxtecan (T-DXd) in patients (pts) with 

-mutant metastatic non–small cell lung cancer (NSCLC): Interim results from the phase 2 DESTINY-Lung02 trial (Abstract LBA 55) 

The clinical benefit and tolerable safety profile of fam-trastuzumab deruxtecan-nxki (Enhertu) was maintained at 5.4 kg/mg vs 6.4 kg/mg in patients with 

-mutated non–small cell lung cancer (NSCLC), confirming the benefit-risk ratio of the FDA-approved dose, according to findings from an interim analysis of the DESTINY-Lung02 trial (NCT04644237). 

The confirmed overall response rate in the prespecified early cohort (PEC) of the study was 53.8% (95% CI, 39.5%-67.8%) at the lower dose level (n = 52) and 42.9% (95% CI, 24.5%-62.8%) at the higher dose level (n = 28). The lower dose also showed superior safety and tolerability, including a lower rate of interstitial lung disease (ILD). 

"Antibody-drug conjugates have 2 very important opportunities. First, if they are really targeted to a specific oncogene or molecular alteration of the tumor—such as HER2, which is dependent mainly on mutations in the exon 20 insertion in lung cancer, it’s a niche, something that is very well defined molecularly—there is a potential here to move them to the frontline. We need to use them instead of chemotherapy, even as monotherapy. I hope that this strategy will move frontline. Trastuzumab deruxtecan has also been examined in HER2 expressing [lung cancer], and there the response rate was not 50% it was 36%. This might not be enough to go frontline, but can we replace a toxic agent such as platinum or platinum-based chemotherapy, can we combine it with an anti–PD-L1/CTLA-4? When you are in this less actionable [arena] you might need to combine it.”

CANOPY-A: Phase III study of canakinumab (CAN) as adjuvant therapy in patients (pts) with completely resected non–small cell lung cancer (NSCLC) (Abstract LBA 49) 

Patients with completely resected non–small cell lung cancer (NSCLC) did not derive a significant benefit with adjuvant canakinumab vs placebo, according to data from the phase 3 CANOPY-A trial (NCT03447769). Disease-free survival (DFS) was 35.0 months vs 29.7 months, respectively (HR, 0.94; 95% CI, 0.78-1.14; one-sided 

 = .258), missing the primary end point of the trial. 

Further, a subgroup analysis of demographics, baseline disease characteristics and biomarkers of interest, showed there were no meaningful differences in DFS. 

OS was not formally tested because DFS did not prove to be statistically significant; however, the data showed an OS HR of 0.722 (95% CI, 0.4821.081). The lung cancer–specific survival was similar between the experimental and control arms, with an HR of 0.900 (95% CI, 0.534-1.517). 

"The role of inflammation in lung cancer has been long studied, but to date, it has not been effectively therapeutically harnessed. Canakinumab is a high-affinity antibody directed against IL-1β, a key mediator of inflammation. 

Evaluation of biomarker data from the entire CANOPY program, which in addition includes a neoadjuvant study as well as 2 studies in advanced disease—1 combined with chemoimmunotherapy in a frontline setting and 1 combined with chemotherapy in the second-line setting—will continue to be evaluated to try and further elucidate the role of IL-1β in NSCLC.”

Phase III EMPOWER-Cervical 1/GOG-3016/ ENGOT-cx9 trial of cemiplimab in recurrent or metastatic (R/M) cervical cancer: long-term survival analysis (Abstract 519MO) 

Cemiplimab (Libtayo) maintained an overall survival (OS) benefit vs chemotherapy as a second-line treatment for patients with recurrent or metastatic cervical cancer who received prior platinum-based chemotherapy, according to data from the long-term survival analysis of the phase 3 EMPOWER-Cervical 1 trial (NCT03257267). 

In this study, investigators analyzed data from 608 patients with recurrent or metastatic cervical cancer after progression on first-line platinum-based chemotherapy. Patients were randomly assigned to receive either 350 mg of cemiplimab intravenously once every 3 weeks (n = 304) or investigator’s choice of single-agent chemotherapy (n = 304). 

Compared with chemotherapy, treatment with cemiplimab significantly improved OS (11.7 months vs 8.5 months; HR, 0.656; 95% CI, 0.545-0.790; 

 < .00001). Cemiplimab reduced the risk of death by 34% in the overall population. 

The effect was seen in patients with squamous cell carcinoma (10.9 months vs 8.8 months; HR, 0.69; 95% CI, 0.56-0.85; 

 = .00023), whose risk for death was reduced by 31%. In patients with adenosquamous carcinoma, cemiplimab treatment reduced the risk of death by 45%, thus increasing OS compared with chemotherapy (13.5 months vs 7.0 months; HR, 0.545; 95% CI, 0.365-0.814). 

The median OS for patients in the PD-L1–positive group taking cemiplimab was 12.1 months vs 7.7 months for those who were PD-L1 positive and assigned chemotherapy (HR, 0.61; 95% CI, 0.45-0.83). For patients with PD-L1–negative status, the median OS with cemiplimab was 10.8 months compared with 7.0 months for those taking placebo, respectively (HR, 0.65; 95% CI, 0.43-0.98). 

"[EMPOWER-Cervical1 data] showed that cemiplimab vs [physician] choice chemotherapy in the first recurrent space, had a really convincing improvement in OS. That benefit was seen not just in PD-L1 positive advanced [disease], but also in [those with] PD-L1 negative–disease. That wasn’t the case in the original 

paper, but we are seeing that now in the presentation with longer follow-up. Pembrolizumab is approved...in the newly diagnosed, advanced setting and cemiplimab [confirms benefit] of to the upfront immunotherapy for advanced disease.”

Overall survival (OS) at 7-year (y) follow-up (f/u) in patients (pts) with newly diagnosed advanced ovarian cancer (OC) and a 

 mutation (BRCAm) who received maintenance olaparib in the SOLO1/ GOG-3004 trial (Abstract 517O) 

Two years of olaparib (Lynparza) maintenance therapy elicited a long-term overall survival (OS) benefit vs placebo in patients with newly diagnosed, advanced ovarian cancer harboring a 

 mutation, according to 7-year follow-up findings from the phase 3 SOLO1/GOG-3004 trial (NCT01844986). 

As of the data cutoff, the median OS was not reached with olaparib treatment vs 75.2 months with placebo treatment (HR, 0.55; 95% CI, 0.400.76; 

 = .0004). The 7-year OS rates were 67.0% in the olaparib arm and 46.5% in the placebo arm. The median duration of follow-up in the olaparib and placebo arms were 88.9 months (range, 85.7-93.6) and 87.4 months (range, 84.391.7), respectively. 

In total, 45.3% of patients in the olaparib arm and 20.6% in the placebo arm still had not received a first subsequent treatment, while 44.3% of patients given placebo received a PARP inhibitor in a subsequent line of therapy vs 14.6% of patients in the olaparib group. 

The time to first subsequent therapy or death also was substantially delayed with olaparib, compared with placebo (median, 64.0 months vs 15.1 months; HR 0.37; 95% CI, 0.28-0.48). This benefit extended beyond first subsequent therapy into the time to second subsequent therapy or death (TSST) (93.2 months vs 40.7 months; HR 0.50; 95% CI, 0.37-0.67). 

"These results support the use of maintenance olaparib to achieve long-term remission in women with newly diagnosed advanced ovarian cancer and a 

 mutation. The potential for cure may also be enhanced. The OS benefit was seen despite over 40% of patients in the placebo group receiving subsequent PARP inhibitor therapy. 

Ten-year survival in women with newly diagnosed advanced epithelial ovarian cancer is 17%. Relapsed advanced ovarian cancer is typically incurable, highlighting the need for effective firstline therapies that delay relapse, prolong survival, and enhance the potential for cure. Seven years of follow-up is a clinically relevant time point for survivorship, and the longest follow-up for any PARP inhibitor in newly diagnosed advanced ovarian cancer. These 7-year results provide further confirmation that the benefit of maintenance olaparib extends well beyond its 2-year treatment cap.”

Neoadjuvant versus adjuvant pembrolizumab for resected stage III-IV melanoma (SWOG S1801) (Abstract LBA 6) 

Compared with adjuvant pembrolizumab (Keytruda) alone, the addition of neoadjuvant pembrolizumab significantly improved eventfree survival (EFS) outcomes for patients with stage III-IV melanoma with an HR of 0.58 (95% CI, 0.39-0.87; 

 = .004), according to data from the phase 2 SWOG S1801 trial (NCT03698019). 

The landmark 2-year EFS rate was 72% in the neoadjuvant arm (n = 159) compared with 49% in the adjuvant arm (n = 154). Tumor-related events—including disease progression, adjuvant therapy delays, and melanoma recurrence— occurred in 38 patients in the neoadjuvant arm and 67 patients in the adjuvant arm. 

Twelve patients had disease progression that precluded surgery and 10 patients had residual disease or developed a metastasis prior to adjuvant therapy in the neoadjuvant arm. In comparison, 17 patients in the adjuvant arm experienced residual disease or developed metastasis prior to starting therapy. 

Pembrolizumab in the neoadjuvant arm also improved EFS in all key subgroups in comparison with the adjuvant group. In particular, patients who were 66 years old or older had an HR of 0.4 (95% CI, 0.21-0.74), male patients had an HR of 0.48 (95% CI, 0.29-0.8), patients with stage IIIIC disease had an HR of 0.4 (95% CI, 0.22-0.75), and patients with 

-mutated disease had an HR of 0.44 (95% CI, 0.21-0.91). 

Overall survival was also looked at in the study, but data were not mature at the time of presentation with only 36 deaths reported on the trial (HR, 0.63; 95% CI, 0.32-1.24; 

"Events occurring during the surgical period occurred in 21 participants in the adjuvant arm, most occurring at a post-operative tumor assessment radiology scan. 

I think it’s hard to argue with the event-free survival that you’re seeing, but we do see that there are some patients who get neoadjuvant therapy and adjuvant therapy who recur quite early. On both [arms of the study], there was a percentage of patients who actually recurred prior to the initiation of adjuvant therapy. So we do need to consider upfront therapy for resectable patients and then also consider for patients in whom the therapy is not working what are our alternative strategies or markers for that resistance. 

Future directions for this trial include completing [the evaluation of] pathologic response outcomes. We’ve centralized the pathologic evaluation of the tumors, so that should be forthcoming, as well as many translational biomarkers to really confirm the hypothesis that neoadjuvant therapy expanded a larger number of T cells than the adjuvant approach. In the future neoadjuvant studies can investigate de-escalation of surgery, de-escalation of adjuvant therapy regimens, duration of treatment, and various other aspects. 

[The trial] also proves that these types of studies can be done across the US, including at community hospitals; about 50% of the sites that are enrolled in S1801 were community oncology practices and not just the academic centers. That’s really important when you think about these multidisciplinary studies that involve surgical oncology and medical oncology. This highlights the ability to do that across the United States.”

Neoadjuvant cemiplimab in patients (pts) with stage II–IV (M0) cutaneous squamous cell carcinoma (CSCC): Primary analysis of a phase II study (Abstract 789O) 

Cemiplimab (Libtayo) produced pathologic complete responses (pCRs) as a neoadjuvant treatment in more than half of patients with resectable, stage II to IV cutaneous squamous cell carcinoma (CSCC), according to a primary analysis of a phase 2 trial (NCT04154943). 

In total, 63.3% of patients (95% CI, 51.7%73.9%) experienced near or complete disappearance of their tumors when treated with the anti–PD-1 monotherapy, representing the highest response rates to this type of therapy in solid tumors. 

Investigators observed a pCR in 40 patients (50.6%; 95% CI, 39.1%-62.1%) and a pathological major response (pMR) in 10 patients (12.7%; 95% CI, 6.2%-22.0%) under independent central pathology review. Twenty patients (25.3%) experienced no pCR or pMR, and 9 patients (11.4%) did not undergo pathologist evaluation. Responses were confirmed by ICPR. 

Moreover, 54 patients demonstrated an objective response on imaging (68.4%; 95% CI, 56.9%-78.4%), which included 5 patients with CRs (6.3%) and 49 with partial responses (62.0%). Sixteen patients had stable disease (20.3%), 8 had progressive disease (10.1%), and 1 patient had no imaging-based evaluation (1.3%). The disease control rate was 89% (95% CI, 80%-95%). 

The most common AEs of any grade were fatigue (30.4%), as well as diarrhea, nausea, and maculopapular rash (13.9% each). 

"Approximately one-third of patients who are PD-L1 negative have a deep pathologic response, suggesting that this biomarker alone may be insufficient for segregating patients for treatment. This underscores the need for histologic confirmation of response. Still, hopefully, we’ll have biomarkers in the future that can help better direct us. 

The take-home message is that we have very early data, only pathologic response at the moment, but also very promising data. Maturation is needed to learn whether CSCC [pathologic response] rate is a surrogate marker for event-free survival. 

Then, do we really need 4 doses of cemiplimab? Can we also achieve the same result with 2 doses? I hope we will see, as soon as possible, a randomized trial to establish this therapy approach in cutaneous squamous cell carcinoma.”

Additional analyses of MOUNTAINEER: a phase II study of tucatinib and trastuzumab for HER2-positive mCRC (Abstract LBA27) 

Tucatinib (Tukysa) plus trastuzumab (Herceptin) improved radiographic response rates in patients with metastatic HER2-positive colorectal cancer (CRC) initially treated with tucatinib monotherapy who later crossed over to receive doublet therapy, further supporting the regimen’s use in this setting, according to updated data from cohort C of the phase 2 MOUNTAINEER trial (NCT03043313). 

Prespecified analyses for cohort C included objective response rate (ORR) by 12 weeks and disease control rate (DCR) by blind independent committee review (BICR); confirmed ORR by BICR for patients who crossed over from the monotherapy to combination regimen; and safety. Patients in cohort C received tucatinib at 300 mg twice daily. 

Among the 30 patients treated with tucatinib, ORR by 12 weeks was 3.3% (95% CI, 0.1%-17.2%) and DCR was 80.0%. Overall, cohort C comprised patients with 1 partial response (PR; 3.3%), 23 instances of stable disease (SD; 76.7%), and 4 occurrences of progressive disease (PD; 6.7%). 

In total, 28 patients crossed over to the combination regimen, inducing a confirmed ORR of 17.9% (95% CI, 6.1%-36.9%) and DCR of 82.1%. Among patients who crossed over, 5 (17.9%) had PRs, 18 (64.3%) had SD, and 5 (17.9%) had PD. 

In cohort C, 93.3% of patients experienced any-grade adverse events (AEs), including 26.7% with grade 3 or higher events. Three patients reported with serious AEs. The most common AEs with tucatinib included diarrhea (33.3%), abdominal pain (20.0%), and fatigue (20.0%), all of which were grade 1 or 2. The most common grade 3 or higher AEs were increased aspartate/alanine aminotransferase (AST/ALT; 6.7% each). 

Among patients who crossed over to the combination regimen, 82.1% of patients reported any-grade AEs, with 21.4% experiencing grade 3 or higher events. Two patients had serious AEs. The most common AE was diarrhea (35.7%), of which all events were grade 1 or 2. Also in this group, the most common grade 3 or higher AEs include ALT/AST increase (7.1% and 10.7%, respectively). Two patients in the crossover group discontinued treatment because of AEs.

"HER2 is seen in approximately 3% of patients with metastatic colorectal cancer and we’ve seen higher rates up to 10% or even more in patients with 

 wild-type disease. Now tucatinib is a tyrosine kinase inhibitor that is highly selective oral therapy that’s already shown activity and other tumor types such as breast cancer and in preclinical xenograft models of HER2-positive colorectal cancer. It’s been noted that the combination of trastuzumab and tucatinib is a potent inhibitor of tumor growth and is more active than either [agent] alone. 

Investigators have previously presented the data on tucatinib plus trastuzumab combination in cohorts A and B, showing a robust response rate of 38% by blinded independent central review. The study allowed for patients in cohort C to crossover to tucatinib combination therapy if they had not responded by 12 weeks of treatment. The post-crossover response rate was 18% with a disease control rate of 82%.”

FRESCO-2: a global phase 3 multiregional clinical trial evaluating the efficacy and safety of fruquintinib in patients with refractory metastatic colorectal cancer (Abstract LBA25) 

Fruquintinib (HMPL-013) resulted in a significant and clinically meaningful improvement in survival vs placebo in heavily pretreated patients with metastatic colorectal cancer (mCRC), according to data from the phase 3 FRESCO-2 trial (NCT04322539). 

The trial met its primary end point of overall survival (OS) and key secondary end point of progression-free survival (PFS). Patients treated with fruquintinib achieved a median OS of 7.4 months (95% CI, 6.7-8.2) vs 4.8 months (95% CI, 4.0-5.8) with placebo (HR, 0.662; 95% CI, 0.549-0.800; 

 < .001). Moreover, treatment with fruquintinib resulted in a median PFS of 3.7 months (95% CI, 3.5-3.8) vs 1.8 months (95% CI, 1.8-1.9) with placebo (HR, 0.321; 95% CI, 0.2670.386; 

"CRC, unfortunately, continues to be one of the leading causes of cancer mortality. Treatment options in the refractory setting are very limited, and this is a huge unmet need. [FRESCO-2] was designed to address that huge unmet need for these patients. 

We are excited about these results. The study was positive and met its primary [OS] end point, with a hazard ratio of 0.66, [translating to] a 34% reduction in the risk of death for patients treated with fruquintinib compared with placebo. This was a huge result for both patients and providers in this setting. 

PFS was a key secondary end point, and there was an improvement in PFS with a hazard ratio of 0.321; this is a statistically and clinically significant result. 

Not only was the drug effective, but it was also well tolerated with a favorable safety profile; this is very important for patients who have a huge tumor burden and several ongoing symptoms. [These findings] support the consideration of this drug as a new treatment option for patients with metastatic CRC.”

Neoadjuvant immune checkpoint inhibition in locally advanced MMR-deficient colon cancer: the NICHE-2 study (Abstract LBA7) 

Four weeks of treatment with nivolumab (Opdivo) plus ipilimumab (Yervoy) elicited major pathologic responses (MPRs) in 95% of patients with mismatch repair–deficient (dMMR) colon cancer, according to findings from the NICHE-2 trial (NL58483.031.16, EudraCT 016-002940-17). 

Additionally, 67% of patients demonstrated pathologic complete responses (pCRs) and none have disease recurrence to date. This treatment was also well tolerated, with investigators observing only 4% grade 3/4 immune-related adverse events (irAEs). 

The nonrandomized, multicenter NICHE-2 trial was initiated by investigators after 32 patients with nonmetastatic dMMR colon cancer in the NICHE-1 trial (NCT03026140) showed 100% pathologic responses and 60% pCRs to an immune checkpoint blockade. 

In NICHE-2, the 112 patients in the intentionto-treat (ITT) population received 3 mg/kg of nivolumab plus 1 mg/kg of ipilimumab in the f irst cycle, then only nivolumab in the second cycle 2 weeks later, followed by surgery within 6 weeks of enrolling on the trial. 

Articles

Data presented at the ESMO Congress 2022 highlighted advances across treatment modalities, including landmark data for trials in melanoma, breast cancer, and lung cancer, as well as early data that made headlines in a subgroup of patients with colon cancer. 

Investigators Highlight Top Advances at ESMO 2022

Optimizing clinical pathways to address financial toxicities faced by patients with cancer requires a complex, multifaceted approach. However, even small in-practice changes may ease the financial burdens and improve outcomes.

Validated measures to describe, quantify, and qualify have proven difficult to establish across all levels of care.

 At an institutional level, assessments from the National Cancer Institute’s Community Oncology Research Program (NCORP) and the National Comprehensive Cancer Network (NCCN) have demonstrated that despite nearly three-fourths of practices having financial screening methodologies in place, effective management protocols are not established.

 Using a benchmark of 75% of NCCN centers (n = 17) having a financial screening process, reports in the community setting were comparable.

 Among 221 practices, 72% had a financial screening process, with 50% reporting a cancer-specific financial navigator among their staff.

Despite the high rates of screening, the most common method for financial screening was identified as in-take forms (68%), which investigators noted may only highlight insurance-related burdens.3 Financial burden of care can influence several aspects of patient quality of life, the most prevalent 3 being material consequences (ie, out-of-pocket expenses, debt, decreased income), psychological effects, and deleterious coping mechanisms (ie, delaying care, nonadherence).

Results of a recent survey of individuals with cancer who received treatment at ambulatory infusion centers (Mayo Clinic in Phoenix, Arizona; and Mississippi Medical Center in Jackson) showed that financial hardship has been demonstrated most predominantly in patient-reported findings. Using several measures, the range of financial hardship was reported in 48% to 68% of participants.

 The authors found that financial literacy may be integral in reducing adverse outcomes and that interventional programs are needed to increase literacy and aid those without it.

“Patient-reported financial hardship from cancer treatment is a growing challenge,” Khera et al wrote in the study.

 “The field of financial hardship is now shifting toward interventions. Understanding the association between health insurance literacy and financial hardship and how financial literacy may change this association is important because these factors are potentially modifiable.” 

One of the crucial tools used to determine f inancial literacy is the FACIT-COST assessment (Financial Toxicity—Functional Assessment of Chronic Illness Therapy Comprehensive Score). This uses a scored assessment (range, 0-44) with lower scores indicative of higher burden.

Topics in the FACIT-COST include the following

I know that I have enough money in savings, retirement, or assets to cover the costs of my treatment. 

My out-of-pocket medical expenses are more than I thought they would be. 

I worry about the financial problems I will have in the future as a result of my illness or treatment. 

I feel I have no choice about the amount of money I spend on care. 

My cancer or treatment has reduced my satisfaction with my present financial situation. My illness has been a f inancial hardship to my family and me.

Additional tools include the National Health Interview Survey and the Health Insurance Literacy Measure, which captured insights on an individual’s ability to evaluate health plan information and select the best plan to cover their health circumstances.

of NCCN centers reporting financial assessments, only 56% reported repeating that assessment. Results from an additional study of NCORP sites showed that patients with metastatic colorectal cancer experienced a “major financial hardship” defined as major debt, loans, refinancing, or a loss in income of at least 20% of cases within in 3 months of starting treatment.

The NCORP investigators proposed adapting the 5As approach, which has had success in smoking cessation, to tackling financial toxicity in the community setting: ask, advise, assess, assist, and arrange.

 Major components of effectiveness rest in the assess and assist steps. Financial navigators, nurses, and clinicians can assess whether altering treatments alleviates the financial burden and reduces nonadherence issues. They then can assist in updating and monitoring outcomes to ensure continued effective care.

Takeaways from several studies presented during the 2022 American Society of Clinical Oncology (ASCO) Quality Care Symposium showed efforts are underway to assess integrative approaches to tackling financial hardships in practice.

Investigators at The Ohio State University in Columbus implemented a study to identify patients with breast, lung, or hematologic malignancies who stated they had financial hardships and to optimize pathways to connect them with appropriate services.

 At 3 clinics—surgical breast oncology, hematologic, and thoracic medical oncology—no f inancial screening systems were in place. The screening asked, “How hard is it for you to pay for the very basics such as food, housing, medical care, and heating?” Responses ranged from not hard at all to very hard, with the option to not respond. Among 4732 participants, 10% of respondents noted financial hardships by choosing “somewhat hard,” “hard,” or “very hard.”

The investigators proposed a workflow that would cycle patients to the appropriate services; however, several hurdles were identified in the areas of accountability for components of the process. For example, if a patient was identified as having financial hardships, who should put the referral in (eg, nurse, advanced practice provider, physician), how should the referral be documented (eg, phone call, email, consult), and who was responsible for follow-up on the referral?

A second workflow tackling these questions demonstrated a more complex, but staggered patient referral system that identified stakeholders. Following the intake nurse asking a screening question, patients were categorized as urgent or not if they identified as having f inancial hardships. From there, individuals categorized as in urgent need were assigned a social worker, whereas those who were not categorized as in urgent need were place on a weekly list and assigned to a patient navigator who would either address the need or refer the individual to a social worker or financial counselor.

These workflows rely on practices having appropriate staff in place to accommodate the steps of this process. Other areas of need include optimizing electronic health records to record and provide these data to the appropriate parties. 

Another study from the O’Neal Comprehensive Cancer Center at University of Alabama at Birmingham came to the same conclusion when examining the referral process in place for patients treated at the gynecologic oncology clinic. In addition to intake questions about ability to afford medication and distress screening conducted by medical assistants and lay navigators, respectively, an additional financial hardship screening using the FACIT-COST was conducted during cycle 

Referrals to social workers, lay navigators, financial counselors, or other appropriate services were made if difficulties were identif ied. Overall, among 115 patients who had at least 1 financial need, 38 were assisted by a lay navigator and 98 had referrals placed, most of which were with social workers (86.7%). In addition to assistance, the investigators reported qualitative data from 43 patient interviews with most participants reporting that they “felt positively” about the financial questions and considered them relevant to their care.

Universal financial screening is feasible and patients are open to participating, the authors noted; however, a dedicated financial hardship tool is needed. Fully integrating the assessment into workflow to ensure continuity of support for f inancial burdens remains an unmet need.

Beyond the scope of major cancer centers, practice size, resources, and locations in the community setting have varying factors at play that may set them up at an increase for handling cases of greater financial hardships.

For example, in a recent study, investigators sought to identify gaps in care pathways based on responses from stakeholders in 10 cancer care sites (5 rural and 5 nonrural practices).

Across the sites, the investigators compiled 6 elements that were identified in the financial assistance processes: distress screening, referrals, resource connection points, pharmaceutical resources, insurance, and community. Identified opportunities included more systemic, proactive, and routine distress screening over time; dedicated staff in financial navigation; and the development of infrastructure to track external resource availability. These internal adjustments could take place across practices; however, investigators also noted that system-level reforms also are needed to influence change, including insurance expansion and pharmaceutical cost regulations.

As with the other studies, facilitators were identified as the key stakeholders in implementing continued change. These must be staff members with institutional knowledge and relationships with external resources who are able to assess, process, and enact solutions for patients facing financial hardships, Biddell et al noted.

“Financial hardship is most common among populations who have historically experienced challenges with accessing cancer care, including [individuals] who have low incomes, are uninsured/underinsured, or are racial/ethnic minorities, but financial hardship is becoming commonplace across the economic spectrum,” Yabroff et al wrote.

 “Advances in expensive cancer treatments threaten to widen disparities in access to care based on the ability to pay. Thus, understanding how institutions and providers identify patients experiencing financial hardship and the strategies used to mitigate hardship and address patient needs is increasingly important.”

Yabroff KR, Bradley CJ, Shih YCT. Improving the process of screening for medical financial hardship in oncology practice. Cancer Epidemiol Biomarkers Prev. 2021;30(4):593-596. doi:10.1158/1055-9965. EPI-21-0111

Khera N, Sugalski J, Krause D, et al. Current practices for screening and management of financial distress at NCCN member institutions. J Natl Compr Canc Netw. 2020;18(7):825-831 doi:10.6004/ jnccn.2020.7538 

McLouth LE, Nightingale CL, Dressler EV, et al. Current practices for screening and addressing financial hardship within the NCI Community Oncology Research Program. Cancer Epidemiol Biomarkers Prev. 2021;30(4):669-675. doi:10.1158/1055-9965.EPI-20-1157 

Dee EC, Chino F. Financial hardship in cancer care-the need to define and intervene on actionable metrics. JAMA Netw Open. 2022;5(7):e2223149. doi:10.1001/jamanetworkopen.2022.23149 

Khera N, Zhang N, Hilal T, et al. Association of health insurance literacy with financial hardship in patients with cancer. JAMA Netw Open. 2022;5(7):e2223141. doi:10.1001/jamanetworkopen.2022.23141 

FACIT-COST. Facit.org. Accessed October 8, 2022. bit.ly/3ERxmMI 

Obeng-Gyasi S. Implementing financial hardship screening in a comprehensive cancer center: what worked and what failed. Presented at: 2022 American Society of Clinical Oncology Quality Care Symposium; September 30-October 1, 2022; Washington DC. 

Pisu M. The added value of a dedicated screening tool to identify patients with financial hardship. Presented at: 2022 American Society of Clinical Oncology Quality Care Symposium; September 30-October 1, 2022; Washington DC. 

Biddell CB, Spees LP, Petermann V, et al. Financial assistance processes and mechanisms in rural and nonrural oncology care settings. JCO Oncol Pract. 2022;18(9):e1392-e1406. doi:10.1200/OP.21.00894

Oncology Live®

Practices Should Refocus Efforts on Helping Patients Address Financial Toxicities 

When assessing monoclonal gammopathy it is important to rule out clinically significant associations requiring treatment. On initial patient consultation, gathering a detailed patient history and thorough physical exam can catch clinically significant pearls to guide next diagnostic steps. It is critical to recall that monoclonal proteins can be produced by both plasma cells and B cells, and identifying the source will determine the treatment in many cases. A referral to a center with multidisciplinary care is best practice to ensure appropriate workup in a timely manner. 

There are recognized monoclonal gammopathies of dermatologic, neurologic, renal, skeletal, and hematologic significance. 

Monoclonal Gammopathy of Dermatologic Significance (MGDS)

There are a variety of skin manifestations driven by either clonal B cell or plasma cell protein production and associated alteration of the immune system. Referral to a dermatology department for skin biopsy is essential in most cases.

Cryoglobulins are immunoglobulins in the serum that precipitate as temperatures cool from core body temperature in the extremities. Type I (monoclonal) and type II (mixed with a monoclonal component) are associated with monoclonal gammopathy. The skin manifestations typically affect the extremities and can include petechiae and purpura, Raynaud phenomenon, skin necrosis, and ulcers. Treatment is either targeted to B cells or plasma cells depending on what is driving the monoclonal protein.

This is a condition associated most with IgGλ monoclonal gammopathy. It is a distinct disorder and not associated with thyroid myxedema or scleroderma. Skin lesions are waxy, firm plaques or papules with biopsy showing mucin deposition and fibroblast proliferation. 

This is often a systemic process leading to heart block, cardiomyopathy, dysphagia due to esophageal dysmotility, hoarseness, restrictive lung disease, acute renal failure, and carpal tunnel. This is treated with systemic plasma celldirected therapy with immunomodulatory drugs (IMiDs) and steroids. There is a role for proteasome inhibitors and autologous stem cell transplant in IMiD-refractory cases.

Dermato-neuro syndrome can develop which is associated with significant morbidity and mortality. It is manifested by memory loss, vertigo, gait disturbance, stroke, seizures, and psychosis. It is typically preceded by malaise with fever. Treatment consists of steroids, intravenous immunoglobulin (IVIG), and plasmapheresis (plasma exchange; PLEX).

TEMPI—or telangiectasias, erythrocytosis with elevated erythropoietin (EPO) level, monoclonal gammopathy, perinephric-fluid collections, and intrapulmonary shunting—has an unclear mechanism. Hallmarks include markedly elevated EPO levels with erythrocytosis in the absence of a JAK2 mutation. These patients respond well to plasma cell–directed therapies.

This urticarial rash is driven by increased IL1. It is typically seen with IgM monoclonal gammopathy with systemic symptoms that include fever, arthritis, arthralgia, bone pain, lymphadenopathy, and hepatosplenomegaly. The disease has an indolent course with a low-risk of progression to Waldenström or B-cell lymphoma. The rash is treated with IL1 inhibitors.

Also known as acute febrile neutrophilic dermatosis, the erythematous annular skin rash can be quite painful and is often associated with fever. Skin punch biopsy reveals neutrophilic infiltrate into the dermis. Treatment of the rash is a combination of steroids and therapy targeted at either the B cell or plasma cell clone producing the monoclonal protein.

Most often associated with inflammatory bowel disease and arthritis, pyoderma gangrenosum has been reported in up to 20% of cases of IgA monoclonal gammopathy. These cases can progress to multiple myeloma, so patients should receive plasma cell–directed therapy. Unfortunately, these patients often prove to be refractory to treatment.

Monoclonal Gammopathy of Neurologic Significance (MGNS)

There exists a wide range of monoclonal protein–driven neurologic conditions. Presenting symptoms may include myopathy, neuropathy (sensory and/or motor), muscle atrophy, and ataxia. These cases should be assessed by both a hematologist and a neurologist. Typical workup includes a thorough neurologic assessment with electromyography and additional studies such as imaging, biopsy, and laboratory tests. A bone marrow biopsy is essential in these cases for both diagnosis and to guide treatment. 

MGNS conditions are compared in the TABLE

POEMS (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, skin changes)

SLONM (sporadic late-onset nemaline myopathy)

CANOMAD (chronic, ataxic, neuropathy, ophthalmoplegia, monoclonal gammopathy—IgM, agglutinins [cold], and disialosyl antibodies)

Monoclonal Gammopathy of Renal Significance (MGRS) 

Monoclonal gammopathy in the setting of unexplained proteinuria and/or declining renal function requires renal biopsy for diagnosis. It is important to elicit the source of monoclonal protein production by obtaining a bone marrow biopsy and advanced imaging as these can be either plasma cell or B-cell clones. 

Treatment is focused on targeting the clonal cells to stop the monoclonal protein production with the goal of preserving renal function. Twenty-four-hour urine studies are helpful to monitor response to treatment. The mechanism of injury determines the site of renal damage. Additional immunofluorescent stains can identify the monoclonal proteins within the renal biopsy. They are as follows

Proliferative glomerulonephritis with monoclonal immunoglobulin deposits 

Cryoglobulinemic glomerulonephritis (type I and II cryoglobulins only) 

POEMS glomerular microangiopathy— cytokine-induced endothelial injury 

Monoclonal immunoglobulin deposition disease 

Monoclonal Gammopathy of Skelatal Significance

There is more evidence emerging regarding an association between monoclonal gammopathy and skeletal changes. With POEMS it is common to see sclerotic bone lesions. In acquired Fanconi syndrome osteomalacia can develop because of hypophosphatemia. The International Myeloma Working Group recommends bisphosphonate use in all cases of monoclonal gammopathy with osteopenia or osteoporosis. The purposed mechanism driving increased bone turnover is an increase in cytokines CCL3/ MIP-1α (osteoclast-activating factor) and DKK1 (osteoblast-suppressive factor).

Monoclonal Gammopathy of Hematologic Significance 

Even small plasma cell or B-cell clones can alter the bone marrow environment and immune response leading to different acquired hematologic disorders. These include acquired pure red cell aplasia, acquired von Willebrand syndrome, (AVWS), cold agglutinin disease, and other rare, acquired bleeding disorders. These are complex conditions that warrant involvement of benign hematology experts.

The mechanism of acquired pure red cell aplasia associated with monoclonal gammopathy is due to an antibody or effector T lymphocytes targeting an erythroid precursor, leading to arrest of erythropoiesis. 

Treatment is a combination of plasma celldirected therapy and immunosuppression. Cyclosporine with or without steroids is the most used immunosuppression regimen. There is evidence for the use of eltrombopag plus immunosuppression in refractory cases.

Anti–von Willebrand factor (VWF) antibodies lead to a reduction of VWF in monoclonal gammopathy-driven AVWS. These patients can have significant bleeding phenotypes. It is important to treat the underlying clonal disorder, provide replacement VWF with either DDAVP or recombinant VWF and reduce the anti-VWf antibodies with either IVIG or PLEX. 

An acquired factor X deficiency can be seen with amyloidosis. This occurs because both factor X and pentraxin-2 (PTX-2) bind to amyloid fibrils. PTX-2 binds to factor X to form a complex with scavenger receptor class A member I, which protects factor X from macrophage clearance. When PTX-2 levels decrease there is increased macrophage clearance of factor X.

Other reported acquired bleeding conditions seen with monoclonal gammopathy driven by auto-antibody formation include Bernard-Soulier with anti-GPIb/IX/V, Glanzmann thrombasthenia with anti-GPIIb/IIIa, and antifibrin antibodies leading to dysfibrinogenemia and hypofibrinogenemia.

 IgM Hyper-viscosity is also a known cause of bleeding diathesis.

Claveau JS, Wetter DA, Kumar S. Cutaneous manifestations of monoclonal gammopathy. Blood Cancer J. 2022;12(4):58. doi:10.1038/s41408-022-00661

Muchtar E, Magen H, Gertz MA. How I treat cryoglobulinemia. Blood. 2017;129(3):289-298. doi:10.1182/blood-2016-09-719773

Lacy MQ, Hogan WJ, Gertz MA, et al. Successful treatment of scleromyxedema with autologous peripheral blood stem cell transplantation. Arch Dermatol. 2005;141(10):1277-1282. doi:10.1001/archderm.141.10.1277

Larios JM, Ciuro J, Varghese TS, Lyons SE. Successful treatment of dermato-neuro syndrome with plasmapheresis. BMJ Case Rep. 2020;13(12):e237170. doi:10.1136/bcr-2020-237170

Sykes DB, O’Connell C, Schroyens W. The TEMPI syndrome. Blood. 2020;135(15):1199-1203. doi:10.1182/blood.201900421

Simon A, Asli B, Braun-Falco M, De Koning H, et al. Schnitzler’s syndrome: diagnosis, treatment, and follow-up. Allergy. 2013;68(5):562-568. doi:10.1111/all.12129 

When assessing monoclonal gammopathy it is important to rule out clinically significant associations requiring treatment.

Vol. 23/No. 21 | Oncology Live®

Investigators Highlight Top Advances at ESMO 2022

Practices Should Refocus Efforts on Helping Patients Address Financial Toxicities

Cracking the “MGUS” Code Reveals Monoclonal Gammopathy of Clinical Significance:

CRC Tumor Sidedness Plays an Increasing Role in Clinical Practice

PARP Inhibitors in Metastatic Castration-Resistant Prostate Cancer: Whom to Treat?

OS Advances Gather Steam in Breast Cancer

Time Required to Address Scientific Questions Generates an Information Dilemma